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}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule10, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"condition": "==1",
"label": "Rule10, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule10"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule11, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"condition": "==1",
"label": "Rule11, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule11"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule12, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"condition": ">=2",
"label": "Rule12, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule12"
},
{
"conditions": [
{
"condition": ">=3",
"label": "Rule13, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule13"
},
{
"conditions": [
{
"condition": "==2",
"label": "Rule14, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"condition": ">=2",
"label": "Rule14, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"condition": ">=4",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule20, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"condition": "==2",
"label": "Rule20, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule20"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule21, Condition1",
"partitionPath": "Benign.Strong"
},
{
"condition": ">=1",
"label": "Rule21, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule21"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule22, Condition1",
"partitionPath": "Benign.Strong"
},
{
"condition": ">=1",
"label": "Rule22, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule22"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule23, Condition1",
"partitionPath": "Benign.Strong"
},
{
"condition": ">=1",
"label": "Rule23, Condition2",
"partitionPath": "Pathogenic.Very Strong"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule23"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule24, Condition1",
"partitionPath": "Benign.Strong"
},
{
"condition": ">=1",
"label": "Rule24, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule24"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule25, Condition1",
"partitionPath": "Benign.Stand Alone"
},
{
"condition": ">=1",
"label": "Rule25, Condition2",
"partitionPath": "Pathogenic.Very Strong"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule25"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule26, Condition1",
"partitionPath": "Benign.Stand Alone"
},
{
"condition": ">=1",
"label": "Rule26, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule26"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule27, Condition1",
"partitionPath": "Benign.Stand Alone"
},
{
"condition": ">=1",
"label": "Rule27, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule27"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule28, Condition1",
"partitionPath": "Benign.Stand Alone"
},
{
"condition": ">=1",
"label": "Rule28, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule28"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule29, Condition1",
"partitionPath": "Benign.Supporting"
},
{
"condition": ">=1",
"label": "Rule29, Condition2",
"partitionPath": "Pathogenic.Very Strong"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule29"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule30, Condition1",
"partitionPath": "Benign.Supporting"
},
{
"condition": ">=1",
"label": "Rule30, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule30"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule31, Condition1",
"partitionPath": "Benign.Supporting"
},
{
"condition": ">=1",
"label": "Rule31, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule31"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule32, Condition1",
"partitionPath": "Benign.Supporting"
},
{
"condition": ">=1",
"label": "Rule32, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule32"
}
],
"metaRules": [
{
"description": "Given set of evidence are not sufficient to make any assertions.",
"inference": "Uncertain Significance - Insufficient Evidence",
"metaRule": "MetaRule1",
"numberOfAssertions": 0,
"uniqueAssertions": []
},
{
"description": "As the rules only suggest one assertion that is Pathogenic, the final assertion is Pathogenic",
"inference": "Pathogenic",
"metaRule": "MetaRule2",
"numberOfAssertions": 1,
"uniqueAssertions": [
"Pathogenic"
]
},
{
"description": "As the rules only suggest one assertion that is Benign, the final assertion is Benign",
"inference": "Benign",
"metaRule": "MetaRule3",
"numberOfAssertions": 1,
"uniqueAssertions": [
"Benign"
]
},
{
"description": "As the rules only suggest one assertion that is Likely Pathogenic, the final assertion is Likely Pathogenic",
"inference": "Likely Pathogenic",
"metaRule": "MetaRule4",
"numberOfAssertions": 1,
"uniqueAssertions": [
"Likely Pathogenic"
]
},
{
"description": "As the rules only suggest one assertion that is Likely Pathogenic, the final assertion is Likely Benign",
"inference": "Likely Benign",
"metaRule": "MetaRule5",
"numberOfAssertions": 1,
"uniqueAssertions": [
"Likely Benign"
]
},
{
"description": "As the rules only suggest one assertion that is Uncertain Significance - Conflicting Evidence - Insufficient Evidence, the final assertion is Uncertain Significance - Conflicting Evidence - Insufficient Evidence",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule6",
"numberOfAssertions": 1,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence"
]
},
{
"description": "Two assertions: Pathogenic and Likely Pathogenic were made. In such case the final call is the highest strength call, hence the allele is Pathogenic",
"inference": "Pathogenic",
"metaRule": "MetaRule7",
"numberOfAssertions": 2,
"uniqueAssertions": [
"Pathogenic",
"Likely Pathogenic"
]
},
{
"description": "Two assertions: Benign and Likely Benign were made. In such case the final call is the highest strength call, hence the allele is Benign",
"inference": "Benign",
"metaRule": "MetaRule8",
"numberOfAssertions": 2,
"uniqueAssertions": [
"Benign",
"Likely Benign"
]
},
{
"description": "Three assertions: Pathogenic, Likely Pathogenic and Uncertain Significance - Conflicting Evidence were made. In such cases the final call is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule9",
"numberOfAssertions": 3,
"uniqueAssertions": [
"Pathogenic",
"Likely Pathogenic",
"Uncertain Significance - Conflicting Evidence"
]
},
{
"description": "Three assertions: Benign, Likely Benign and Uncertain Significance - Conflicting Evidence were made. In such cases the final call is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule10",
"numberOfAssertions": 3,
"uniqueAssertions": [
"Benign",
"Likely Benign",
"Uncertain Significance - Conflicting Evidence"
]
},
{
"description": "Two assertions: Pathogenic and Uncertain Significance - Conflicting Evidence were made. The final call in this case is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule11",
"numberOfAssertions": 2,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence",
"Pathogenic"
]
},
{
"description": "Two assertions: Likely Pathogenic and Uncertain Significance - Conflicting Evidence were made. The final call in this case is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule12",
"numberOfAssertions": 2,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence",
"Likely Pathogenic"
]
},
{
"description": "Two assertions: Benign and Uncertain Significance - Conflicting Evidence were made. The final call in this case is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule13",
"numberOfAssertions": 2,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence",
"Benign"
]
},
{
"description": "Two assertions: Likely Benign and Uncertain Significance - Conflicting Evidence were made. The final call in this case is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule14",
"numberOfAssertions": 2,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence",
"Likely Benign"
]
},
{
"description": "Three assertions: Likely Pathogenic, Likely Benign and Uncertain Significance - Conflicting Evidence were made. In such cases the final call is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule15",
"numberOfAssertions": 3,
"uniqueAssertions": [
"Likely Pathogenic",
"Likely Benign",
"Uncertain Significance - Conflicting Evidence"
]
},
{
"description": "Three assertions: Likely Pathogenic, Benign and Uncertain Significance - Conflicting Evidence were made. In such cases the final call is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule16",
"numberOfAssertions": 3,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence",
"Likely Pathogenic",
"Benign"
]
},
{
"description": "Three assertions: Pathogenic, Likely Benign and Uncertain Significance - Conflicting Evidence were made. In such cases the final call is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule17",
"numberOfAssertions": 3,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence",
"Pathogenic",
"Likely Benign"
]
},
{
"description": "Three assertions: Pathogenic, Benign and Uncertain Significance - Conflicting Evidence were made. In such cases the final call is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule18",
"numberOfAssertions": 3,
"uniqueAssertions": [
"Pathogenic",
"Benign",
"Uncertain Significance - Conflicting Evidence"
]
},
{
"description": "Four assertions: Likely Pathogenic, Pathogenic, Likely Benign and Uncertain Significance - Conflicting Evidence were made. In such cases the final call is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule19",
"numberOfAssertions": 4,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence",
"Likely Pathogenic",
"Likely Benign",
"Pathogenic"
]
},
{
"description": "Four assertions: Likely Pathogenic, Pathogenic, Benign and Uncertain Significance - Conflicting Evidence were made. In such cases the final call is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule20",
"numberOfAssertions": 4,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence",
"Likely Pathogenic",
"Pathogenic",
"Benign"
]
},
{
"description": "Four assertions: Likely Pathogenic, Likely Benign, Benign and Uncertain Significance - Conflicting Evidence were made. In such cases the final call is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule21",
"numberOfAssertions": 4,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence",
"Likely Pathogenic",
"Likely Benign",
"Benign"
]
},
{
"description": "Four assertions: Pathogenic, Likely Benign, Benign and Uncertain Significance - Conflicting Evidence were made. In such cases the final call is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule22",
"numberOfAssertions": 4,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence",
"Pathogenic",
"Likely Benign",
"Benign"
]
},
{
"description": "",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule27",
"numberOfAssertions": 2,
"uniqueAssertions": [
"Pathogenic",
"Benign"
]
},
{
"description": "",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule28",
"numberOfAssertions": 2,
"uniqueAssertions": [
"Likely Pathogenic",
"Benign"
]
},
{
"description": "",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule34",
"numberOfAssertions": 3,
"uniqueAssertions": [
"Likely Benign",
"Pathogenic",
"Benign"
]
},
{
"description": "",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule35",
"numberOfAssertions": 3,
"uniqueAssertions": [
"Likely Benign",
"Likely Pathogenic",
"Benign"
]
},
{
"description": "",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule37",
"numberOfAssertions": 3,
"uniqueAssertions": [
"Pathogenic",
"Likely Pathogenic",
"Benign"
]
},
{
"description": "",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule44",
"numberOfAssertions": 4,
"uniqueAssertions": [
"Likely Benign",
"Pathogenic",
"Likely Pathogenic",
"Benign"
]
},
{
"description": "",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule23",
"numberOfAssertions": 5,
"uniqueAssertions": [
"Likely Benign",
"Pathogenic",
"Likely Pathogenic",
"Uncertain Significance - Conflicting Evidence",
"Benign"
]
}
],
"pointRules": [
{
"conditions": [
{
"condition": ">=10",
"label": "Rule1, Condition1"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"condition": ">=6",
"label": "Rule2, Condition2"
},
{
"condition": "<=9",
"label": "Rule2, Condition1"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"condition": ">=0",
"label": "Rule3, Condition1"
},
{
"condition": "<=5",
"label": "Rule3, Condition2"
}
],
"inference": "Uncertain Significance",
"rule": "Rule3"
},
{
"conditions": [
{
"condition": ">=-6",
"label": "Rule4, Condition1"
},
{
"condition": "<=-1",
"label": "Rule4, Condition2"
}
],
"inference": "Likely Benign",
"rule": "Rule4"
},
{
"conditions": [
{
"condition": "<=-7",
"label": "Rule5, Condition1"
}
],
"inference": "Benign",
"rule": "Rule5"
}
]
}
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"text": "",
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"text": "The values used to calculate the PM2 thresholds were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/500 or lower), where the most frequent pathogenic variant accounts for no more than 2% of cases (e.g., has an allele frequency of ≤0.02 in cases based on the upper bound of 95% CI), and where the penetrance of a pathogenic variant is expected to be at least 50% (Kelly _et al._ 2018[11](#pmid_29300372)).\n\nA threshold of **≤0.00004** in the subpopulation with the highest frequency when using the upper bound of the 95% CI activates this rule.\n\n1. Alternatively, this is equivalent to the variant NOT being observed more than once (≤1 allele) in gnomAD v.2.1.1 in one of the non-founder populations (e.g., absence required from the Other and Ashkenazi Jewish subpopulations).\n2. Applying a threshold of ≤0.00004 (upper bound of 95% CI of the allele frequency in gnomAD) is equivalent to the variant being seen in a single subpopulation and that subpopulation meets any of the following:\n * **Allele Count (AC) in Allele Number (AN)**\n * ≤1 in ≥120,000\n * ≤2 in ≥160,000\n * ≤3 in ≥195,000\n * ≤4 in ≥230,000\n\ngnomAD is the preferred database for this calculation, but currently only displays the filtering allele frequency (FAF), which is equivalent to a lower bound estimate of the 95% CI, when the upper bound is what is needed.\n\n* Confidence interval tools, such as [Confit-de-MAF](https://www.genecalculators.net/confit-de-maf.html), can be used to determine the upper bound of the 95% CI of the observed allele frequency.\n\nDue to current technical limitations of next generation sequencing technologies, minor allele frequencies for complex variants (e.g., large indels) may not be accurately represented in population databases.\n\nCaution should be used when a variant is only identified, or over-represented, in one of the smaller gnomAD populations, as the gnomAD allele frequencies may not accurately represent the true population frequency.\n\nPopulation databases may contain affected or pre-symptomatic individuals for diseases with reduced penetrance/variable onset.",
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"text": "",
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"id": "0028",
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"strength": "Strong",
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"text": "",
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"specificationType": [
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"Gene-specific"
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"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable to missense variants in _MYH7_ in the specific regions listed below (Walsh _et al._ 2019[10](#pmid_30696458)). \n\n1. Transcripts ENST00000355349 & NM\\_000257.4\n2. Codons 167-931\\*\n\nData from HCM case cohorts was used to derive these cluster regions. Therefore, this rule should NOT be applied when additional evidence for the variant supports that the variant causes a phenotype other than HCM (e.g., variant seen in multiple DCM cases).\n\nEnrichment was not observed for DCM in any genes.\n\nRule should NOT be combined with PM5 because presence of pathogenic variants in the same codon/region were used to determine clustering and would be double-counting evidence.\n\n_\\* This region is updated from v1.0 (Kelly et al. 2018_[_11_](#pmid_29300372)_)._",
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"applicability": "Not Applicable",
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"text": "",
"type": "EvidenceLineStrength"
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"modifier": "makelly2",
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"gene": [
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"geneType": "nuclear",
"label": "PP4",
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"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
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"text": "",
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"modifier": "makelly2",
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"strength": "Stand Alone",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "119",
"instructionsToUse": "",
"specificationType": [
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"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
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"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
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{
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
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"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
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"evidenceCategory": "De novo Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PM6",
"ns": "002",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
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"completed": true
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"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0037",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Applicable",
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"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Refer to SVI guidance on number/combination of cases required based on phenotype specificity[2](#url_c73e109e-b916-5a72-b7b1-1762446f3c11).\n\nFor most cardiomyopathies, it is recommended to default to “phenotype consistent with gene but not highly specific”. Clinical judgment is required for shifting to a higher or lower phenotypic consistency. \n\nSee PS2 for additional considerations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637780",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637780",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5AqS--D"
},
{
"entContent": {
"_uniqueProp": "002_PP5_nuclear_MYH7",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "002",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432780",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638432780",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5AqW--a"
},
{
"entContent": {
"_uniqueProp": "002_PP2_nuclear_MYH7",
"additionalComments": "Application of this rule takes into consideration empirical data quantifying levels of rare missense variant enrichment in HCM referral cohorts compared to population-based cohorts (Walsh et al. 2019 PMID:30696458) rather than the missense constraint score in gnomAD. For MYH7, there is evidence for regional enrichment of rare missense variants (see PM1 specifications).",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Functional Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "002",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637792",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637792",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5Aq---I"
},
{
"entContent": {
"_uniqueProp": "002_BP1_nuclear_MYH7",
"additionalComments": "For the current genes where null variants are a known mechanism, pathogenic missense variants have also been reported.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "002",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637778",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637778",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5AqS--H"
},
{
"entContent": {
"_uniqueProp": "002_PM5_nuclear_MYH7",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "002",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "105",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion can be used at MODERATE if a different missense variant at the same codon has been classified as _pathogenic_ using these modified guidelines without application of PM5.\n\nThe impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to SUPPORTING if the predicted impact is not expected to be equivalent or more severe.\n\nPM5 should not be combined with PM1. If both are applicable at MODERATE weight, use of PM5 is most appropriate since it is variant specific.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion can be considered at SUPPORTING if a different missense variant at the same codon has been classified as _likely pathogenic_ using these modified guidelines without application of PM5.\n\nThe impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as likely pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to NOT APPLICABLE if the predicted impact is not expected to be equivalent or more severe.\n\nPM5 should not be combined with PM1. The one with the higher strength should be applied, but if both are applicable at SUPPORTING weight, use of PM5 is most appropriate since it is variant specific.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637777",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637777",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5AqS--E"
},
{
"entContent": {
"_uniqueProp": "002_BS2_nuclear_MYH7",
"additionalComments": "Inherited cardiomyopathies generally display reduced penetrance, variable expressivity, and adult-onset. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Population Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "002",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0069",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0076",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637774",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637774",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5AqG--n"
},
{
"entContent": {
"_uniqueProp": "002_PM3_nuclear_MYH7",
"additionalComments": "It is acknowledged that there is increasing evidence supporting that some of these genes/variants may also be recessive (e.g., MYL2, MYL3), but addressing those edge cases was outside the scope of this current guideline.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Allelic Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "002",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637773",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637773",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5AqW--X"
},
{
"entContent": {
"_uniqueProp": "002_BP6_nuclear_MYH7",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "002",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432779",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638432779",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5Aq---H"
},
{
"entContent": {
"_uniqueProp": "002_BP7_nuclear_MYH7",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "002",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "117",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Also applicable to **intronic variants outside the splice consensus sequence (-4 and +7 outward)** for which splicing prediction algorithms predict no impact to the splice consensus sequence NOR the creation of a new splice site AND the nucleotide is not highly conserved.\n\nRule can be combined with BP4 to make a variant likely benign per Richards _et al._ 2015[1](#pmid_25741868).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637794",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637794",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5AqW--T"
},
{
"entContent": {
"_uniqueProp": "002_PP3_nuclear_MYH7",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "002",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "100",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "As many _in silico_ algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.\n\nUse of REVEL (Ioannidis _et al._ 2016[14](#pmid_27666373)) is recommended at thresholds of **≥0.70 for PP3**.\n\nClinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.\n\nPositive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.\n\n[SpliceAI](https://spliceailookup.broadinstitute.org)[13](#pmid_30661751) is recommended for evaluation of predicted splice impacts.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637793",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637793",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5AqW--Y"
},
{
"entContent": {
"_uniqueProp": "002_BA1_nuclear_MYH7",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Population Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "002",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "102",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency is **≥0.001** based on the **filtering allele frequency (FAF)** in **gnomAD** in the subpopulation with the highest frequency (popmax).\n\nThe values used to calculate the BA1 threshold were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/300 or lower).\n\nThe threshold is applicable when assessing variants in the context of autosomal dominant cardiomyopathy. \n\ngnomAD is the preferred database for this calculation. If a subpopulation specific FAF other than the popmax is needed, this value can be calculated using the AlleleFrequencyApp on the [CardioDB website](https://cardiodb.org/allelefrequencyapp/).\n\n1. Using the Inverse AF tab, enter in the population size and the number of alleles identified and it will calculate the FAF. \n2. Set confidence to 0.95 (95%).\n3. If the FAF is ≥0.001, this rule can be applied.\n\nThe FAF by platform (e.g., exome vs. genome; v.2.1.1 vs. v.3.1.1) should be considered, the larger population is most likely to have the most accurate representation of “true” population allele frequency.\n\nCaution is needed when considering any population cohorts that are smaller than the smallest subpopulations within gnomAD v.2.1.1 (e.g., ~5000 individuals or ~10,000 alleles). Despite this conservative nature of this threshold and approach, in smaller cohorts, the observed allele frequency may less accurately reflect the true allele frequency. Traditionally, once a variant is classified as Benign, it is rarely re-evaluated and so the highest confidence is needed to establish that classification on an allele frequency alone.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637791",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637791",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5Aq---F"
},
{
"entContent": {
"_uniqueProp": "002_PS4_nuclear_MYH7",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Population Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "002",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "111",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Currently few well-designed case-control studies have been performed for inherited cardiomyopathies. Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). \n\nCohorts used in these analyses should meet the following criteria: \n\n1. The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype\\*). \n * When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded. This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).\n2. The controls should not be derived from study populations that might be enriched for the specified disorder.\n3. The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).\n4. The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).\n5. The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).\n6. The population diversity of the case and control cohorts are broadly similar.\n7. Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh _et al._ 2017[8](#pmid_27532257), [DECIPHER](https://www.deciphergenomics.org/gene/MYH7/patient-overlap/snvs)).\n\nTo account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:\n\n* **STRONG** evidence requires the lower bound of the 95% confidence interval (CI) around the odds ratio (OR) estimate to be **≥20**\n\nA PS4 calculator is available at [www.cardiodb.org](https://www.cardiodb.org/ps4_calculator/ps4_calculator.html).\n\nIf multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered). \n\n**\\*RELEVANT PHENOTYPES:**\n\n1. Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. \n2. For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. \n3. Additional considerations for LVNC and end-stage HCM: \n * Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson _et al._ 2017[9](#pmid_28395867); Oechslin _et al._ 2017[6](#pmid_28545618); Hershberger _et al._ 2017[5](#pmid_29212902); Ross _et al._ 2020[7](#pmid_31143950)), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).\n\nHCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "123",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Currently few well-designed case-control studies have been performed for inherited cardiomyopathies. Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). \n\nCohorts used in these analyses should meet the following criteria: \n\n1. The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype\\*). \n * When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded. This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).\n2. The controls should not be derived from study populations that might be enriched for the specified disorder.\n3. The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).\n4. The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).\n5. The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).\n6. The population diversity of the case and control cohorts are broadly similar.\n7. Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh _et al._ 2017[8](#pmid_27532257), [DECIPHER](https://www.deciphergenomics.org/gene/MYH7/patient-overlap/snvs)).\n\nTo account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:\n\n* **MODERATE** evidence requires the lower bound of the 95% CI around the OR to be **≥10**\n\nA PS4 calculator is available at [www.cardiodb.org](https://www.cardiodb.org/ps4_calculator/ps4_calculator.html).\n\nIf multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered). \n\n**\\*RELEVANT PHENOTYPES:**\n\n1. Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. \n2. For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. \n3. Additional considerations for LVNC and end-stage HCM: \n * Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson _et al._ 2017[9](#pmid_28395867); Oechslin _et al._ 2017[6](#pmid_28545618); Hershberger _et al._ 2017[5](#pmid_29212902); Ross _et al._ 2020[7](#pmid_31143950)), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).\n\nHCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "115",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Currently few well-designed case-control studies have been performed for inherited cardiomyopathies. Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). \n\nCohorts used in these analyses should meet the following criteria: \n\n1. The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype\\*). \n * When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded. This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).\n2. The controls should not be derived from study populations that might be enriched for the specified disorder.\n3. The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).\n4. The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).\n5. The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).\n6. The population diversity of the case and control cohorts are broadly similar.\n7. Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh _et al._ 2017[8](#pmid_27532257), [DECIPHER](https://www.deciphergenomics.org/gene/MYH7/patient-overlap/snvs)).\n\nTo account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:\n\n* **SUPPORTING** evidence requires the lower bound of the 95% CI around the OR to be **≥5**\n\nA PS4 calculator is available at [www.cardiodb.org](https://www.cardiodb.org/ps4_calculator/ps4_calculator.html).\n\nIf multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered). \n\n**\\*RELEVANT PHENOTYPES:**\n\n1. Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. \n2. For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. \n3. Additional considerations for LVNC and end-stage HCM: \n * Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson _et al._ 2017[9](#pmid_28395867); Oechslin _et al._ 2017[6](#pmid_28545618); Hershberger _et al._ 2017[5](#pmid_29212902); Ross _et al._ 2020[7](#pmid_31143950)), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).\n\nHCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637788",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637788",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5AqS--G"
},
{
"entContent": {
"_uniqueProp": "002_PS3_nuclear_MYH7",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Functional Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"instructionsToUse": "Evaluation of studies/assays is required prior to application of functional evidence at any strength.\n\nRefer to SVI guidance for functional evidence (Brnich _et al._ 2020[4](#pmid_31892348)).\n\nIn the context of cardiomyopathy, very few functional assays currently meet criteria sufficient for application of this rule at a STRONG level. Examples of the types of study/assays that MAY be relevant are described, but further definition of cardiomyopathy models/assays is outside the scope of these guidelines.",
"label": "PS3",
"ns": "002",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "109",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**In vitro splicing assays (e.g., RNA studies)**\n\n_In vitro_ splicing assays may be considered as **STRONG** evidence, providing the following criteria are met.\n\n* Prior knowledge of predominant transcripts in cardiac tissue\n\nAnalysis undertaken using RNA extracted from cardiac tissue from the individual with the variant\n\nAnalysis undertaken using RNA extracted from whole blood providing the relevant transcripts (isoforms) are expressed in blood and are at sufficient levels to assess splice disruption.\n\nAssay shows a clear, reproducible and convincing effect on splicing (i.e. a distinct splice product, present at a level comparable to the splice product from the wild-type allele), which is not observed in controls\n\n* Confirmation of abnormal splice product by Sanger sequencing\n\n**NOTE:** Mini-gene assay in non-patient derived cell lines are NOT considered to provide STRONG evidence.\n\n**NOTE:** Whether to activate this rule needs to be reconciled with the variant spectrum and disease mechanism for the gene at hand (i.e., consider whether the effect is likely to lead to LOF or an in-frame alteration and whether this type of effect is expected to be disease causing) (Abou Tayoun _et al._ 2018[3](#pmid_30192042)).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**In vivo models (e.g., variant knock-in animal models)**\n\nMammalian variant-specific knock-in animal models that produce a phenotype consistent with the clinical phenotype in humans (e.g., structural and/or functional cardiac abnormalities, premature death, arrhythmia) may be considered as **MODERATE** evidence\n\n**NOTE:** The following assays/models do NOT meet criteria\n\n1. Assays that are known to be associated with non-specific cardiac phenotypes (e.g., morpholino-induced pericardial edema in zebrafish)\n2. In vivo evidence that is not variant specific, such as whole gene alterations (i.e., cDNA or whole gene transgenic mice and whole or partial gene knock-out mice)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "_**In vitro**_ **assays (e.g., biochemical assays of myofilament function, motility assays, human iPSC-CM)**\n\nWhile some _in vitro_ assays may provide evidence that a variant in a cardiomyopathy gene has an effect on protein and/or myofilament function, at present, there are no validated “gold-standard” assays that are considered to reliably predict the clinical phenotype.\n\nAs such, in the cardiomyopathy genes listed in these guidelines, data from individual _in vitro_ studies are unlikely to meet the criteria required to assign this rule at more than SUPPORTING level.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637785",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637785",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5AqG--j"
},
{
"entContent": {
"_uniqueProp": "002_PS2_nuclear_MYH7",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "De novo Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "002",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0016",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "112",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Refer to SVI guidance on number/combination of cases required based on phenotype specificity[2](#url_c73e109e-b916-5a72-b7b1-1762446f3c11)).\n\nFor most cardiomyopathies, it is recommended to default to **Phenotype consistency: “Phenotype consistent with gene but not highly specific”**. Clinical judgment is required for shifting to a higher or lower category. \n\nFor use as a STRONG or VERY STRONG criterion, ideally parents have been thoroughly clinically evaluated without evidence of cardiomyopathy (ideally using a combination of ECG and echocardiogram or cardiac MRI for maximum sensitivity).\n\nA family history consistent with _de novo_ inheritance should not have any clinical signs or symptoms suggestive of cardiomyopathy in a 1st or 2nd degree relative, for example: \n\n1. Sudden death under 60 years of age\n2. Heart transplant\n3. Implantable cardiac defibrillator (ICD) under 60 years of age\n4. Features of cardiomyopathy (e.g., systolic dysfunction, hypertrophy, left ventricular enlargement in an individual without risk factors).\n5. Other related/overlapping cardiomyopathies\n\nExamples of non-suspicious family history may include non-specific clinical features (e.g., palpitations, syncope, borderline/inconclusive echocardiogram findings, heart attack if age appropriate and suspected to result from coronary artery disease), but every attempt should be made to clarify features. \n\nGenerally, this criterion is only applicable in the ABSENCE of any other possible disease-causing variants. If other pathogenic or likely pathogenic variants are present, consider decreasing points assigned or overall weight.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637783",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637783",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5AqW--W"
},
{
"entContent": {
"_uniqueProp": "002_PM4_nuclear_MYH7",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "002",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "108",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Strength of rule should be carefully considered and may require downgrading to SUPPORTING based on the predicted impact of the variant, including the size of the deletion/insertion, its location, and conservation of the region. \n\nFor genes where PVS1 is not applicable (i.e., where there is no evidence that pLOF variants cause disease), consider using this rule at MODERATE or SUPPORTING strength for truncating variants that do NOT undergo nonsense mediated decay (NMD).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637775",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637775",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5Aq---G"
},
{
"entContent": {
"_uniqueProp": "002_PVS1_nuclear_MYH7",
"additionalComments": "Not applicable for MYH7.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "002",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0244",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "114",
"instructionsToUse": "",
"specificationType": [
"Modified rule strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637789",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637789",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5AqG--k"
},
{
"entContent": {
"_uniqueProp": "002_PP1_nuclear_MYH7",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Segregation Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "002",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "103",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at **≥7 segregations** (LOD score of 2.1) for **STRONG**.\n\nAlthough rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)[12](#pmid_27236918) can be considered: \n\n* STRONG evidence requires ≥5 segregations (LOD score of 1.5)\n\nOnly genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.\n\nPhenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis. \n\nImportant considerations include:\n\n1. Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant. If linkage disequilibrium is a concern, consider downgrading strength of segregation. \n2. Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1.\n3. Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. \n4. Caution is needed when distantly related (≥3rd degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "113",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at **≥5** **segregations** (LOD score of 1.5) for **MODERATE**.\n\nAlthough rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)[12](#pmid_27236918) can be considered: \n\n* MODERATE evidence requires ≥4 segregations (LOD score of 1.2)\n\nOnly genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.\n\nPhenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis. \n\nImportant considerations include:\n\n1. Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant. If linkage disequilibrium is a concern, consider downgrading strength of segregation. \n2. Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).\n3. Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. \n4. Caution is needed when distantly related (≥3rd degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "101",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at **≥3** **segregations** (LOD score of 0.9) for **SUPPORTING**. The thresholds as proposed by Jarvik and Browning (2016)[12](#pmid_27236918) are the same at ≥3 segregations (LOD score of 0.9) for supporting.\n\nOnly genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.\n\nPhenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis. \n\nImportant considerations include:\n\n1. Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant. If linkage disequilibrium is a concern, consider downgrading strength of segregation. \n2. Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).\n3. Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. \n4. Caution is needed when distantly related (≥3rd degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637787",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637787",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5AqG--i"
},
{
"entContent": {
"_uniqueProp": "002_BP4_nuclear_MYH7",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "002",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "116",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "As many _in silico_ algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.\n\nUse of REVEL (Ioannidis et al. 2016[14](#pmid_27666373)) is recommended at thresholds of **≤0.40 for BP4**.\n\nClinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.\n\nPositive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.\n\n[SpliceAI](https://spliceailookup.broadinstitute.org)[13](#pmid_30661751) is recommended for evaluation of predicted splice impacts.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637786",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637786",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5AqG--m"
},
{
"entContent": {
"_uniqueProp": "002_BP3_nuclear_MYH7",
"additionalComments": "Not applicable to the current genes. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "002",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637784",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637784",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5AqS--F"
},
{
"entContent": {
"_uniqueProp": "002_BP2_nuclear_MYH7",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Allelic Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "002",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "118",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Other variants must be pathogenic as defined by these specifications.\n\nTesting of parents or other informative relatives is often required to determine _cis_/_trans_ status.\n\nIf a variant is seen in _trans_ (or as double heterozygous) with another pathogenic variant in ≥2 cases and the phenotype is not more severe than when either of the two variants are seen in isolation, this rule may be applied (i.e., high confidence this variant is NOT contributing to disease).\n\n* \\<1% of cases of HCM have >1 pathogenic or likely pathogenic variant (0.6%; Alfares _et al._ 2015[17](#pmid_25611685)).\n\nThis rule cannot be applied when the variant has only been observed in _cis_ with a pathogenic variant as its significance in isolation is unknown in this scenario. \n\nCaution is needed if using this criterion as a primary piece of evidence for classifying a variant as likely benign/benign (i.e., only 2 SUPPORTING criteria are sufficient for a likely benign classification).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637782",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637782",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5AqW--U"
},
{
"entContent": {
"_uniqueProp": "002_BS4_nuclear_MYH7",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Segregation Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "002",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "121",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Any non-segregations should be carefully evaluated to rule out a phenocopy or the presence of a second disease-causing variant before considering it as conflicting or benign evidence. \n\n1. The presence of “phenocopies” (e.g., athlete’s heart, hypertensive heart disease, ischemic cardiomyopathy, alcoholic cardiomyopathy, diabetic cardiomyopathy) can mimic non-segregation (i.e., lack of segregation) among affected individuals. \n2. Families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent ‘non-segregation’.\n\nBecause of these possibilities, **multiple (≥2) non-segregations** that are highly unlikely to be phenocopies or due to alternate variants (e.g., those without a possible alternate cause) **are required to apply this rule**. A higher number of non-segregations is necessary for instances where alternative causes are possible (e.g., non-segregation in a sibling with childhood onset cardiomyopathy versus a grandparent with hypertension and HCM).\n\nCareful consideration of the above points is required when using this data as conflicting evidence, especially when overall evidence supports likely pathogenic or pathogenic.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637779",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637779",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5AqS--I"
},
{
"entContent": {
"_uniqueProp": "002_BS1_nuclear_MYH7",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Population Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "002",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "120",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
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],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** \n\nPS3 may be applied to the following assays:\n\n* RNA, mini-gene, or other assay demonstrating an impact on splicing.\n\nPS3\\_Moderate: \n\n* Mighell et al. 2018 (PMID: 29706350): Massively parallel functional assay interrogating phosphatase activity. \n * In the supplementary material (Table S2) search for the variant in columns A or B and make sure the variant in question is listed as TRUE under column I (high confidence). If not, do not use as evidence.\n * Under column G, the cumulative score is listed. Apply PS3\\_moderate for all variants with scores ≤ -1.11.\n\nPS3\\_Supporting: Other studies demonstrating lipid phosphatase activity \\<50% of wild-type or abnormal _in vitro_ cellular assay or transgenic model with phenotype different from wild-type that does not meet PS3\\_moderate. Examples of _in vitro_ cellular assays to be considered for PS3\\_supporting evidence may include:\n\n* _In vitro_ assay demonstrating >50% reduction in phosphatase activity compared to wild type control. Phosphatase assays for which criteria may be applied must include a catalytic dead control, such as p.C124S, as well as at least three biological replicates: Myers et al. 1998 (PMID: 9811831), Stambolic et al. 1998 (PMID: 9778245), Han et al. 2000 (PMID: 10866302), Rodriguez-Escudero et al. 2011 (PMID: 21828076), Costa et al. 2015 (PMID: 26504226), Malek et al. 2017 (PMID: 29056325).\n* Decreased PTEN or increased pAKT expression: Tan 2011 (PMID: 21194675), Spinelli 2015 (PMID: 25527629).\n* Disruption of protein cellular localization: Lobo et al. 2009 (PMID: 19457929), He et al. 2012 (PMID: 22962422), Gil et al. 2015 (PMID: 25875300)\n* Aberrant cellular phenotypes, including defective cell migration, proliferation, and invasion: Costa et al. 2015 (PMID: 26504226), Malek et al. 2017 (PMID: 29056325)",
"label": "PS3",
"ns": "003",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect on the gene or gene product.\n\n* RNA, mini-gene, or other assay shows impact on splicing",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Well-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect on the gene or gene product.\n\n* Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phosphatase activity \\<50% of wild-type or abnormal _in vitro_ cellular assay or transgenic model with phenotype different from wild type that does not meet PS3\\_moderate.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638181",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638181",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHIa---"
},
{
"entContent": {
"_uniqueProp": "003_BS4_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: Two or more families are require for strong evidence level.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:**\n\nBS4: Two or more families are require for strong evidence level.\n\nBS4\\_Supporting: Lack of segregation in one family.",
"label": "BS4",
"ns": "003",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of two or more families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of one family.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638175",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638175",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHLi--B"
},
{
"entContent": {
"_uniqueProp": "003_PM4_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: For in-frame insertions or deletions, criteria may apply only if the variant impacts at least one residue in one of the catalytic motifs specified in the PM1 criteria. Criteria will also apply for variants resulting in truncation 3’ to c.1121 (NM_000314.6) or variants resulting in protein extension.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** For in-frame insertions or deletions, criteria may apply only if the variant impacts at least one residue in one of the catalytic motifs specified in the PM1 criteria. Criteria will also apply for variants resulting in protein extension.",
"label": "PM4",
"ns": "003",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif (see PM1), and variants causing protein extension.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638171",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638171",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHQ---_"
},
{
"entContent": {
"_uniqueProp": "003_BS2_nuclear_PTEN",
"additionalComments": "PTEN EP Specifications: Variant must be observed in the homozygous state in a healthy or PHTS-unaffected individual. Two independent observations are required if the homozygous status is not confirmed via parental testing. If BS1 is also applied, this criteria will be applied at the supporting evidence level to avoid a variant reaching benign status solely based on homozygous occurrences due to high population frequency (BS1+BS2).\nBS2_Supporting: Two homozygous observations with no clinical data provided, or meets criteria for BS2 but BS1 is also applied.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specifications:** \n\nBS2: Variant must be observed in the homozygous state in a healthy or PHTS-unaffected individual. Two independent observations are required if the homozygous status is not confirmed via parental testing. If BS1 is also applied, this criteria will be applied at the supporting evidence level to avoid a variant reaching benign status solely based on homozygous occurrences due to high population frequency (BS1+BS2).\n\nBS2\\_Supporting: Two homozygous observations with no clinical data provided, or meets criteria for BS2 but BS1 is also applied.",
"label": "BS2",
"ns": "003",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the homozygous state in a healthy or PHTS-unaffected individual. One observation if homozygous status confirmed, two if not confirmed. To be applied at supporting evidence level if BS1 is also applied.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Two homozygous observations with no clinical data provided, or meets criteria for BS2 but BS1 is also applied.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638170",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638170",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHFO--A"
},
{
"entContent": {
"_uniqueProp": "003_BP6_nuclear_PTEN",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "003",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432814",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638432814",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHGG---"
},
{
"entContent": {
"_uniqueProp": "003_BP6_nuclear_PTEN",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "003",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432814",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638432814",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHGG---"
},
{
"entContent": {
"_uniqueProp": "003_PP2_nuclear_PTEN",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "003",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638188",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638188",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHUy---"
},
{
"entContent": {
"_uniqueProp": "003_BP5_nuclear_PTEN",
"additionalComments": "PTEN EP Specifications: At least two such cases are required for criteria to apply. In addition, the other gene/disorder must be considered highly penetrant AND the patient’s personal/family history must demonstrate no overlap between the other gene and PTEN.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specifications:** At least two such cases are required for criteria to apply. In addition, the other gene/disorder must be considered highly penetrant AND the patient’s personal/family history must demonstrate no overlap between the other gene and _PTEN_.",
"label": "BP5",
"ns": "003",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease. Other gene/disorder must be considered highly penetrant AND patient’s personal/family history must demonstrate no overlap between other gene and PTEN.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638186",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638186",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHNO---"
},
{
"entContent": {
"_uniqueProp": "003_PS4_nuclear_PTEN",
"additionalComments": "Use 1: The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\nPTEN EP Commentary: This criterion is unlikely to be used in this manner for a condition as rare as PHTS. However, if sufficiently powered, a case-control study finding an odds ratio >2 for a PHTS component phenotype with p<0.05 and 95% confidence interval with lower limit >1.5, this criteria may be applied. However, this criterion may not be applied in combination with PP4.\n\nUse 2: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.\n PTEN EP Specifications: This criterion may not be applied if BS1 applies. Phenotype specificity scores are added across independent probands and calculated as follows:\n * Adults:\n * 1 point per proband with Cleveland Clinic (CC) score >30 (Tan 2011)\n * 0.5 points per proband with CC score of 25-29.\n * Children: 1 point per proband with pediatric phenotype score >5 (please see supplementary information in manuscript for scoring rubric).\n * 0.5 points per proband with pediatric phenotype score of 4, but autism/developmental delay/intellectual disability may not contribute to the score.\nPS4_Very Strong: Probands with specificity score >16.\nPS4: Probands with specificity score of 4-15.5.\nPS4_Moderate: Probands with specificity score of 2-3.5.\nPS4_Supporting: Proband(s) with specificity score of 1-1.5.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Commentary:** This criterion is unlikely to be used in this manner for a condition as rare as PHTS. However, if sufficiently powered, a case-control study finding an odds ratio >2 for a PHTS component phenotype with p\\<0.05 and 95% confidence interval with lower limit >1.5, this criteria may be applied. However, this criterion may _not_ be applied in combination with PP4.\n\n* Use 2: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.\n\n**PTEN EP Specifications:** This criterion may not be applied if BS1 applies. Phenotype specificity scores are added across independent probands and calculated as follows:\n\nAdults: \n\n* 1 point per proband with Cleveland Clinic (CC) score ≥ 30 (Tan 2011)\n* 0.5 points per proband with CC score of 25-29.\n\nChildren:\n\n* 1 point per proband with pediatric phenotype score ≥ 5 (please see supplementary information in manuscript for scoring rubric).\n* 0.5 points per proband with pediatric phenotype score of 4, but autism/developmental delay/intellectual disability may not contribute to the score.\n\nPS4\\_Very Strong: Probands with specificity score ≥16.\n\nPS4: Probands with specificity score of 4-15.5.\n\nPS4\\_Moderate: Probands with specificity score of 2-3.5.\n\nPS4\\_Supporting: Proband(s) with specificity score of 1-1.5.",
"label": "PS4",
"ns": "003",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Probands with specificity score ≥16 (see text).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Probands with specificity score 4-15.5 (see text) OR The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Probands with specificity score of 2-3.5 (see text).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology. Proband(s) with specificity score of 1-1.5 (see text).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638184",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638184",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHRi---"
},
{
"entContent": {
"_uniqueProp": "003_PP1_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: Requires 3 or 4 meioses in order to apply.\nPP1_Strong: At least 7 meioses required across at least two families.\nPP1_Moderate: Requires 5 or 6 meioses in order to apply.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** \n\nPP1: Requires 3 or 4 meioses in order to apply.\n\nPP1\\_Strong: At least 7 meioses required across at least two families.\n\nPP1\\_Moderate: Requires 5 or 6 meioses in order to apply.",
"label": "PP1",
"ns": "003",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members, with ≥7 meioses observed across at least two families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638183",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638183",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHO----"
},
{
"entContent": {
"_uniqueProp": "003_BP6_nuclear_PTEN",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "003",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432814",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638432814",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHGG---"
},
{
"entContent": {
"_uniqueProp": "003_PM2_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: Criteria may be applied if a variant is present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within a subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%). Please see supplementary information in manuscript supporting application of PM2 for ultra-rare alleles.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** Criteria may be applied if a variant is present at \\<0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within a subpopulation, allele frequency in that subpopulation must be \\<0.00002 (0.002%). Please see supplementary information in manuscript supporting application of PM2 for ultra-rare alleles.",
"label": "PM2",
"ns": "003",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent in population\n\n* Databases present at \\<0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be \\<0.00002 (0.002%).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638193",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638193",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHL2---"
},
{
"entContent": {
"_uniqueProp": "003_BP7_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: Intronic variants must be positioned at or beyond +7/-21. Nucleotide may be defined as “not conserved” with PhastCons score <1 and PhyloP score <0.1.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** Intronic variants must be positioned at or beyond +7/-21.",
"label": "BP7",
"ns": "003",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638190",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638190",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHTW---"
},
{
"entContent": {
"_uniqueProp": "003_BA1_nuclear_PTEN",
"additioanlComments": "PTEN EP Specification: To be applied for variants with allele frequency >0.01 (>1%) in a studied population with >2,000 alleles tested and variant present in >5 alleles. Please see supplementary information in manuscript for data supporting this lowered allele frequency threshold.",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "To be applied for variants with filtering allele frequency >0.00056 (>0.056%) in gnomAD. Please see information in BS1 section for data supporting this cutoff.",
"label": "BA1",
"ns": "003",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "gnomAD Filtering allele frequency >0.00056 (0.056%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638187",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638187",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHOO---"
},
{
"entContent": {
"_uniqueProp": "003_BP2_nuclear_PTEN",
"additionalComments": "PTEN EP Specifications: The other variant may be either pathogenic or likely pathogenic. This rule may also be applied for at least three observations of the variant in cis or unknown phase with different pathogenic or likely pathogenic PTEN variants.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specifications:** The other variant may be either pathogenic or likely pathogenic. This rule may also be applied for at least three observations of the variant _in cis_ or unknown phase with different pathogenic or likely pathogenic _PTEN_ variants.",
"label": "BP2",
"ns": "003",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638178",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638178",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHSm---"
},
{
"entContent": {
"_uniqueProp": "003_PM6_nuclear_PTEN",
"additionalComments": "PM6_Very Strong: Four or more occurrences of PM6 OR two occurrences of PM6 AND one occurrence of PS2.\nPM6_Strong: Two occurrences of PM6.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "PM6\\_Very Strong: Four or more occurrences of PM6 OR two occurrences of PM6 AND one occurrence of PS2.\n\nPM6\\_Strong: Two occurrences of PM6 OR occurrence of PM6 for an individual with a highly specific phenotype (meets criteria to count towards PS4).\n\n* Of note, when PM6\\_S is applied for a single individual with phenotype specificity, the individual will not be counted towards PS4 as well.",
"label": "PM6",
"ns": "003",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Two probands with presumed _de novo_ occurrence (maternity/ paternity not confirmed) with the disease and no family history.\n\n* May also be used for a proband with presumed de novo occurrence for an individual with a highly specific phenotype (meets criteria to count towards PS4)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed _de novo,_ but without confirmation of paternity and maternity, in proband with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638176",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638176",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHJu---"
},
{
"entContent": {
"_uniqueProp": "003_BP1_nuclear_PTEN",
"additionalComments": "This rule is not applicable to PTEN.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "003",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638174",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638174",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHQa---"
},
{
"entContent": {
"_uniqueProp": "003_PM3_nuclear_PTEN",
"additionalComments": "This rule is not applicable to PTEN.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "003",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638169",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638169",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHSO---"
},
{
"entContent": {
"_uniqueProp": "003_BS1_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: To be applied for variants with allele frequency of 0.001 up to 0.01 (0.1% up to 1%) in a studied population with >2,000 alleles tested and variant present in >5 alleles. Please see supplementary information in manuscript for data supporting this lowered allele frequency threshold.\nBS1_Supporting: To be applied for variants with allele frequency of 0.000043 up to 0.001 (0.0043% up to 0.1%) in a studied population with >2,000 alleles tested and variant present in >5 alleles. Threshold based on the approach published by Whiffin et al. (PMID 28518168) using the following values:\n * Prevalence: 1 in 9,000 (based on 15 disease-associated alleles present among the gnomAD population of ~135,000 individuals)\n * Allelic heterogeneity: 22/282 (based on prevalence of most common pathogenic PTEN variants, p.R130X and p.R335X, per Tan et al. PMID 21194675 and Bubien 2013 PMID 23335809)\n *Penetrance: 10% (overall cancer by age 40 for men with pathogenic germline PTEN variants is approximately 20% per Bubien 2013 PMID 23335809).",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** \n\nBS1: To be applied for variants with filtering allele frequency of 0.000043 up to 0.00056 (0.0043% up to 0.056%) in gnomAD. \n\nBS1\\_Supporting: To be applied for variants with filtering allele frequency of 0.0000043 up to 0.000043 (0.00043% up to 0.0043%) in gnomAD. \n\nBA1, BS1, and BS1\\_P thresholds are based on the approach published by Whiffin et al. (PMID 28518168) using the following values:\n\n* Prevalence: 1 in 9,000 (based on 15 disease-associated alleles present among the gnomAD population of ~135,000 individuals)\n* Allelic heterogeneity: 22/282 (based on prevalence of most common pathogenic _PTEN_ variants, p.R130X and p.R335X, per Tan et al. PMID 21194675 and Bubien 2013 PMID 23335809)\n* Penetrance: 10% (overall cancer by age 40 for men with pathogenic germline _PTEN_ variants is approximately 20% per Bubien 2013 PMID 23335809)\n\nUsing these data points results in a BS1 value of 0.000043. BA1 was calculated by setting allelic heterogeneity to 1, and BS1\\_P by reducing BS1 by an order of magnitude.",
"label": "BS1",
"ns": "003",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Allele frequency from 0.0000043 (0.00043%) up to 0.000043 (0.0043%).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638168",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638168",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHK2---"
},
{
"entContent": {
"_uniqueProp": "003_PM1_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: Defined to include residues in one of PTEN’s catalytic motifs, which include the WPD loop (residues 90-94), P-loop (also described as phosphatase core, residues 123-130), and the TI-loop (residues 166-168) (NP_ 000305.3) (Lee 1999).",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** Defined to include residues in one of PTEN’s catalytic motifs, which include the WPD loop (residues 90-94), P-loop (also described as phosphatase core, residues 123-130), and the TI-loop (residues 166-168) (NP\\_ 000305.3) (Lee 1999).",
"label": "PM1",
"ns": "003",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168 (NP_ 000305.3)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638192",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638192",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHMq---"
},
{
"entContent": {
"_uniqueProp": "003_PS2_nuclear_PTEN",
"additionalComments": "",
"additonalComments": "PS2_Very Strong: Two or more occurrences of PS2 OR two or more occurrences of PM6 AND one occurrence of PS2.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "PS2\\_Very Strong: Two or more occurrences of PS2 OR two or more occurrences of PM6 AND one occurrence of PS2.",
"label": "PS2",
"ns": "003",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638179",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638179",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHHW---"
},
{
"entContent": {
"_uniqueProp": "003_PS1_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: PS1 will be applied as described and expanded to include a different nucleotide substitution for an intronic splice site variant if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tools. Caution should be used when applying this criteria to exonic variants causing aberrant splicing.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** PS1 will be applied as described and expanded to include a different nucleotide substitution for an intronic splice site variant if the predicted impact is equal to or greater than the known pathogenic variant per _in silico_ splicing tools. Caution should be used when applying this criteria to exonic variants causing aberrant splicing.",
"label": "PS1",
"ns": "003",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638177",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638177",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHKi---"
},
{
"entContent": {
"_uniqueProp": "003_BS3_nuclear_PTEN",
"additionalComments": "PTEN EP Specifications: BS3 may be applied to the following assays:\n * For missense variants: Lipid phosphatase activity comparable to wild type in addition to a second assay appropriate to the protein domain demonstrating no statistically significant difference from wild type. Phosphatase assays for which criteria may be applied must include a catalytic dead control, such as p.C124S (NP_ 000305.3), as well as at least three biological replicates (Myers 1998, Stambolic 1998, Han 2000, Rodriguez-Escudero 2011, Costa 2015, Malek 2017). Examples of second assays may include:\n * Decreased PTEN or increased pAKT expression (Tan 2011, Spinelli 2015).\n * Disruption of protein cellular localization (Lobo 2009, He 2012, Gil 2015).\n * Aberrant cellular phenotypes, including defective cell migration, proliferation, and invasion (Costa 2015, Malek 2017).\n * For intronic or synonymous variants: RNA, mini-gene, or other assay demonstrate no impact on splicing.\n BS3_Supporting: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specifications:** \n\nBS3: For intronic or synonymous variants: RNA, mini-gene, or other assay demonstrate no impact on splicing.\n\nBS3\\_Supporting: _In vitro_ or _in vivo_ functional study or studies showing no damaging effect on protein function.\n\n**PTEN EP Specifications:** BS3\\_supporting may be applied to the following assays:\n\n* Mighell et al. 2018 (PMID: 29706350): Massively parallel functional assay interrogating phosphatase activity. \n * In the supplementary material (Table S2) search for the variant in columns A or B and make sure the variant in question is listed as TRUE under column I (high confidence). If not, do not use as evidence.\n * Under column G, the cumulative score is listed. Apply BS3\\_supporting for all variants with scores > 0.\n* For missense variants: Other studies showing lipid phosphatase activity comparable to wild type in addition to a second assay appropriate to the protein domain demonstrating no statistically significant difference from wild type. Phosphatase assays for which criteria may be applied must include a catalytic dead control, such as p.C124S (NP\\_ 000305.3), as well as at least three biological replicates: Myers et al. 1998 (PMID: 9811831), Stambolic et al. 1998 (PMID: 9778245), Han et al. 2000 (PMID: 10866302), Rodriguez-Escudero et al. 2011 (PMID: 21828076), Costa et al. 2015 (PMID: 26504226), Malek et al. 2017 (PMID: 29056325)\n* Examples of second assays may include:\n * Decreased PTEN or increased pAKT expression: Tan et al. 2011 (PMID: 21194675), Spinelli et al. 2015 (PMID: 25527629).\n * Disruption of protein cellular localization: Lobo et al. 2009 (PMID: 19457929), He et al. 2012 (PMID: 22962422), Gil et al. 2015 (PMID: 25875300).\n * Aberrant cellular phenotypes, including defective cell migration, proliferation, and invasion: Costa et al. 2015 (PMID: 26504226)\n * Malek et al. 2017 (PMID: 29056325).",
"label": "BS3",
"ns": "003",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established _in vitro_ or _in vivo_ functional studies shows no damaging effect on protein function. To be applied to intronic or synonymous variants, RNA, mini-gene or other splicing assay demonstrating no splicing impact.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "_In vitro_ or _in vivo_ functional study or studies showing no damaging effect on protein function.\n\n* Phosphatase activity >0 per Mighell et al. 2018, PMID: 29706350.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638172",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638172",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHVS---"
},
{
"entContent": {
"_uniqueProp": "003_PP5_nuclear_PTEN",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "003",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432815",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638432815",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHPO---"
},
{
"entContent": {
"_uniqueProp": "003_PP5_nuclear_PTEN",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "003",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432815",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638432815",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHPO---"
},
{
"entContent": {
"_uniqueProp": "003_PP3_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: To be applied only to synonymous or intronic variants where at least 2 out of 3 in silico models predict a splicing impact. Not to be applied for variants which may impact the intron 1 splice donor or acceptor sites, and to be used cautiously for variants which may impact the intron 6 splice acceptor.\nPTEN EP Commentary: Given the lack of known benign or likely benign PTEN missense variants, the Expert Panel was unable to test the accuracy of in silico predictors to be used as evidence to apply BP4 or PP3 for PTEN missense variants. While investigating potential in silico tools, the Expert Panel also came to find that some algorithm predictions were highly sensitive to sequence alignment, further limiting confidence in these tools. Should the Expert Panel classify several missense variants as benign or likely benign, another attempt will be made to validate in silico tools to apply PP3/BP4 for missense variants. Please see supplementary information in manuscript detailing validation of splicing in silico tools and challenges presented by the specified donor/acceptor sites.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** To be applied to synonymous or intronic variants where SpliceAl and VarSeak _in silico_ models predict a splicing impact (SpliceAl: scores 0.5-1 are consider evidence of pathogenic. VarSeak: Class 4 and 5 are consider evidence of pathogenic). May also be applied to missense variants with REVEL score > 0.7.\n\n**PTEN EP Commentary:** Per Bayesian adaptation of the ACMG/AMP variant interpretation framework (Tavtigian et al., 2018), odds of pathogenicity (OddsPath) were estimated for various numbers of previously classified controls. When REVEL scores > 0.7 were used as evidence of pathogenic and \\< 0.5 were used as evidence of benign, the oddsPath was equated with moderate evidence strength for pathogenic conditions. Given that the VCEP also applies PP2 for missense variants, we decided to downgrade the evidence strength to be used at a supporting level.",
"label": "PP3",
"ns": "003",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.\n\n* Splicing variants: Concordance of SpliceAl and VarSeak\n* Missense variants: REVEL score > 0.7",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638189",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638189",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHUO---"
},
{
"entContent": {
"_uniqueProp": "003_PVS1_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: For nonsense or frameshift variants at the 3’ end of the gene NOT predicted to result in nonsense-mediated decay, PVS1 may still be applied if the protein is disrupted at or 5’ to c.1121 (NM_000314.6). Please see supplementary information in manuscript for evidence supporting this cutoff.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** Follow SVI guidance, using PTEN-specific information. Per the PVS1 workflow guidance provided in Tayoun et al. 2018 (PMID 30192042), the following will apply:\n\n1. Nonsense, frameshift variants:\n * PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD); the predicted NMD cutoff for PTEN occurs at c.1121 (p.D375).\n * For nonsense or frameshift variants at the 3’ end of the gene NOT predicted to result in nonsense-mediated decay, PVS1 may still be applied if the protein is disrupted at or 5’ to c.1121 (NM\\_000314.6). Please see supplementary information in manuscript for evidence supporting this cutoff.\n * PVS1\\_Moderate applies to variants resulting in protein truncation 3’ of this cutoff.\n2. Splicing variants (+/- 1,2 intronic positions): \n * Only apply to the variants resulting NMD (please refer to decision tree) OR entire exon deletion: \n * Exons 1,2,4,5,6 OR 7 deletions OR multi-exon deletion: PVS1 (Resulting frameshift)\n * Exons 3,8 OR 9 deletions: PVS1\\_Strong (in-frame but truncated/altered region is critical to protein function).\n3. Deletion (Single/multi exon to full gene): Please refer to decision tree.\n4. Duplication: Please refer to decision tree.\n5. Initiation codon: PVS1 applies to initiation codon variants.\n\n**PTEN EP Commentary:** No known alternative start codon in other transcripts. There are sufficient patients’ data from literature and labs support the pathogenicity of initiation codon variants.",
"label": "PVS1",
"ns": "003",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use PTEN PVS1 decision tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use PTEN PVS1 decision tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use PTEN PVS1 decision tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
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"ldhId": "135638185",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638185",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
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},
{
"entContent": {
"_uniqueProp": "003_BP3_nuclear_PTEN",
"additionalComments": "This rule is not applicable to PTEN.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "003",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
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},
"entType": "CriteriaCode",
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638180",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHO2---"
},
{
"entContent": {
"_uniqueProp": "003_PM5_nuclear_PTEN",
"additionalComments": "PTEN EP Specifications:\n * This rule may be applied when the known variant is likely pathogenic unless applying would lead to a higher (pathogenic) classification for the variant being assessed.\n * The variant in question need not be novel but must have a BLOSUM62 (Henikoff 1992) score equal to or less than the known variant.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specifications:**\n\n* This rule may be applied when the known variant is likely pathogenic unless applying would lead to a higher (pathogenic) classification for the variant being assessed.\n* The variant in question need not be novel but must have a BLOSUM62 (Henikoff 1992) score equal to or less than the known variant.",
"label": "PM5",
"ns": "003",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before. In addition, variant being interrogated must have BLOSUM62 score equal to or less than the known variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638173",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638173",
"modified": "2026-04-06T16:10:18.575Z",
"modifier": "JasmineBakerBCM",
"rev": "_lUMNHT2---"
}
],
"Disease": [
{
"entContent": {
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"lbl": "PTEN hamartoma tumor syndrome",
"meta": {
"basicPropertyValues": [
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"val": "https://github.com/monarch-initiative/mondo/issues/9178"
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},
{
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"val": "https://rarediseases.info.nih.gov/diseases/12800/pten-hamartoma-tumor-syndrome"
},
{
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{
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"val": "http://www.orpha.net/ORDO/Orphanet_306498"
}
],
"definition": {
"val": "An autosomal dominant syndrome caused by pathogenic variants in the PTEN gene, characterized by hamartomas, overgrowth, neurodevelopmental disorders and an increased risk of various cancers, including breast, thyroid, and endometrial cancer. PHTS encompasses Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Proteus-like syndrome.",
"xrefs": [
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]
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"subsets": [
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],
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{
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"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
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},
{
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},
{
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"xrefs": [
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}
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},
{
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},
{
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]
},
"type": "CLASS"
},
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"name": "PTEN hamartoma tumor syndrome",
"preferredModeOfInheritance": {
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"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0017623",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0017623",
"entType": "Disease",
"ldhId": "135642014",
"ldhIri": "https://cspec.genome.network/cspec/Disease/id/135642014",
"modified": "2025-10-07T16:14:50.633Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7yNzy---"
}
],
"EvidenceCategory": [
{
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"label": "De novo Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642492",
"ldhIri": "https://cspec.genome.network/cspec/EvidenceCategory/id/135642492",
"modified": null,
"rev": "_inf5Asm--t"
},
{
"entContent": {
"label": "Functional Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642491",
"ldhIri": "https://cspec.genome.network/cspec/EvidenceCategory/id/135642491",
"modified": null,
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},
{
"entContent": {
"label": "Population Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642486",
"ldhIri": "https://cspec.genome.network/cspec/EvidenceCategory/id/135642486",
"modified": null,
"rev": "_inf5AsS--_"
},
{
"entContent": {
"label": "Other Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
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"ldhIri": "https://cspec.genome.network/cspec/EvidenceCategory/id/135642490",
"modified": null,
"rev": "_inf5Asm--r"
},
{
"entContent": {
"label": "Allelic Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642488",
"ldhIri": "https://cspec.genome.network/cspec/EvidenceCategory/id/135642488",
"modified": null,
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},
{
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"sepioId": ""
},
"entType": "EvidenceCategory",
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"ldhIri": "https://cspec.genome.network/cspec/EvidenceCategory/id/135642487",
"modified": null,
"rev": "_inf5Asi--_"
},
{
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"label": "Other Database",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642489",
"ldhIri": "https://cspec.genome.network/cspec/EvidenceCategory/id/135642489",
"modified": null,
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},
{
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"label": "Segregation Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642485",
"ldhIri": "https://cspec.genome.network/cspec/EvidenceCategory/id/135642485",
"modified": null,
"rev": "_inf5Asi---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056958559977500,
"agr": "HGNC:9588",
"alias_name": [
"mutated in multiple advanced cancers 1"
],
"alias_symbol": [
"MMAC1",
"TEP1",
"PTEN1"
],
"ccds_id": [
"CCDS31238"
],
"cosmic": "PTEN",
"date_approved_reserved": "1997-04-21",
"date_modified": "2021-05-26",
"date_name_changed": "2008-07-31",
"ena": [
"U92436"
],
"ensembl_gene_id": "ENSG00000171862",
"entrez_id": "5728",
"enzyme_id": [
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"3.1.3.48",
"3.1.3.67"
],
"gene_group": [
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"PTEN protein phosphatases",
"Phosphoinositide phosphatases"
],
"gene_group_id": [
837,
902,
1079
],
"hgnc_id": "HGNC:9588",
"iuphar": "objectId:2497",
"location": "10q23.31",
"location_sortable": "10q23.31",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_311|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_311.xml"
],
"mane_select": [
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{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
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"text": "Due to variable expressivity and severity, extensive clinical workup for RASopathy spectrum features is warranted, thus general population data should not be used for this criterion. Clinical laboratories are encouraged to accumulate more than 3 instances of well phenotyped family members before applying this strong criterion.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0076",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638332",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638332",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--B"
},
{
"entContent": {
"_uniqueProp": "004_BP6_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
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"HRAS",
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"RAF1",
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"instructionsToUse": "",
"label": "BP6",
"ns": "004",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432844",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638432844",
"modified": "2022-01-19T20:31:29.467Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--I"
},
{
"entContent": {
"_uniqueProp": "004_PM1_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "See supplemental material for approved functional domains and residues. This evidence rule can also be applied for the same analogous residue positions/regions in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
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"MONDO:0021060",
"MONDO:0054637"
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"SOS2"
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"geneType": "nuclear",
"label": "PM1",
"ns": "004",
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"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "PM1 upgraded in strength to Strong",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": "Analogous Gene",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See supplemental material for approved functional domains and residues. This evidence rule can also be applied for the same analogous residue positions/regions in highly analogous groupings below:\nGroup 1: HRAS, NRAS, KRAS\nGroup 2: MAP2K1, MAP2K2\nGroup 3: SOS1, SOS2",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638354",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--g"
},
{
"entContent": {
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"disease": [
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"geneType": "nuclear",
"label": "BP7",
"ns": "004",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": "General",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\nThis rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
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}
]
},
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638352",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_inf5Apa--X"
},
{
"entContent": {
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"additionalComments": "",
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"MONDO:0021060",
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],
"geneType": "nuclear",
"label": "PP3",
"ns": "004",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": "None",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638351",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638351",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--f"
},
{
"entContent": {
"_uniqueProp": "004_PS2_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "PS2_Very Strong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
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"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "De novo Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "004",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0016",
"instructionsToUse": "",
"specificationType": "Strength",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": "None",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (paternity confirmed) in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638341",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638341",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--D"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Benign",
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"disease": [
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"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
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"evidenceCategory": "Allelic Data",
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],
"geneType": "nuclear",
"label": "BP2",
"ns": "004",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": "None",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638340",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638340",
"modified": "2021-11-05T21:07:12.074Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--C"
},
{
"entContent": {
"_uniqueProp": "004_BP1_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
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"MONDO:0009026",
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"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Computational And Predictive Data",
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],
"geneType": "nuclear",
"label": "BP1",
"ns": "004",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0082",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638336",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638336",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--C"
},
{
"entContent": {
"_uniqueProp": "004_PP2_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "PP2 is applicable to all RASopathy genes described and curated herein.",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
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"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Functional Data",
"gene": [
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"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "004",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0061",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "PP2 is applicable to all RASopathy genes described and curated herein.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638350",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638350",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_inf5Apa--W"
},
{
"entContent": {
"_uniqueProp": "004_BA1_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "An allele frequency ≥0.05% was approved. See supplemental material for additional frequency information.",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Population Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "004",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "An allele frequency ≥0.05% was approved. See supplemental material for additional frequency information.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638349",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638349",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--E"
},
{
"entContent": {
"_uniqueProp": "004_PVS1_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "LOF and/or haploinsufficiency has not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype, therefore in general this rule is not applicable. Note that PTPN11 is currently the only gene with a confirmed association to another non-RASopathy disorder due to LOF alleles. Variants in PTPN11 with predicted LOF should not be evaluated by these RASopathy specific criteria, but should defer to non-adjusted criteria. Given that some historical LOF variants (e.g. canonical splice sites) could potentially result in a gain of function, users should assess using these criteria and non-adjusted criteria to identify the highest likelihood of pathogenicity for all associated diseases. We recommend that the ClinGen Dosage Sensitivity Map Status (http://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/index.shtml) be reviewed for any new apparently LOF disease associations prior to classification assessment.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "004",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0244",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "LOF and/or haploinsufficiency has not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype, therefore in general this rule is not applicable. Note that PTPN11 is currently the only gene with a confirmed association to another non-RASopathy disorder due to LOF alleles. Variants in PTPN11 with predicted LOF should not be evaluated by these RASopathy specific criteria, but should defer to non-adjusted criteria. Given that some historical LOF variants (e.g. canonical splice sites) could potentially result in a gain of function, users should assess using these criteria and non-adjusted criteria to identify the highest likelihood of pathogenicity for all associated diseases. We recommend that the ClinGen Dosage Sensitivity Map Status (http://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/index.shtml) be reviewed for any new apparently LOF disease associations prior to classification assessment.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638347",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638347",
"modified": "2022-01-19T20:33:33.485Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--S"
},
{
"entContent": {
"_uniqueProp": "004_BS4_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "Requires only one informative meiosis and does not require an additional piece of supporting evidence to classify variant as likely benign.",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Segregation Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "004",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": "General",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Requires only one informative meiosis and does not require an additional piece of supporting evidence to classify variant as likely benign.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638337",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638337",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_inf5Apa--U"
},
{
"entContent": {
"_uniqueProp": "004_PM2_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "The variant must be completely absent from all population databases.",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Population Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "004",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0011",
"instructionsToUse": "",
"specificationType": "General",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The variant must be completely absent from all population databases.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0030",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638355",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638355",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--F"
},
{
"entContent": {
"_uniqueProp": "004_PS4_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "PS4: ≥5 independent occurrences\nPS4_Moderate: ≥3 independent occurrences\nPS4_Supporting: ≥1 independent occurrences",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Population Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "004",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": "General",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥5 independent occurrences.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0057",
"instructionsToUse": "",
"specificationType": "Strength",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥3 independent occurrences.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0032",
"instructionsToUse": "",
"specificationType": "Strength",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥1 independent occurrences.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638346",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638346",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--S"
},
{
"entContent": {
"_uniqueProp": "004_PP1_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "PP1_Moderate: ≥5 informative meioses\nPP1_Strong: ≥7 informative meioses",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Segregation Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "004",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"specificationType": "Strength",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Usage of PP1 requires at least three informative meioses. Segregation in more than one family is recommended.\n≥7 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"specificationType": "Strength",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Usage of PP1 requires at least three informative meioses. Segregation in more than one family is recommended.\n≥5 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": "General",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Usage of PP1 requires at least three informative meioses. Segregation in more than one family is recommended.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638345",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638345",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--R"
},
{
"entContent": {
"_uniqueProp": "004_PM6_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "PM6_Strong: ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.\nPS2_VeryStrong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "De novo Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "004",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"specificationType": "Strength",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": "None",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638338",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638338",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_inf5Apa--V"
},
{
"entContent": {
"_uniqueProp": "004_PM5_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes. This evidence rule can also be used for pathogenic missense variants seen in the same analogous residue position in highly analogous groupings below:\nGroup 1: HRAS, NRAS, KRAS\nGroup 2: MAP2K1, MAP2K2\nGroup 3: SOS1, SOS2\n\nThis rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a “mutational hot-spot”. For example, Gly12 in HRAS is listed as a hot-spot for PM1 usage. In these situations, only PM1 should be used when combining criteria for final variant classification in order to avoid premature designation of a likely pathogenic classification in the absence of other evidence for pathogenicity.",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "004",
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"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638906",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638906",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--i"
},
{
"entContent": {
"_uniqueProp": "005_PP4_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "005",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0018",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Patient's phenotype highly specific for gene or fully sequenced gene set (see specifications in Table 7).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638905",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638905",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--f"
},
{
"entContent": {
"_uniqueProp": "005_BP7_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "005",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Silent variant with no predicted impact to splicing.\nNo changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638904",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638904",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--i"
},
{
"entContent": {
"_uniqueProp": "005_PP2_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": "Advise against using this rule because there are few such genes that this would apply to, particularly genes associated to autosomal recessive hearing loss.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "005",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638902",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638902",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--e"
},
{
"entContent": {
"_uniqueProp": "005_PS2_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS2",
"ns": "005",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0016",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 points per tables 5a and 5b:\nExamples: 2 proven de novo occurrences; OR 1 proven + 2 assumed de novo occurrences; OR\n4 assumed de novo occurrences.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 points per tables 5a and 5b:\nExamples: 1 proven de novo occurrence; OR 2 assumed de novo occurrences.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "004",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 point per tables 5a and 5b:\nExamples: 1 proven de novo occurrence (phenotype consistent but not specific to gene); OR\n1 assumed de novo occurrence; OR 2 assumed de novo occurrences (phenotype/gene not specific).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0043",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 points per tables 5a and 5b:\nExample: 1 assumed de novo occurrence (phenotype/gene not specific).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638893",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638893",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--Y"
},
{
"entContent": {
"_uniqueProp": "005_BP2_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "005",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a dominant variant/observed in cis with a pathogenic variant (use with caution).\nUse with caution. For genes that are associated with both dominant and recessive hearing loss, consider whether an earlier onset/more severe phenotype could be present if variant is identified in trans with a dominant variant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638892",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638892",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Aq----"
},
{
"entContent": {
"_uniqueProp": "005_PM6_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "005",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See PS2 above",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638890",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638890",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--c"
},
{
"entContent": {
"_uniqueProp": "005_BP1_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "005",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638888",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638888",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--A"
},
{
"entContent": {
"_uniqueProp": "005_BS3_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "005",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0072",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0085",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Functional study shows no deleterious effect (predefined list).\n* Recommend that functional evidence is not used as strong evidence, due to the absence of well-established functional studies for hearing loss genes.\n* Guidance on functional evidence at supporting level is as follows (see functional spreadsheets attached):\n * GJB2: electrical coupling assays, dye transfer assays → BS3_Supporting\n * Dye Transfer Assays: Expect results that compare the fluorescence of a variant-transfected cell to both a negative control (or H2O injected control) and a wildtype-transfected cell. BS2_Supporting can be applied if the variant results in dye transfer comparable to the wildtype.\n * Electrical Coupling Assays: Expect results comparing the current of the variant-transfected cells to both a negative control (or H2O injected control) and a wildtype-transfected cell. BS2_Supporting would be applied if the variant results in a current comparable to the wildtype.\n * SLC26A4: Radio isotope and fluorescence assays → BS3_Supporting\n * Radio Isotope Assays: BS3_Supporting would be applied if the variant results in iodide efflux levels comparable to the wildtype.\n * Fluorescence assay: BS3_Supporting would be applied if the variant results in fluorescence comparable to the wildtype\n * COCH: Localization, secretion, and dimerization studies performed using immunofluorescence and Western blotting techniques → BS3_Supporting\n * Localization: BS3_Supporting would be applied if the variant results in extracellular deposits comparable to the wildtype.\n * Secretion: BS3_Supporting would be applied if the variant results in secretion comparable to the wildtype.\n * Dimerization: In a non-reducing environment, wildtype cochlin migrate quickly and appear smaller than in the reduced state because the structure is maintained by disulfide bonds. BS3_Supporting would be applied if the variant results in molecular weight and size comparable to the wildtype.\n* If not listed above, OK to use BS3_Supporting for other genes/functional analyses if\n * The assay has been validated by a known pathogenic and benign variant AND\n * There is plausible reason that the function the assay is testing relates to the phenotype AND\n * The assay conditions are likely to mimic the physiological environment.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638886",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638886",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Apm---"
},
{
"entContent": {
"_uniqueProp": "005_PM3_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "005",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0038",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 points awarded from tables 7a and 7b\nExample: Detected in trans in ≥4 probands with a pathogenic variant (recessive).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0058",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 points awarded from tables 7a and 7b\nExample: Detected in trans in 2 probands with a pathogenic variant (recessive).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "007",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 point awarded from tables 7a and 7b.\nExample: Detected in trans with a pathogenic variant (recessive).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0027",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 points awarded from tables 7a and 7b\nExamples: Two variants that meet PM2_Supporting detected in trans; OR\na homozygous variant meeting PM2_Supporting.\n",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638883",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638883",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--a"
},
{
"entContent": {
"_uniqueProp": "005_PP3_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "005",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "REVEL score ≥0.7, or predicted impact to splicing using MaxEntScan.\n* Use REVEL and MAXENTSCAN.\n * For missense variants, award PP3 if REVEL score is ≥0.7.\n * If splicing is predicted to be impacted, either creation of a cryptic splice site, or disruption of a native splice site, award PP3.\n* For splice variants (except for canonical -/+1 or 2), use MAXENTSCAN.\n * For -/+ 1 or 2 splice variants, do not use PP3 if you are using PVS1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638903",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638903",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--N"
},
{
"entContent": {
"_uniqueProp": "005_BP5_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "005",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant in an autosomal dominant gene found in a patient with an alternate explanation.\n* Autosomal recessive: Do not use. An individual could be carrier of pathogenic variant and have an alternate cause. Therefore, BP5 shouldn’t be used as evidence for benign in this case.\n* Autosomal dominant: Can use BP5 as outlined by Richards 2015.\n\n * Caveat: consider whether multiple pathogenic autosomal dominant variants could cause a more severe phenotype or whether multigenic inheritance is known to occur (example: Bardet-Biedl syndrome).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638900",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638900",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--h"
},
{
"entContent": {
"_uniqueProp": "005_PS4_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS4",
"ns": "005",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Fisher Exact or Chi-Squared analysis shows statistical increase in cases over controls, OR\nAutosomal dominant: ≥15 probands with variant, and variant meets PM2_Supporting.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0057",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Autosomal dominant: ≥6 probands with variant, and variant meets PM2_Supporting.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0032",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Autosomal dominant: ≥2 probands with variant, and variant meets PM2_Supporting.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638898",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638898",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--Z"
},
{
"entContent": {
"_uniqueProp": "005_BP6_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP6",
"ns": "005",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432874",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638432874",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--e"
},
{
"entContent": {
"_uniqueProp": "005_BA1_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BA1",
"ns": "005",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "MAF of ≥0.005 (0.5%) for autosomal recessive; MAF of ≥0.001 (0.1%) for autosomal dominant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638901",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638901",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--b"
},
{
"entContent": {
"_uniqueProp": "005_BP4_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "005",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Computational evidence suggests no impact; REVEL score ≤0.15 or no impact to splicing in MaxEntScan.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638896",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638896",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--d"
},
{
"entContent": {
"_uniqueProp": "005_PS3_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS3",
"ns": "005",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Knock-in mouse model demonstrates the phenotype.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0039",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Validated functional studies show a deleterious effect (predefined list): GJB2: electrical coupling assays, dye transfer assays → PS3_Moderate\n* Dye Transfer Assays: Expect results that compare the fluorescence of a variant-transfected cell to\nboth a negative control (or H2O injected control) and a wildtype-transfected cell. PS3_Moderate\nwould be applied if the variant results in no dye transfer or significantly different dye transfer when\ncompared to the wildtype.\n* Electrical Coupling Assays: Expect results comparing the current of the variant-transfected cells to both a negative control (i.e. H2O injected control) and a wildtype-transfected cell. PS3_Moderate would be applied if the variant results in significantly different current compared to the wildtype, and the current is comparable to background levels/negative control.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0045",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "SLC26A4: Radio isotope and fluorescence assays → PS3_Supporting\n* Radio Isotope Assays: PS3_Supporting would be applied when cells transfected with mutant SLC26A4 show a statistically significant decreased efflux of iodide compared to wildtype pendrin.\n* Fluorescence Assays: PS3_Supporting would be applied when a cell transfected with the mutant SLC26A4 shows a statistically significant difference in fluorescence (ΔFmax %) compared to the wildtype protein, and when the fluorescence is not significantly different from that of an empty vector control.\nCOCH: Localization, secretion, and dimerization studies performed using immunofluorescence and\nWestern blotting techniques →PS3_Supporting\n* Localization: PS3_Supporting would be applied if the mutant cochlin protein does not aggregate into extracellular deposits or in the perinuclear region, comparable to the localization of wildtype cochlin.\n* Secretion: PS3_Supporting would be applied if cochlin protein containing the variant does not show secretion from transfected cells, but aggregates in cell regions such as the ER, Golgi and nucleus or is degraded.\n* Dimerization: In a non-reducing environment, wildtype cochlin migrate quickly and appear smaller than in the reduced state because the structure is maintained by disulfide bonds. PS3_Supporting would be applied if the cochlin protein containing the variant forms more, or less, stable disulfide bonds when compared to the wildtype in non-reducing conditions.\n* If not listed above, OK to use PS3_Supporting for other genes/functional analyses if\n * The assay has been validated by a known pathogenic and benign variant AND \n * There is plausible reason that the function the assay is testing relates to the phenotype AND\n * The assay conditions are likely to mimic the physiological environment.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638895",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638895",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--Y"
},
{
"entContent": {
"_uniqueProp": "005_BP3_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "005",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0081",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame indels in repeat region without known function.\nNo changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638894",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638894",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--c"
},
{
"entContent": {
"_uniqueProp": "005_BS4_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "005",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Non-segregation with disease.\n* Phenotype+/genotype-\n * Strong evidence for benign.\n * Be cautious when using this as the possibility for phenocopy is high. The hearing loss phenotype should be consistent within the family to consider it a non-segregation, though intra-familial variability has been reported. Factors to consider are:\n * Age of onset (ie. congenital/early childhood vs. adult onset).\n * Hearing loss prevalence increases significantly with age. A congenital hearing loss in a child and a late onset hearing loss in a grandparent would not be a consistent phenotype.\n * Severity (ie - mild vs. profound).\n * Minor differences may exist among family members.\n * Keep in mind that progression in older individuals may account for a discrepancy between individuals.\n * Sex -based differences (infertility, genes on X chromosomes)\n * Audiogram shape.\n * May not be completely consistent among family members even with same etiology.\n* Genotype+/phenotype-\n * Confounding variables to applying this rule: Age-related/sex-related penetrance, variable expressivity, etc.\n * If the gene is associated with later onset and individual with the non-segregation is beyond the expected age that the hearing loss would occur, consider applying BS4_Supporting\n * Recommend only using for fully penetrant genes (typically genes associated with AR hearing loss).\n * Must be confident that patient is truly unaffected and a hearing loss is not missed or subclinical. Be cautious if only phenotyping was newborn hearing screening. Diagnostic audiometric testing (auditory brainstem response (ABR) or audiogram should be required).\n * Any evidence for reduced penetrance, do not use BS4",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638889",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638889",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--_"
},
{
"entContent": {
"_uniqueProp": "005_PM4_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "005",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length change due to an in-frame deletion or insertion that are not located in repetitive regions.\n* No changes. Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638885",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638885",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Api--s"
},
{
"entContent": {
"_uniqueProp": "005_BS1_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS1",
"ns": "005",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "MAF of ≥0.003 (0.3%) for autosomal recessive; MAF of ≥0.0002 (0.02%) for autosomal dominant. Likely benign, provided there is no conflicting evidence.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0086",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "MAF of ≥0.0007 (0.07%) for autosomal recessive. No BS1_Supporting criteria for autosomal dominant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638882",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638882",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--g"
},
{
"entContent": {
"_uniqueProp": "005_PVS1_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PVS1",
"ns": "005",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene with established LOF as a disease mechanism; see PVS1_Strong, PVS1_Moderate, PVS1_Supporting for reduced evidence applications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0020",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "See PVS1 flow chart for PVS1_Strong variants in gene where LOF is a known mechanism of disease.\n* PVS1 should also be considered for the following genes with variants assessed in the Hearing Loss Variant Pilot: GJB2, CDH23, USH2A, SLC26A4, MYO6, MYO7A, TECTA, KCNQ4.\n* For other genes, LOF must be an established disease mechanism, and the gene/disease association must be Strong or Definitive clinical validity level as outlined in Strande et al. 2017 (PMID: 28552198).\n* If above criteria is met, follow PVS1 flowchart as recommended by the SVI.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0026",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See PVS1 flowchart for PVS1_Moderate variants in gene where LOF is a known mechanism of disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "001",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "See PVS1 flowchart for PVS1_Supporting variants in gene where LOF is a known mechanism of disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638899",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638899",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--X"
},
{
"entContent": {
"_uniqueProp": "005_PP1_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP1",
"ns": "005",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0023",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Segregation in three affected relatives for recessive and five affected relatives for dominant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0040",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Segregation in two affected relatives for recessive and 4 affected relatives for dominant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Segregation in one affected relative for recessive and two affected relatives for dominant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638897",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638897",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--d"
},
{
"entContent": {
"_uniqueProp": "005_PS1_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "005",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as an established pathogenic variant; OR\nsplice variants at same nucleotide and with similar impact prediction as previously reported pathogenic variant.\n* Established variant must meet criteria for pathogenicity by the HL specifications\n * Can also use PS1 for splice variants located in the splice consensus sequence, at the same nucleotide position as a previously reported pathogenic variant\n * Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T\n* No additional hearing loss specifications for missense variants. Follow recommendations as outlined in Richard 2015 and/or the Sequence Variant Interpretation working group within ClinGen.\n\n* Caveat (from ACMG/AMP guidelines): Assess the possibility that the variant may act directly through the DNA change (e.g. through splicing disruption as assessed by at least computational analysis) instead of through the amino acid change)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0046",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638891",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638891",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Api--r"
},
{
"entContent": {
"_uniqueProp": "005_PM5_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM5",
"ns": "005",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0056",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at same codon as two different pathogenic missense variants.\n* Located at an amino acid residue with known pathogenic variation (at least 2 other variants at the same site meet pathogenic criteria for based on independent data)\n* Caveat: Assess whether the variants in question could have an impact at the DNA level, such as through splicing impacts.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at same codon as another pathogenic missense variant.\nNo changes. Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0048",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638887",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638887",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--b"
},
{
"entContent": {
"_uniqueProp": "005_BS2_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "005",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observation of variant (biallelic with known pathogenic variant for recessive) in controls inconsistent with disease penetrance.\n* Advise caution when using this rule, since most of hearing loss is autosomal recessive, and autosomal dominant hearing loss could display reduced penetrance or variable expression.\n* However, if biallelic observations in controls are inconsistent with disease penetrance, this may be applicable.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
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"rev": "_inf5Ale--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Conflicting Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642231",
"ldhIri": "https://cspec.genome.network/cspec/Assertion/id/135642231",
"modified": null,
"rev": "_inf5Ale--_"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Benign",
"sepioId": "LN:LA6675-8"
},
"entType": "Assertion",
"ldhId": "135642236",
"ldhIri": "https://cspec.genome.network/cspec/Assertion/id/135642236",
"modified": null,
"rev": "_inf5Alm--A"
}
],
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "006_PP5_nuclear_PAH",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PAH"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "006",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432905",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638432905",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Ata--2"
},
{
"entContent": {
"_uniqueProp": "006_PM2_nuclear_PAH",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Population Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "006",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Threshold \\<0.0002 (0.02%)\n\nThe 0.0002 cutoff is based on disease frequency of 1:12,000 and the most common PAH pathogenic variant, R408W, the ExAC frequency is 0.0006594 (ExAC MAF: 0.001109 74/66718 European Non-Finnish) and gnomAD overall: 0.0009056 (gnomAD MAF: 0.001728 219/126,700 European Non-Finnish).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638988",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638988",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Ati-_F"
},
{
"entContent": {
"_uniqueProp": "006_PP2_nuclear_PAH",
"additionalComments": "",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Functional Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "006",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638983",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638983",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Atq--Y"
},
{
"entContent": {
"_uniqueProp": "006_PP1_nuclear_PAH",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Segregation Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "006",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* 3 affected segregations + 0 unaffected segregations OR\n* 2 affected segregations + 3 unaffected segregations",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* 2 affected segregations + 0 unaffected segregations",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* 1 affected family member + 3 unaffected segregations",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638978",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638978",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Ati-_D"
},
{
"entContent": {
"_uniqueProp": "006_BP1_nuclear_PAH",
"additionalComments": "",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "006",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638969",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638969",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Ati--W"
},
{
"entContent": {
"_uniqueProp": "006_BS3_nuclear_PAH",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Functional Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "006",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In vitro enzyme activity >85% compared to wild type\n\n* Expression systems: placing the mutant (and wildtype) cDNA into plasmid vectors and introducing these into host cells. Transiently transfected human or other mammalian host cells are the closest available approximation to the in vivo situation (e.g., COS cells) (Trunzo, et al. Gene. 2016. 594:138-143).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638967",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638967",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Ata--5"
},
{
"entContent": {
"_uniqueProp": "006_BS1_nuclear_PAH",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Population Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "006",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency ≥0.002 (0.2%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638963",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638963",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Atm--X"
},
{
"entContent": {
"_uniqueProp": "006_PVS1_nuclear_PAH",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PVS1",
"ns": "006",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Applicable as described in Tayoun et al. 2018.\n\n* Any nonsense or frameshift variant occurring upstream of c.1285\n* Any canonical splice site predicted to disrupt reading frame and undergo nonsense mediated decay\n\nPVS1 (RNA): splicing assay data - assays demonstrating a variant leads to aberrant splicing profile that can be categorized against a PVS1 decision tree\n\n* Use the PVS1 decision tree to determine code strength\n* Applicable as described in Walker et al. (PMID: 36865205)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use PVS1\\_strong with:\n\n* Any nonsense or frameshift variant occurring downstream of c.1285\n* Any canonical splice site predicted to preserve reading frame (skipping of exons 1, 9, 10) or affect the last exon (exon 13)\n* Initiator codon variant",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638980",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638980",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Ati--N"
},
{
"entContent": {
"_uniqueProp": "006_PS4_nuclear_PAH",
"additionalComments": "This criterion is not applicable for PAH. For proband counting, use PM3 criterion.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Population Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "006",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0053",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0057",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0032",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638979",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638979",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Atq--b"
},
{
"entContent": {
"_uniqueProp": "006_PS3_nuclear_PAH",
"additionalComments": "Functional studies with sufficient analyses to calculate OddsPath reaching strong have not been identified. Therefore, the strength of this criteria is modified to PS3_moderate or PS3_supporting for future or existing studies.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Functional Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "006",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Functional studies with sufficient analyses to calculate OddsPath reaching strong have not been identified. Therefore, the strength of this criteria is modified to PS3\\_moderate or PS3\\_supporting for future or existing studies.\n\nIn vitro enzyme activity \\<50% compared to wild type controls.\n\n* Expression systems placing the mutant (and wild-type) cDNAs into plasmid vectors and introducing these into human or other mammalian host cells, which is the closest available approximation to the in vivo situation (e.g., COS cells) (Trunzo et al. Gene. 2016. 594:138-143. PMID: 27620137).\n* With ≥11 benign/pathogenic variant controls used in assay\n* NOTE: no papers that meet PS3\\_Moderate criteria have been identified by the PAH VCEP at time of this specification update. However, there may be future studies that meet the above criteria where a moderate level of evidence can be applied.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "In vitro enzyme activity ≤50% compared to wild type controls\n\n* with ≤10 benign/pathogenic variant controls used in assay",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638976",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638976",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Ati--U"
},
{
"entContent": {
"_uniqueProp": "006_PS2_nuclear_PAH",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "De novo Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "006",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0016",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. Only applicable when proband has a known pathogenic variant in trans with the de novo variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638974",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638974",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Atm--V"
},
{
"entContent": {
"_uniqueProp": "006_BP2_nuclear_PAH",
"additionalComments": "",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Allelic Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "006",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0084",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638973",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638973",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Atm--W"
},
{
"entContent": {
"_uniqueProp": "006_BP6_nuclear_PAH",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PAH"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "006",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432904",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638432904",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Atm--Z"
},
{
"entContent": {
"_uniqueProp": "006_PM1_nuclear_PAH",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Functional Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "006",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Active site residues in PAH include: Tyr138, Arg158, Val245, Tyr268, Thr278, Pro279, Glu289, Ala300, Asp315, Phe331, Ala345, Gly346, Ser349, Tyr377\n* Substrate binding residues in PAH are: 46-48, 63-69\n* Cofactor binding residues in PAH are: His285, His290, Glu330, 246-266, 280-283, 322-326, 377-379\n* Do not apply if PP3\\_Strong applies",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638987",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638987",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Ati--Q"
},
{
"entContent": {
"_uniqueProp": "006_PP3_nuclear_PAH",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"instructionsToUse": "Per SVI recommendations (PMID: 36865205), PP3 should not be used for variants with experimental evidence of altered splicing; for variants without experimental evidence of altered splicing, PP3 can be used for variants that have a SpliceAI delta score of ≥0.2.",
"label": "PP3",
"ns": "006",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* Applicable as described in Pejaver et al (PMID: 36413997): REVEL score ≥0.932 for missense variants\n* PP3 + PM1 should not exceed Strong",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable as described in Pejaver et al (PMID: 36413997): REVEL score 0.773 - 0.932 for missense variants",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Applicable as described in Pejaver et al. (PMID: 36413997):\n\n* REVEL score of 0.644 - 0.733 for missense variants\n* In frame deletion or insertion predicted deleterious by 2 out of 3 tools (PROVEAN, MutationTaster, MutPred-InDel)\n* Predicted impact on splicing by SpliceAI (score >0.5)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638984",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638984",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Atm--a"
},
{
"entContent": {
"_uniqueProp": "006_BA1_nuclear_PAH",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Population Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "006",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "An allele frequency ≥0.015 (1.5%), which is calculated with genetic heterogeneity of 90% to account for defects of BH4 metabolism, and penetrance of 80% to account for individuals who come to attention after becoming clinically symptomatic.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638982",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638982",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Ati--S"
},
{
"entContent": {
"_uniqueProp": "006_BP3_nuclear_PAH",
"additionalComments": "",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "006",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638975",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638975",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Atq--a"
},
{
"entContent": {
"_uniqueProp": "006_PM4_nuclear_PAH",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "006",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable as described",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638966",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638966",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Ati--P"
},
{
"entContent": {
"_uniqueProp": "006_PS1_nuclear_PAH",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "006",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same predicted splicing impact as a previously classified (likely) pathogenic variant\n\nApplicable as described in Walker et al. (PMID: 36865205)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638972",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638972",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Ati-_B"
},
{
"entContent": {
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"additionalComments": "",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
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],
"evidenceCategory": "De novo Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "006",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638971",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638971",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Ati-_C"
},
{
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
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"defaultStrength": "Benign Strong",
"disease": [
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],
"evidenceCategory": "Segregation Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BS4",
"ns": "006",
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"sepioID": "SEPIO-CG:99042",
"specificationType": [],
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"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0071",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applicable as described",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638970",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638970",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Ati-_E"
},
{
"entContent": {
"_uniqueProp": "006_PM5_nuclear_PAH",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009861"
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PM5",
"ns": "006",
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"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable as described.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Applicable when the different missense change is likely pathogenic.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638968",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638968",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Ati--X"
},
{
"entContent": {
"_uniqueProp": "006_BS2_nuclear_PAH",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Population Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "006",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Only to be used when variant is observed in the homozygous state in a healthy adult.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638965",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638965",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Ata--8"
},
{
"entContent": {
"_uniqueProp": "006_PP4_nuclear_PAH",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
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],
"evidenceCategory": "Other Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PP4",
"ns": "006",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Plasma phenylalanine concentration persistently above 120 µmol/L (2mg/dL), and either normal urine pterins and normal DHPR activity, or sequencing of genes in the BH4 cofactor metabolism pathway to exclude a defect of BH4 cofactor metabolism.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "A plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) without analysis of urine pterins, DHPR activity, or sequencing to exclude defects of BH4 cofactor metabolism.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638986",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638986",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Atm--Y"
},
{
"entContent": {
"_uniqueProp": "006_BP7_nuclear_PAH",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "006",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applicable as described by Walker et al. (PMID: 36865205).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Per SVI recommendations (PMID: 36865205), use BP7 only if BP4 is met; for variants with experimental evidence supporting that they do not alter splicing, use BP7\\_strong (RNA)\n\n* intronic variants must be outside +7/-21 nt\n* exonic variants must be outside first and last 3 bases of exon",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638985",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638985",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Ata--0"
},
{
"entContent": {
"_uniqueProp": "006_BP5_nuclear_PAH",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Other Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "006",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Applicable as described",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638981",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638981",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Ati--Z"
},
{
"entContent": {
"_uniqueProp": "006_BP4_nuclear_PAH",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"instructionsToUse": "BP4\\_very strong: applicable as described in Pejaver et al.",
"label": "BP4",
"ns": "006",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applicable as described in Pejaver et al.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Applicable as described in Pejaver et al.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Applicable as described in Pejaver et al.\n\n* REVEL score of 0.183 - 0.290 for missense variants\n* In frame deletion or insertion predicted benign by PROVEAN, MutationTaster, and MutPred-InDel\n* No predicted impact on splicing by SpliceAI (score \\<0.1)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638977",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638977",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
"rev": "_inf5Atq--Z"
},
{
"entContent": {
"_uniqueProp": "006_PM3_nuclear_PAH",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Allelic Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "006",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Applicable as described in SVI recommendations for in trans criterion",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applicable as described in SVI recommendations for in trans criterion",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable as described in SVI recommendations for in trans criterion",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Applicable as described in SVI recommendations for in trans criterion",
"type": "EvidenceLineStrength"
}
]
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"inference": "Likely Benign",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
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],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule19"
}
]
}
},
"entType": "RuleSet",
"ldhId": "135640693",
"ldhIri": "https://cspec.genome.network/cspec/RuleSet/id/135640693",
"modified": "2024-07-16T15:03:45.519Z",
"modifier": "mweaver",
"rev": "_inf5BHe--e"
}
]
},
"ldFor": {
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{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
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"approved": true
},
"step4": {
"approvalDate": "2018-04-27T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Phenylketonuria",
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"title": "Phenylketonuria Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50015",
"entIri": "http://clinicalgenome.org/affiliation/50015",
"entType": "Organization",
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"ldhIri": "https://cspec.genome.network/cspec/Organization/id/135637639",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
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],
"SequenceVariantInterpretation": [
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"entContent": {
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"notes": "",
"references": [
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"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
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},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
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"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_inf5BXe---"
}
]
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"ldhIri": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/135637578",
"modified": "2025-04-01T17:55:57.548Z",
"modifier": "sharriso",
"rev": "_jdH83dW---"
},
{
"entContent": {
"approvedOn": "2022-03-29T00:00:00.000Z",
"description": "This version specified for the following genes: CDH1",
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"shortTitle": "CDH1 Specification",
"specificationSource": "https://www.clinicalgenome.org/site/assets/files/7580/clingen_cdh1_acmg_specifications_v3_1.pdf",
"states": [
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"current": true,
"event": {
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},
"name": "Released"
}
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"tagNameSpaces": [
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"title": "ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1",
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},
"entId": "GN007",
"entType": "SequenceVariantInterpretation",
"ld": {
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"entContent": {
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"sepioId": "LN:LA26334-5"
},
"entType": "Assertion",
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"ldhIri": "https://cspec.genome.network/cspec/Assertion/id/135642232",
"modified": null,
"rev": "_inf5Ale---"
},
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"entContent": {
"curationActivity": "Variant Pathogenicity",
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"sepioId": "LN:LA6675-8"
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"ldhIri": "https://cspec.genome.network/cspec/Assertion/id/135642236",
"modified": null,
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},
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"entContent": {
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"modified": null,
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},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
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},
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"ldhIri": "https://cspec.genome.network/cspec/Assertion/id/135642231",
"modified": null,
"rev": "_inf5Ale--_"
},
{
"entContent": {
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"sepioId": "LN:LA26333-7"
},
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"ldhIri": "https://cspec.genome.network/cspec/Assertion/id/135642235",
"modified": null,
"rev": "_inf5Ale--_"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance",
"sepioId": "LN:LA26333-7"
},
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"ldhIri": "https://cspec.genome.network/cspec/Assertion/id/135642234",
"modified": null,
"rev": "_inf5Ale--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Pathogenic",
"sepioId": "LN:LA6668-3"
},
"entType": "Assertion",
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"ldhIri": "https://cspec.genome.network/cspec/Assertion/id/135642233",
"modified": null,
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],
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{
"entContent": {
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"additionalComments": null,
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "Note the CDH1 rule specification does not require a conservation prediction. We allow use of BP7 with BP4, as appropriate, to classify variants meeting both criteria as likely benign.",
"label": "BP7",
"ns": "007",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Synonymous and intronic variants at or beyond +7 to -21 locations.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639066",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639066",
"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--a"
},
{
"entContent": {
"_uniqueProp": "007_PP3_nuclear_CDH1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "PP3 cannot be applied for canonical splice sites. PP3 code also does not apply to the last nucleotide of exon 3 (c.387G). Do not use protein-based computational prediction models for missense variants.",
"label": "PP3",
"ns": "007",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variants affecting the same splice site as a well-characterized variant with similar or worse in silico/ RNA predictions.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "At least three in silico splicing predictors in agreement (SpliceAI, MaxEntScan, SSF, GeneSplicer, HSF, TraP, varSEAK).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639065",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639065",
"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apa--S"
},
{
"entContent": {
"_uniqueProp": "007_PVS1_nuclear_CDH1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "RNA analysis is recommended for splicing alterations, and if the RNA evidence does not support the prediction, the strength should be updated.",
"label": "PVS1",
"ns": "007",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Per modified CDH1 PVS1 decision tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0020",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Per modified CDH1 PVS1 decision tree.\nOther CDH1 caveats:\n * Use PVS1_Strong as the default strength of evidence for canonical splice site variants and follow the site-specific recommendations in the splicing table. \n * CDH1 Exonic deletions or tandem duplications of in-frame exons (exon 4,5,8,9,12,13,15).\n",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0026",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Per modified CDH1 PVS1 decision tree.\nOther CDH1 caveats:\n * G to non-G variants disrupting the last nucleotide of an exon.\n * Canonical splice sites predicted or demonstrated experimentally to result in in-frame partial skipping/insertion (e.g., Exon 3 donor site).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639061",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639061",
"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--e"
},
{
"entContent": {
"_uniqueProp": "007_PP1_nuclear_CDH1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "Based strength of rule code on number of meioses across one or more families.",
"label": "PP1",
"ns": "007",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0023",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥Seven informative meioses across ≥2 families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0040",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Five-six informative meioses across ≥1 family.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Three-four informative meioses across ≥1 family.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639059",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639059",
"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--K"
},
{
"entContent": {
"_uniqueProp": "007_BP3_nuclear_CDH1",
"additionalComments": "Not applicable for CDH1.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "007",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639056",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639056",
"modified": "2022-01-19T20:33:33.902Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--e"
},
{
"entContent": {
"_uniqueProp": "007_PS2_nuclear_CDH1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "Use ClinGen’s de novo point system for a highly specific phenotype (see Table S2).",
"label": "PS2",
"ns": "007",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0016",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥Two patients meet the HDGC individual phenotype criteria w/ parental confirmation.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "One patient meets the HDGC individual phenotype criteria w/ parental confirmation.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "004",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0043",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639055",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639055",
"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--J"
},
{
"entContent": {
"_uniqueProp": "007_PM5_nuclear_CDH1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "The nonsense or frameshift variant must not impact splicing based on RNA assay or splicing predictions.",
"label": "PM5",
"ns": "007",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "008",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0048",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "PM5_supporting is applicable to nonsense and frameshift variants that are predicted/proved to undergo NMD or located upstream of the last known pathogenic truncating variant. Site-specific recommendations for the application of PM5_Supporting for canonical splicing variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639049",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639049",
"modified": "2022-05-13T22:06:58.681Z",
"modifier": "neethus",
"rev": "_inf5Ap6--Q"
},
{
"entContent": {
"_uniqueProp": "007_PM4_nuclear_CDH1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "PM4 is not applied to small in-frame indels because the impact of amino acid level changes of CDH1 variants is inconclusive.",
"label": "PM4",
"ns": "007",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Only apply to stop-loss variants\nVariant example: CDH1 c.2647T>C (p.Ter883Glnext*29).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639047",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639047",
"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apa--Q"
},
{
"entContent": {
"_uniqueProp": "007_BS2_nuclear_CDH1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "We allow a variant to reach a likely benign classification based on BS2 alone.\nBS2 cannot be applied to variants in which more than 30% of reported individuals meet HDGC criteria.",
"label": "BS2",
"ns": "007",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant seen in ≥10 individuals w/o GC, DGC, gSRC tumors, or LBC & whose families do not suggest HDGC.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant seen in ≥3 individuals w/o GC, DGC, SRC tumors, or LBC & whose families do not suggest HDGC.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639046",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639046",
"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--h"
},
{
"entContent": {
"_uniqueProp": "007_PM3_nuclear_CDH1",
"additionalComments": "Not applicable for CDH1.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "007",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0038",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0058",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "007",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0027",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639045",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639045",
"modified": "2022-01-19T20:33:33.902Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--U"
},
{
"entContent": {
"_uniqueProp": "007_BS1_nuclear_CDH1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "99.99% CI; subpopulation must ≥ 2,000 alleles and have a minimum of five variant alleles present. We allow a variant to reach a likely benign classification based on BS1 alone.",
"label": "BS1",
"ns": "007",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "MAF cutoff of 0.1%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639044",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639044",
"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--L"
},
{
"entContent": {
"_uniqueProp": "007_PP5_nuclear_CDH1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"CDH1"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "007",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432935",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638432935",
"modified": "2022-01-19T20:31:30.459Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--J"
},
{
"entContent": {
"_uniqueProp": "007_PM2_nuclear_CDH1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "Use gnomAD to determine allele frequency. The mean coverage of CDH1 in the population database used should be at least 30x.",
"label": "PM2",
"ns": "007",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0030",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≤ One out of 100,000 alleles in gnomAD cohort; if present in ≥2 individuals within a subpopulation, must be present in ≤ One out of 50,000 alleles.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639069",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639069",
"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apa--P"
},
{
"entContent": {
"_uniqueProp": "007_PP2_nuclear_CDH1",
"additionalComments": "Not applicable for CDH1.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "007",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639064",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639064",
"modified": "2022-01-19T20:33:33.902Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--M"
},
{
"entContent": {
"_uniqueProp": "007_BP5_nuclear_CDH1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "This applies if a P/LP variant is identified in an alternate gene known to cause HDGC (currently only CTNNA1).",
"label": "BP5",
"ns": "007",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Per original ACMG/AMP guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639062",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639062",
"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--j"
},
{
"entContent": {
"_uniqueProp": "007_PS1_nuclear_CDH1",
"additionalComments": "Not applicable for CDH1.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "007",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0050",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0046",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639053",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639053",
"modified": "2022-01-19T20:33:33.902Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--d"
},
{
"entContent": {
"_uniqueProp": "007_BS4_nuclear_CDH1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "Beware of the presence of phenocopies (e.g., breast cancer) that can mimic lack of segregation. Also, families may have more than one pathogenic variant contributing to another AD disorder.",
"label": "BS4",
"ns": "007",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Per original ACMG/AMP guidelines.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639051",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639051",
"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apa--T"
},
{
"entContent": {
"_uniqueProp": "007_BS3_nuclear_CDH1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "This rule can only be used to demonstrate lack of splicing and can only be applied to Synonymous, Intronic or Non-coding variants. BS3 may be downgraded based on quality of data.",
"label": "BS3",
"ns": "007",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
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"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Functional RNA studies demonstrating no impact on transcript composition.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0085",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639048",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639048",
"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--i"
},
{
"entContent": {
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"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"CDH1"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "007",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432934",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638432934",
"modified": "2022-01-19T20:31:30.459Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--L"
},
{
"entContent": {
"_uniqueProp": "007_PP4_nuclear_CDH1",
"additionalComments": "Not applicable for CDH1.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "007",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0018",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0063",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639067",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639067",
"modified": "2022-01-19T20:33:33.902Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--V"
},
{
"entContent": {
"_uniqueProp": "007_BA1_nuclear_CDH1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "99.99% CI; subpopulation must ≥ 2,000 alleles and have a minimum of five variant alleles present.",
"label": "BA1",
"ns": "007",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "MAF cutoff of 0.2%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639063",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639063",
"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--g"
},
{
"entContent": {
"_uniqueProp": "007_PS4_nuclear_CDH1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "Use the 2020 updated clinical practice guidelines (PMID: 32758476) as the HDGC phenotype criteria.\nPS4 cannot be applied to variants that meet BS1 or BA1, or to variants in which less than 30% of reported individuals meet HDGC criteria.",
"label": "PS4",
"ns": "007",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥Sixteen families meet HDGC criteria.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Four - Fifteen families meet HDGC criteria.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0057",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Two or three families meet HDGC criteria.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0032",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One family meets HDGC criteria.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639060",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639060",
"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--f"
},
{
"entContent": {
"_uniqueProp": "007_BP4_nuclear_CDH1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "Do not use protein based computational prediction models and BP4 is not applicable for missense variants.",
"label": "BP4",
"ns": "007",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Splicing predictions only. At least three in silico splicing predictors in agreement (SpliceAI, MaxEntScan, SSF, GeneSplicer, HSF, TraP, varSEAK).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639058",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639058",
"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--Z"
},
{
"entContent": {
"_uniqueProp": "007_PM6_nuclear_CDH1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "Use ClinGen’s de novo point system for a highly specific phenotype.",
"label": "PM6",
"ns": "007",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": ">Four patients meet the HDGC individual phenotype criteria w/o parental confirmation.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥Two patients meet the HDGC individual phenotype criteria w/o parental confirmation.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "One patient meets the HDGC individual phenotype criteria w/o parental confirmation",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639052",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639052",
"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apa--R"
},
{
"entContent": {
"_uniqueProp": "007_PM1_nuclear_CDH1",
"additionalComments": "Not applicable for CDH1.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "007",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "006",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639068",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639068",
"modified": "2022-01-19T20:33:33.902Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--W"
},
{
"entContent": {
"_uniqueProp": "007_PS3_nuclear_CDH1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "This rule can only be applied to demonstrate splicing defects.",
"label": "PS3",
"ns": "007",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "RNA assay demonstrating abnormal out-of-frame transcripts.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0039",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "RNA assay demonstrating abnormal in-frame transcript.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0045",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639057",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639057",
"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--R"
},
{
"entContent": {
"_uniqueProp": "007_BP2_nuclear_CDH1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "Evidence code is dependent on the strength of data. Take consideration of the quality of sequencing data when applying code.",
"label": "BP2",
"ns": "007",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant observed in trans w/known pathogenic variant (phase confirmed) OR observed in the homozygous state in individual w/o personal &/or family history of DGC, LBC, or SRC tumors.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant is observed in cis (or phase is unknown) w/ a pathogenic variant\nOR observed in the homozygous state in gnomAD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639054",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639054",
"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--Y"
},
{
"entContent": {
"_uniqueProp": "007_BP1_nuclear_CDH1",
"additionalComments": "Not applicable for CDH1.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "007",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0206",
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"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0063",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639148",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639148",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZhm---"
},
{
"entContent": {
"_uniqueProp": "008_PVS1_nuclear_RUNX1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": "**ClinGen Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) notes:**\n\n(1) We recommend using RUNX1 isoform c as the default transcript (NM\\_001754.4), since this is the isoform used for annotation by most clinical laboratories.\n\n(2) Three major isoforms (a, b, c) are expressed by use of two promotors and alternative splicing. Expression of the short human RUNX1a isoform has been shown to favor expansion of the hematopoietic stem cell (HSC) pool, whereas expression of the full length RUNX1b and RUNX1c isoforms function to promote hematopoietic differentiation. _RUNX1_ LOF variants are a common mechanism of disease in familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML). C-terminal truncating variants not predicted to undergo nonsense-mediated mRNA decay (NMD) are classified as **PVS1\\_strong**, deletions of exon 1-3, presumably only affecting RUNX1 isoform c, meet **PVS1\\_moderate**.\n\n(3) Most splicing effects are based on predictions. The rules can be modified in the future if new functional evidence3 becomes available. The rules can be modified in the future if RNA evidence becomes available using Walker et al., 2023, PMID: 37352859 [5](#PMID_37352859) as a guide; modification of strength should be based on the quality of the RNA study where:\n\n1. Comparison to a control is necessary\n2. Patient RNA is better than minigene assays\n3. Primers are designed to capture the possibility of multi-exonic/multi-cassette events\n4. NMD inhibitors (e.g., puromycin, proprietary molecule found in PAXgene tubes), particularly when the predicted effect is nonsense-mediated decay, are used\n5. Quantification of the effect by SNP analysis is better than PSI (percent splicing index) analysis is better than capillary electrophoresis is better than estimation by gel band density\n6. Multiple studies are better than a single study\n\n\\*Caution should be used in modifying strength when the effect of the splicing impact is incomplete (\"leaky\" splice site) or unclear\n\n_**RUNX1**_ **Specification:**\n\nPer modified _RUNX1_ **PVS1** decision tree for single-nucleotide variants (SNVs) and CNVs and table of splicing effects. Strength-modified: **PVS1, PVS1\\_Strong, PVS1\\_Moderate**\n\n**PVS1\\_Variable (RNA):** When RNA/splicing data is available for a variant, apply PVS1 at the appropriate strength level based on the predicted effect of the aberrant mRNA on protein translation as it corresponds to the PVS1\\_Variable splicing table. Strength may also be modified based on the quality of the RNA analysis (as described above). For \"leaky\" splice sites, strength level should be decreased by one if a near-complete impact is demonstrated, but no code should be applied if an incomplete impact is demonstrated. Refer to Walker et al., 2023, PMID: 37352859 [5](#PMID_37352859) for additional guidance.\n\nSNVs, Indels/Delins, Splicing Variants\n\n\\[_RUNX1_ PVS1 decision tree for SNVs\\]\n\nCNVs\n\n\\[_RUNX1_ PVS1 decision tree for CNVs\\]\n\nCanonical Splice Site Variants (see Supplemental Table) \n\n\\[Summary of splicing effects\\]",
"label": "PVS1",
"ns": "008",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 8,
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639142",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639142",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZu----"
},
{
"entContent": {
"_uniqueProp": "008_PP1_nuclear_RUNX1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. \n\n**MM-VCEP notes:**\n\n1. The MM-VCEP adopted the approach being taken by other ClinGen-EPs and supported by the SVI and other work with additional meioses supporting higher evidence levels based on calculated LOD scores of 0.9, 1.5 and 2.1, respectively, with three or four meioses for **PP1**, five or six meioses for **PP1\\_moderate** and seven or more meioses for **PP1\\_strong**. \n2. Affected individuals show at least one of the \\_RUNX1\\_-phenotypic criteria (see **PS2**).\n3. Only genotype and phenotype positive individuals and obligate carriers are counted.\n4. The MM-VCEP waived the ACMG/AMP recommendations for demonstrating co-segregation in more than one family given that many _RUNX1_ variants are unique to families and do not occur in other unrelated families.\n\n_**RUNX1**_ **Specification:**\n\n**PP1\\_Strong**: ≥ 7 meioses observed within one or across multiple families.\n\n**PP1\\_Moderate**: 5 or 6 meioses observed within one or across multiple families.\n\n**PP1**: 3 or 4 meioses observed within one or across multiple families.",
"label": "PP1",
"ns": "008",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**PP1\\_Strong**: ≥ 7 meioses observed within one or across multiple families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**PP1\\_Moderate**: 5 or 6 meioses observed within one or across multiple families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**PP1**: 3 or 4 meioses observed within one or across multiple families.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639140",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639140",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZqq---"
},
{
"entContent": {
"_uniqueProp": "008_PS2_nuclear_RUNX1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": "_De novo_ (both maternity and paternity confirmed) in a patient with the disease and no family history \n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, _etc._ can contribute to non-maternity. \n\n**MM-VCEP notes:**\n\n(1) The FPD/AML phenotype is not highly specific and there is substantial genetic heterogeneity. We thus concluded that due to the lack of a highly specific phenotype and genetic heterogeneity, the maximum allowable value is 1 point contributing to the overall score.\n\n(2) The phenotype of a deleterious _RUNX1_ mutation encompasses at least one of the following three criteria:\n\n1. **Mild to moderate** **thrombocytopenia** **with normal platelet size and volume in the absence of other causative factors** such as autoimmune (e.g. antibodies against platelet surface antigens) or drug-related thrombocytopenia. \n2. **Platelet ultrastructural and/or functional defects** including platelet alpha or dense granule secretion defects or impaired platelet aggregation - particularly in response to collagen and epinephrine.\n3. Diagnosis of a **hematologic malignancy, most commonly affecting the myeloid lineage causing acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)**, less frequently involving the lymphoid lineage manifesting as T-acute lymphoblastic leukemia (T-ALL). There are rare case-reports of patients with germline _RUNX1_ mutations and mixed myeloproliferative syndromes/MDS such as chronic myelomonocytic leukemia, as well as case-reports of patients with B-ALL, and hairy-cell leukemia.\n\n(3) No family history is defined as the absence of the variant and any of the \\_RUNX1\\_-phenotypic criteria in first and second-degree relatives.\n\n(4) The maximum allowable strength by combining **PS2** and **PM6** is to apply one moderate or two supporting rules (the maximum allowable value is still 1 point).\n\n_**RUNX1**_ **Specification:**\n\nFollowing the ClinGen Sequence Variant Interpretation (SVI) Working Group guidance, _de novo_ _RUNX1_ variants will be scored at the third tier of the point-based system (“Phenotype consistent with gene but not highly specific and high genetic heterogeneity”) with maximum allowable value of 1 point contributing to overall score:\n\n**PS2\\_Moderate:** ≥ 2 proven _de novo_ occurrences (both maternity and paternity confirmed) in patients with FPD/AML phenotype.\n\n**PS2\\_Supporting**: 1 proven _de novo_ occurrence (both maternity and paternity confirmed) in a patient with FPD/AML phenotype.",
"label": "PS2",
"ns": "008",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 8,
"id": "0016",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0051",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**PS2\\_Moderate:** ≥ 2 proven _de novo_ occurrences (both maternity and paternity confirmed) in patients with FPD/AML phenotype.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**PS2\\_Supporting**: 1 proven _de novo_ occurrence (both maternity and paternity confirmed) in a patient with FPD/AML phenotype.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639136",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639136",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZe2---"
},
{
"entContent": {
"_uniqueProp": "008_BP2_nuclear_RUNX1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": "**MM-VCEP notes:**\n\n**BP2** is applicable per the original ACMG/AMP guidelines. _In vivo_, mice lacking Runx1 die during mid-embryonic development. Biallelic pathogenic variants in _RUNX1_ have never been reported in FPD/AML patients. A variant _in trans_ with a known pathogenic variant or observation of the variant in the homozygous state in individuals without FPD/AML phenotype can be considered supporting benign evidence.",
"label": "BP2",
"ns": "008",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -4,
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639135",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639135",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZvK---"
},
{
"entContent": {
"_uniqueProp": "008_PP5_nuclear_RUNX1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "008",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432965",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638432965",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZvq---"
},
{
"entContent": {
"_uniqueProp": "008_PM2_nuclear_RUNX1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": "**MM-VCEP notes:**\n\n1. New gnomAD MAF threshold for PM2\\_supporting ≤ 0.00005 to account for larger population in gnomAD v4.The mean coverage of _RUNX1_ in the population database used should be at least 20x.\n\n_**RUNX1**_ **Specification:**\n\n**PM2\\_Supporting:** Minor allele frequency ≤ 0.00005 with at least 2000 alleles tested around and 20x coverage at the position.\n\nCaveat: \n\n\\*We recommend evaluating PM2\\_supporting using the GrpMax FAF when it is available in gnomAD v4.1.0. If a GrpMax FAF value is not available, we recommend requiring that all subpopulations meet the PM2\\_supporting threshold.",
"label": "PM2",
"ns": "008",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**PM2\\_Supporting:** Minor allele frequency ≤ 0.00005 with at least 2000 alleles tested around and 20x coverage at the position.\n\nCaveat: \n\n\\*We recommend evaluating PM2\\_supporting using the GrpMax FAF when it is available in gnomAD v4.1.0. If a GrpMax FAF value is not available, we recommend requiring that all subpopulations meet the PM2\\_supporting threshold.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639150",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639150",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZd6---"
},
{
"entContent": {
"_uniqueProp": "008_BS3_nuclear_RUNX1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": "**MM-VCEP notes:**\n\n1. **Transactivation assays** demonstrating altered transactivation compared to wt are often performed as functional studies to evaluate the pathogenicity of a _RUNX1_ variant. Promoter sequences of _M-CSFR_, _PF4_, _C-FMS_ and _GZMB_, containing consensus _RUNX1_ binding sites TGTGGT, have been used for this purpose. The transactivation assay must include wt and known pathogenic controls, as well as co-expression with CBFâ.\n2. Data from **secondary assays** are frequently used to evaluate an altered function of mutant RUNX1. Electrophoretic mobility shift assays and yeast hybrid assays are performed to demonstrate decreased DNA binding affinity, and co-immunoprecipitation assays, fluorescence resonance energy transfer assays and affinity assays can demonstrate diminished heterodimerization ability of mutant RUNX1 with CBFâ. Abnormal cellular localization of mutant RUNX1 can be shown by immunofluorescence and cell-fractionation with Western Blot. Sorted primary hematopoietic stem and progenitor cells can be used for demonstration of reduced colony-forming potential and xenotransplantation experiments may reveal abnormal function of mutant RUNX1 _in vivo._\n\n_**RUNX1**_ **Specification:**\n\n**BS3:** Transactivation assays demonstrating normal transactivation (80-115% of wt) AND data from a secondary assay demonstrating normal function. \n\n**BS3\\_Supporting:** Transactivation assays demonstrating normal transactivation (80-115% of wt).",
"label": "BS3",
"ns": "008",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "**BS3:** Transactivation assays demonstrating normal transactivation (80-115% of wt) AND data from a secondary assay demonstrating normal function.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "**BS3\\_Supporting:** Transactivation assays demonstrating normal transactivation (80-115% of wt).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639129",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639129",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZhC---"
},
{
"entContent": {
"_uniqueProp": "008_PM4_nuclear_RUNX1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n\n**MM-VCEP notes:**\n\n1. The RHD has been established as highly conserved DNA binding domain without any benign variation in ClinVar. Thirteen somatic and/or germline mutational hotspots within the RHD have been identified: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204. \n2. Variants in other parts of the RHD (AA 89-204) have been described as likely pathogenic/pathogenic before. There was additional evidence of germline pathogenic/likely pathogenic _RUNX2_ variants affecting AA 89 and 94 (PMID 17290219)[6](#PMID_17290219), a gene with a Runt Homology Domain that has 90% sequence homology with _RUNX1_. AA 89 is also still part of the b-sheet of the CBF heterodimerization domain, which is functionally important. Thus, we prompt to establish PM4\\_supporting with reduced strength-level for these variants.\n3. No reported germline _RUNX1_ mutations in AA residues 77-88 of the RHD to date. If there is more evidence available, this region may be expanded in the future to other parts of the RHD or the protein.\n\n_**RUNX1**_ **Specification:**\n\n**For in-frame/indel variants:**\n\n**PM4\\_strong:** In-frame deletion/insertion impacting at least one of the following AA residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204.\n\n**PM4\\_Supporting:**\n\nIn-frame deletion/insertion impacting at least one of the other AA residues 89-204 within the RHD.\n\n**For stop loss variants:**\n\n**PM4:** Stop-loss variant causing a protein extension.",
"label": "PM4",
"ns": "008",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**For in-frame/indel variants:**\n\n**PM4\\_strong:** In-frame deletion/insertion impacting at least one of the following AA residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204.\n\n**For stop loss variants:**\n\n**PM4:** Stop-loss variant causing a protein extension.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "In-frame deletion/insertion impacting at least one of the following amino acid residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**PM4\\_Supporting:**\n\nIn-frame deletion/insertion impacting at least one of the other AA residues 89-204 within the RHD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639128",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639128",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZuW---"
},
{
"entContent": {
"_uniqueProp": "008_BP4_nuclear_RUNX1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": "**MM-VCEP notes:**\n\n1. For _in-silico_ evaluation of missense variants, the MM-VCEP recommends using REVEL, a meta-predictor combining 13 individual tools with high sensitivity and specificity and that has recently demonstrated highest performance compared to any individual tool or other ensemble methods.\n2. The threshold of REVEL is based on the evaluation of 25 germline PATH/LPATH and 25 BEN/LBEN missense variants in _RUNX1_. With the comparison of 11 different ensemble in-silico predictors (BayesDel AF, CADD, Condel, DANN, Eigen, FATHMM-MKL, MetaLR, MetaSVM, REVEL, UMD predictor, VEST) and their respective AUC, REVEL was found to be among the highest performing tools (AUC=1) and the new threshold for PP3 and BP4 was based on the REVEL scores at 90% sensitivity and 90% specificity, respectively.\n3. We compared the performance of the new splice predictor SpliceAI and MES, which has been shown to be the highest performing tool pre-SpliceAI by using a test set of 202 variants in genes associated with inherited hematologic malignancies/AA/BMF or cytopenia. The thresholds for PP3 and BP4 were established based on the SpliceAI score at 90% sensitivity (PP3, ≥ 0.38) and 90% specificity (BP4, ≤ 0.20).\n\n_**RUNX1**_ **Specification:**\n\n**For missense variants:**\n\n**BP4:** REVEL score \\< 0.50 AND SpliceAI ≤ 0.20\n\n**For synonymous and Intronic variants:**\n\n**BP4:** SpliceAI ≤ 0.20",
"label": "BP4",
"ns": "008",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -4,
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "**For missense variants:**\n\n**BP4:** REVEL score \\< 0.50 AND SpliceAI ≤ 0.20\n\n**For synonymous and Intronic variants:**\n\n**BP4:** SpliceAI ≤ 0.20",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639139",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639139",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZgC---"
},
{
"entContent": {
"_uniqueProp": "008_BP3_nuclear_RUNX1",
"additionalComments": "MM-VCEP notes: \n\nRUNX1 does not contain a repetitive region without known function. BP3 is therefore deemed not applicable. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "008",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639137",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639137",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZxm---"
},
{
"entContent": {
"_uniqueProp": "008_PS1_nuclear_RUNX1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": "**MM-VCEP Notes:**\n\n(1) The previously established pathogenic variant must be reviewed by the MM-VCEP and asserted pathogenic/likely pathogenic before this rule can be applied.\n\n(2) For missense variants, RNA data or agreement in splicing predictor show no impact on splicing.\n\n(3) For splice site variants, do not apply this code except for variants in the canonical donor/acceptor (“dinucleotide”) sites, the U2 donor motif (last 3 bases of the exon and 6 nucleotides of the intron), or the U2 acceptor motif (20 nucleotides of the intron and 1st base of the exon). Splicing predictions for the variant being evaluated and the known pathogenic/likely pathogenic (as assessed by VCEP rules) should match before consideration of the criterion, with at least similar scores. Do not apply for +2G>C variants.\n\n_**RUNX1**_ **Specification:**\n\n**For missense variants:**\n\n**PS1:** Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\n\n**PS1\\_Moderate:** Same amino acid change as a previously established likely pathogenic variant regardless of nucleotide change.\n\n**For splice site variants:** \n\n**PS1\\_Variable:** Follow recommendations from the ClinGen SVI Splicing Subgroup (Walker et al., 2023, PMID: 37352859 [5](#PMID_37352859))\n\n\\[PS1 splicing application\\]",
"label": "PS1",
"ns": "008",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**PS1:** Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\n\n**For splice site variants:** \n\n**PS1\\_Variable:** Follow recommendations from the ClinGen SVI Splicing Subgroup (Walker et al., 2023, PMID: 37352859 [5](#PMID_37352859))",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**PS1\\_Moderate:** Same amino acid change as a previously established likely pathogenic variant regardless of nucleotide change.\n\n**For splice site variants:** \n\n**PS1\\_Variable:** Follow recommendations from the ClinGen SVI Splicing Subgroup (Walker et al., 2023, PMID: 37352859 [5](#PMID_37352859))",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639134",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639134",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZju---"
},
{
"entContent": {
"_uniqueProp": "008_PM6_nuclear_RUNX1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": "**MM-VCEP notes:**\n\n(1) FPD/AML phenotype is not highly specific and there is substantial genetic heterogeneity. We thus concluded that due to the lack of a highly specific phenotype and genetic heterogeneity, the maximum allowable value is 1 point contributing to the overall score.\n\n(2) The phenotype of a deleterious RUNX1 mutation encompasses at least one of the three phenotypic criteria (see PS2).\n\n(3) No family history is defined as the absence of the variant and any of the RUNX1-phenotypic criteria in first and second-degree relatives.\n\n(4) The maximum allowable strength by combining PS2 and PM6 is to apply one moderate or two supporting rules (the maximum allowable value is still 1 point).\n\n_**RUNX1**_ **Specification:**\n\nFollowing the SVI guidance, assumed _de novo_ _RUNX1_ variants will be scored at the third tier of the point-based system with maximum allowable value of 1 point contributing to overall score:\n\n**PM6**: ≥ 4 assumed _de novo_ occurrences (without confirmation of maternity and paternity) in patients with FPD/AML phenotype.\n\n**PM6\\_Supporting**: 2 or 3 assumed _de novo_ occurrences (without confirmation of maternity and paternity) in patients with FPD/AML phenotype.",
"label": "PM6",
"ns": "008",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 8,
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "_**RUNX1**_ **Specification:**\n\nFollowing the SVI guidance, assumed _de novo_ _RUNX1_ variants will be scored at the third tier of the point-based system with maximum allowable value of 1 point contributing to overall score:\n\n**PM6**: ≥ 4 assumed _de novo_ occurrences (without confirmation of maternity and paternity) in patients with FPD/AML phenotype.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "_**RUNX1**_ **Specification:**\n\nFollowing the SVI guidance, assumed _de novo_ _RUNX1_ variants will be scored at the third tier of the point-based system with maximum allowable value of 1 point contributing to overall score:\n\n**PM6\\_Supporting**: 2 or 3 assumed _de novo_ occurrences (without confirmation of maternity and paternity) in patients with FPD/AML phenotype.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639133",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639133",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZxC---"
},
{
"entContent": {
"_uniqueProp": "008_PM5_nuclear_RUNX1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. \n\n**MM-VCEP notes:**\n\n1. RNA data or SpliceAI ≤ 0.20\n2. The previously established pathogenic variant must be reviewed by the MM-VCEP and asserted pathogenic/likely pathogenic before this rule can be applied.\n3. For missense variants, the Grantham score of the alternate residue of the new variant should be equal or higher to that of the alternate residue of the known pathogenic/likely pathogenic variant. \\[Grantham score table\\]\n\n \n\n(Grantham, 1974, PMID: 4843792[7](#PMID_4843792))\n\n4\\. There are at least two nonsense/frameshift variants that were curated as pathogenic in each exon (exons 3-7) without applying PM5\\_Supporting.\n\n_**RUNX1**_ **Specification:**\n\n**PM5\\_Strong:** Missense change at an AA residue where ≥ 2 different missense changes which have been determined to be pathogenic before (after accounting for Grantham scores).\n\n**PM5:** Missense change at an AA residue where a different missense change which has been determined to be pathogenic before (after accounting for Grantham scores).\n\n**PM5\\_Supporting**: Missense change at an AA residue where a different missense change which has been determined to be likely pathogenic before (after accounting for Grantham scores).\n\n**PM5\\_Supporting** is also applied to nonsense/frameshift variants that are downstream of c.98 (in transcript NM\\_001754.4). \n\nCaveats:\n\n\\*Of note, the variant must not impact splicing based on RNA assay or SpliceAI ≤ 0.20.\n\n\\*The nonsense/frameshift variants before c.98 only affect one of the _RUNX1_ functional transcript. PVS1 is also not appliable in this region based on the _RUNX1_ PVS1 decision tree.\n\n\\*PM5 cannot be used if PM1 was applied at any strength level.",
"label": "PM5",
"ns": "008",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**PM5\\_Strong:** Missense change at an AA residue where ≥ 2 different missense changes which have been determined to be pathogenic before (after accounting for Grantham scores).\n\nCaveats:\n\n\\*Of note, the variant must not impact splicing based on RNA assay or SpliceAI ≤ 0.20.\n\n\\*The nonsense/frameshift variants before c.98 only affect one of the _RUNX1_ functional transcript. PVS1 is also not appliable in this region based on the _RUNX1_ PVS1 decision tree.\n\n\\*PM5 cannot be used if PM1 was applied at any strength level.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**PM5:** Missense change at an AA residue where a different missense change which has been determined to be pathogenic before (after accounting for Grantham scores).\n\nCaveats:\n\n\\*Of note, the variant must not impact splicing based on RNA assay or SpliceAI ≤ 0.20.\n\n\\*The nonsense/frameshift variants before c.98 only affect one of the _RUNX1_ functional transcript. PVS1 is also not appliable in this region based on the _RUNX1_ PVS1 decision tree.\n\n\\*PM5 cannot be used if PM1 was applied at any strength level.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**PM5\\_Supporting**: Missense change at an AA residue where a different missense change which has been determined to be likely pathogenic before (after accounting for Grantham scores).\n\n**PM5\\_Supporting** is also applied to nonsense/frameshift variants that are downstream of c.98 (in transcript NM\\_001754.4).\n\nCaveats:\n\n\\*Of note, the variant must not impact splicing based on RNA assay or SpliceAI ≤ 0.20.\n\n\\*The nonsense/frameshift variants before c.98 only affect one of the _RUNX1_ functional transcript. PVS1 is also not appliable in this region based on the _RUNX1_ PVS1 decision tree.\n\n\\*PM5 cannot be used if PM1 was applied at any strength level.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639130",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639130",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZsW---"
},
{
"entContent": {
"_uniqueProp": "008_BP6_nuclear_RUNX1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "008",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432964",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638432964",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZpa---"
},
{
"entContent": {
"_uniqueProp": "008_BP7_nuclear_RUNX1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": "**MM-VCEP notes:**\n\n1. Conservation is no longer a requirement for BP7 based on its limited predicted power and recommendations from the ClinGen SVI Splicing Subgroup (Cheung et al., 2019, 30503770; Walker et al., 2023, PMID: 37352859[9](#PMID_37352859)). \n2. Splicing effects are currently based solely on predictions. The rules can be modified in the future if RNA evidence becomes available using Walker et al., 2023, PMID: 37352859[9](#PMID_37352859) as a guide; modification of strength should be based on the quality of the RNA study where:\n 1. Comparison to a control is necessary\n 2. Patient RNA is better than minigene assays\n 3. Primers are designed to capture the possibility of multi-exonic/multi-cassette events\n 4. NMD inhibitors (e.g., puromycin, proprietary molecule found in PAXgene tubes), particularly when the predicted effect is nonsense-mediated decay, are used\n 5. Quantification of the effect by SNP analysis is better than PSI (percent splicing index) analysis is better than capillary electrophoresis is better than estimation by gel band density\n 6. Multiple studies are better than a single study\n\n\\* Caution should be used in modifying strength when the effect of the splicing impact is incomplete (\"leaky\" splice site) or unclear.\n\n_**RUNX1**_ **Specification:**\n\n**BP7:** Applicable for\n\n* Synonymous variants – excluding those in the last 3 nucleotides preceding a canonical donor splice site or the first nucleotide following a canonical acceptor splice site – with SpliceAI ∆ scores ≤ 0.20.\n* Intronic variants with SpliceAI ∆ scores ≤ 0.20.\n\n**BP7\\_Variable (RNA):** \n\n* Applicable for variants with RNA data, with weighting based on the quality of the available RNA data.",
"label": "BP7",
"ns": "008",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -4,
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "**BP7:** Applicable for\n\n* Synonymous variants – excluding those in the last 3 nucleotides preceding a canonical donor splice site or the first nucleotide following a canonical acceptor splice site – with SpliceAI ∆ scores ≤ 0.20.\n* Intronic variants with SpliceAI ∆ scores ≤ 0.20.\n\n**BP7\\_Variable (RNA):** \n\n* Applicable for variants with RNA data, with weighting based on the quality of the available RNA data.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639147",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639147",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZlq---"
},
{
"entContent": {
"_uniqueProp": "008_BP5_nuclear_RUNX1",
"additionalComments": "BP5 is not applicable. In rare circumstances, a patient can carry two pathogenic variants in genes predisposing to hematologic malignancies.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "008",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639143",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639143",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZgi---"
},
{
"entContent": {
"_uniqueProp": "008_PS4_nuclear_RUNX1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": "**MM-VCEP notes:**\n\n(1) There is currently no published _RUNX1_ case control study. The criteria of a case control study can be added into the rules, if such a study will be published in the future. The original ACMG/AMP criterion states that in the absence of a published case-control study, the observation of the variant in multiple unrelated patients with the same phenotype and its absence in controls, may be used. The MM-VCEP created a “quasi-case-control study” with the estimated number of probands worldwide and the overall gnomAD population as control cohort. In order to apply this code, the proband has to meet the \\_RUNX1\\_-phenotypic criteria (see **PS2**) and the variant has to be either absent from gnomAD or only present once.\n\n_**RUNX1**_ **Specification:**\n\n**PS4:** ≥ 4 probands meeting at least one of the \\_RUNX1\\_-phenotypic criteria (OR 127.1).\n\n**PS4\\_Moderate:** 2-3 probands meeting at least one of the \\_RUNX1\\_-phenotypic criteria (OR 63.5-95.3).\n\n**PS4\\_Supporting:** 1 proband meeting at least one of the \\_RUNX1\\_-phenotypic criteria (OR 31.8).",
"label": "PS4",
"ns": "008",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 8,
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**PS4:** ≥ 4 probands meeting at least one of the \\_RUNX1\\_-phenotypic criteria (OR 127.1).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**PS4\\_Moderate:** 2-3 probands meeting at least one of the \\_RUNX1\\_-phenotypic criteria (OR 63.5-95.3).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**PS4\\_Supporting:** 1 proband meeting at least one of the \\_RUNX1\\_-phenotypic criteria (OR 31.8).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639141",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639141",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZnW---"
},
{
"entContent": {
"_uniqueProp": "008_BS4_nuclear_RUNX1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": "**MM-VCEP notes:**\n\nThis code should only be applied for genotype-negative, phenotype-positive family members. \n\n_**RUNX1**_ **Specification:**\n\n**BS4: Applicable when observed in ≥ 2 informative meioses.**",
"label": "BS4",
"ns": "008",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "**BS4:** Applicable when observed in ≥ 2 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -1,
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639132",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639132",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZka---"
},
{
"entContent": {
"_uniqueProp": "008_BS2_nuclear_RUNX1",
"additionalComments": "MM-VCEP notes: \n\nBS2 is not applicable since FPD/AML patients display incomplete penetrance and the average age of onset of hematologic malignancies is 33 years. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "008",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0069",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639127",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639127",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZou---"
},
{
"entContent": {
"_uniqueProp": "008_PM1_nuclear_RUNX1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": "**MM-VCEP notes:**\n\n1. The Runt homology domain (RHD) has been established as highly conserved DNA binding domain without any benign variation in ClinVar. Thirteen somatic and/or germline mutational hotspots within the RHD have been identified: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204. \n2. Variants in other parts of the RHD (amino acid (AA) 89-204) have been described as likely pathogenic/pathogenic before. There was additional evidence of germline pathogenic/likely pathogenic _RUNX2_ variants affecting AA 89 and 94 (PMID 17290219) \\[00\\](#PMID\\_ 17290219), a gene with a Runt Homology Domain that has 90% sequence homology with _RUNX1_. AA 89 is also still part of the b-sheet of the CBF heterodimerization domain, which is functionally important. Thus, we prompt to establish PM1\\_supporting with reduced strength-level for these variants.\n3. No reported germline _RUNX1_ mutations in AA residues 77-88 of the RHD to date. If there is more evidence available, this region may be expanded in the future to other parts of the RHD or the protein.\n\n_**RUNX1**_ **Specification:**\n\n**PM1\\_strong:** Variant affecting one of the following 13 AA residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204. \n\n**PM1\\_Supporting**: Variant affecting one of the other AA residues 89-204 within the RHD.",
"label": "PM1",
"ns": "008",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0028",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**PM1\\_strong:** Variant affecting one of the following 13 AA residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0054",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**PM1\\_Supporting**: Variant affecting one of the other AA residues 89-204 within the RHD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639149",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639149",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZo----"
},
{
"entContent": {
"_uniqueProp": "008_PP3_nuclear_RUNX1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": "**MM-VCEP notes:**\n\n1. For _in-silico_ evaluation of missense variants, the MM-VCEP recommends using REVEL, a meta-predictor combining 13 individual tools with high sensitivity and specificity and that has recently demonstrated highest performance compared to any individual tool or other ensemble methods.\n2. The threshold of REVEL is based on the evaluation of 25 germline PATH/LPATH and 25 BEN/LBEN missense variants in _RUNX1_. With the comparison of 11 different ensemble in-silico predictors (BayesDel AF, CADD, Condel, DANN, Eigen, FATHMM-MKL, MetaLR, MetaSVM, REVEL, UMD predictor, VEST) and their respective AUC, REVEL was found to be among the highest performing tools (AUC=1) and the new threshold for PP3 and BP4 was based on the REVEL scores at 90% sensitivity and 90% specificity, respectively.\n3. We compared the performance of the new splice predictor SpliceAI and MES, which has been shown to be the highest performing tool pre-SpliceAI by using a test set of 202 variants in genes associated with inherited hematologic malignancies/AA/BMF or cytopenia. The thresholds for PP3 and BP4 were established based on the SpliceAI score at 90% sensitivity (PP3, ≥ 0.38) and 90% specificity (BP4, ≤ 0.20).\n4. For some variant types that REVEL or SpliceAI scores are not available, multiple other predictors in agreements can be used in PP3.\n5. **PP3** cannot be applied for canonical splice site variants.\n\n_**RUNX1**_ **Specification:**\n\n**For missense variants:**\n\n**PP3:** REVEL score ≥ 0.88 or SpliceAI ≥ 0.38, including the creation of cryptic novel splice sites.\n\n**For synonymous and intronic (intron 4-8) variants:**\n\n**PP3:** SpliceAI ≥ 0.38, including the creation of cryptic novel splice sites.\n\nCaveats:\n\n\\*Do not use for variants with a predicted splicing effect that is proven by RNA analysis. See **PVS1\\_Variable (RNA)**.\n\n\\*Do not use for for canonical splice site variants.",
"label": "PP3",
"ns": "008",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
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"strength": "Stand Alone",
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"text": "",
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"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**For missense variants:**\n\n**PP3:** REVEL score ≥ 0.88 or SpliceAI ≥ 0.38, including the creation of cryptic novel splice sites.\n\n**For synonymous and intronic (intron 4-8) variants:**\n\n**PP3:** SpliceAI ≥ 0.38, including the creation of cryptic novel splice sites.\n\nCaveats:\n\n\\*Do not use for variants with a predicted splicing effect that is proven by RNA analysis. See **PVS1\\_Variable (RNA)**.\n\n\\*Do not use for for canonical splice site variants.",
"type": "EvidenceLineStrength"
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"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZqG---"
},
{
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"additionalComments": "MM-VCEP notes: \n\nThe recommended cutoff for PP2 by the SVI is a missense constraint z score of ≥ 3.09 which was not met by RUNX1 (2.48 on ExAC and 2.08 on gnomAD). In addition, there are 9 benign/likely benign missense RUNX1 variants in ClinVar.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "008",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
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"applicability": "Not applicable",
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"type": "EvidenceLineStrength"
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"applicability": "Not applicable",
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"specificationType": [],
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"text": "",
"type": "EvidenceLineStrength"
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"strength": "Strong",
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"text": "",
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"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZiC---"
},
{
"entContent": {
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"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": "**MM-VCEP notes:**\n\nFPD/AML with germline _RUNX1_ mutation is a rare disorder. The phenotype of carriers of a germline _RUNX1_ mutation includes three criteria (mild to moderate thrombocytopenia, platelet ultrastructural and/or functional defects and diagnosis of a hematologic malignancy). Of these three criteria, thrombocytopenia is the most common feature. Most clinical laboratories establish their platelet count reference values by measuring samples from at least 120 healthy individuals and identifying the most outlying 5% of observed values. Most often, these outlying observations are split evenly between the ends of the test result distribution in the reference population, 2.5% at each end of the distribution, resulting in a two-sided reference interval. Using this approach, the prevalence of thrombocytopenia can be defined as 1 in 40 (lower 2.5%) in general population. The penetrance in families with _RUNX1_ germline mutation is high to near-complete. We identified a family with a penetrance of 85% among known carriers of the mutation as the pedigree with the lowest penetrance to date. So far, no founder mutations in _RUNX1_ have been reported, _de novo_ variants are rare but have been described. The MM-VCEP modified **BA1** using extremely conservative values to account for the unknown prevalence and disease attribution to _RUNX1_. In order to obtain a \\_RUNX1\\_-specific population allele frequency for **BA1**, we utilized the Whiffin/Ware calculator (http://cardiodb.org/allelefrequencyapp/) with a prevalence of 1 in 40, a conservative unascertained penetrance estimate of 85%, an allelic heterogeneity of 100% and a maximum genetic heterogeneity of 10%. A 95% confidence interval was used to develop the threshold. The threshold developed for application of **BA1** as a stand-alone criterion is a minor allele frequency of equal to or higher than 0.0015 (0.15%).\n\nThe MM-VCEP also adopted the SVI recommendation that the variant be present in any general continental population dataset with a minimum number of 2,000 alleles and variant present in ≥ 5 alleles.\n\n_**RUNX1**_ **Specification:**\n\n**BA1:** Minor allele frequency ≥ 0.0015 (0.15%) in any general continental population dataset with ≥ 2,000 alleles tested and variant present in ≥ 5 alleles.",
"label": "BA1",
"ns": "008",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "_**RUNX1**_ **Specification:**\n\n**BA1:** Minor allele frequency ≥ 0.0015 (0.15%) in any general continental population dataset with ≥ 2,000 alleles tested and variant present in ≥ 5 alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
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"strength": "Very Strong",
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"text": "",
"type": "EvidenceLineStrength"
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"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
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"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
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"strengthSepioID": "SEPIO:0000699",
"text": "",
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{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
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"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
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]
},
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"ldhId": "135639144",
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"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZiq---"
},
{
"entContent": {
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"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect on the gene or gene product.\n\n**MM-VCEP notes:**\n\n1. **Transactivation assays** demonstrating altered transactivation compared to wildtype (wt) are often performed as functional studies to evaluate the pathogenicity of a _RUNX1_ variant. Promoter sequences of _M-CSFR_, _PF4_, _C-FMS_ and _GZMB_, containing consensus _RUNX1_ binding sites TGTGGT, have been used for this purpose. The transactivation assay must include wt and known pathogenic controls, as well as co-expression with CBFâ.\n2. Data from **secondary assays** are frequently used to evaluate an altered function of mutant RUNX1. Electrophoretic mobility shift assays and yeast hybrid assays are performed to demonstrate decreased DNA binding affinity, and co-immunoprecipitation assays, fluorescence resonance energy transfer assays and affinity assays can demonstrate diminished heterodimerization ability of mutant RUNX1 with CBFâ. Abnormal cellular localization of mutant RUNX1 can be shown by immunofluorescence and cell-fractionation with Western Blot. Sorted primary hematopoietic stem and progenitor cells can be used for demonstration of reduced colony-forming potential and xenotransplantation experiments may reveal abnormal function of mutant RUNX1 _in vivo._\n\n_**RUNX1**_ **Specification:**\n\n**PS3:** Transactivation assays demonstrating altered transactivation (\\<20% of wt, and/or reduced to levels similar to well established pathogenic variants such as R201Q or R166Q) AND data from a secondary assay demonstrating altered function. Not applicable if variant meets **PVS1**. If variant meets **PVS1\\_strong**, upgrade to **PVS1**.\n\n**PS3\\_Moderate:** Transactivation assays demonstrating altered transactivation (\\<20% of wt and/or reduced to levels similar to well established pathogenic variants such as R201Q or R166Q) OR ≥ 2 secondary assays demonstrating altered function.\n\n**PS3\\_Supporting:** Transactivation assays demonstrating enhanced transactivation (>115% of wt).",
"label": "PS3",
"ns": "008",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 8,
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"defaultPoint": 4,
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**PS3:** Transactivation assays demonstrating altered transactivation (\\<20% of wt, and/or reduced to levels similar to well established pathogenic variants such as R201Q or R166Q) AND data from a secondary assay demonstrating altered function. Not applicable if variant meets **PVS1**. If variant meets **PVS1\\_strong**, upgrade to **PVS1**.",
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},
{
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"defaultPoint": 2,
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**PS3\\_Moderate:** Transactivation assays demonstrating altered transactivation (\\<20% of wt and/or reduced to levels similar to well established pathogenic variants such as R201Q or R166Q) OR ≥ 2 secondary assays demonstrating altered function.",
"type": "EvidenceLineStrength"
},
{
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"instructionsToUse": "",
"specificationType": [
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"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**PS3\\_Supporting:** Transactivation assays demonstrating enhanced transactivation (>115% of wt).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639138",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639138",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZma---"
},
{
"entContent": {
"_uniqueProp": "008_BP1_nuclear_RUNX1",
"additionalComments": "MM-VCEP notes: \n\nBP1 is not applicable for RUNX1, because both truncating and missense variants cause FPD/AML. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "008",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639131",
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"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZwa---"
},
{
"entContent": {
"_uniqueProp": "008_PM3_nuclear_RUNX1",
"additionalComments": "MM-VCEP notes:\n\nFPD/AML is inherited in an autosomal dominant manner, thus PM3 is not applicable. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "008",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
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"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 8,
"id": "0038",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 4,
"id": "0058",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 2,
"id": "007",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0027",
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"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639126",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639126",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZmC---"
},
{
"entContent": {
"_uniqueProp": "008_BS1_nuclear_RUNX1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS1",
"ns": "008",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"defaultPoint": -4,
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "**MM-VCEP notes:**\n\nSimilarly, for the **BS1** calculation, we utilized the Whiffin/Ware calculator (http://cardiodb.org/allelefrequencyapp/) with a prevalence of 1 in 40, a conservative unascertained penetrance estimate of 85%, an allelic heterogeneity of 100% and a maximum genetic heterogeneity of 1% (one magnitude lower than for **BA1**). A 95% confidence interval was used to develop the threshold. We developed a range for application of **BS1** for variants with a minor allele frequency between 0.00015 (0.015%) and 0.0015 (0.15%). \n\n1. The MM-VCEP also adopted the SVI recommendation that the variant be present in any general continental population dataset with a minimum number of 2,000 alleles and variant present in ≥ 5 alleles.\n2. The variant can be classified as likely benign based on **BS1** alone if there is no contradictory evidence supporting pathogenicity.\n\n_**RUNX1**_ **Specification:**\n\n**BS1:** Minor allele frequency between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental population dataset with ≥ 2,000 alleles tested and variant present in ≥ 5 alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -1,
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639125",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639125",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZtS---"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0011071",
"lbl": "hereditary thrombocytopenia and hematologic cancer predisposition syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/8567"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0011071"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/platelet_disorder_familial_with_associated_myeloid_malignancy"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C563324"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/725034002"
},
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"instructionsToUse": "",
"label": "PP5",
"ns": "009",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432995",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638432995",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3da---"
},
{
"entContent": {
"_uniqueProp": "009_PP4_nuclear_TP53",
"additionalComments": "Not applicable",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency of likely somatic variants in blood among patients undergoing multigene panel testing is high for variants in _TP53_ (PMID: 29189820). _TP53_ variants observed at a low variant allele fraction (VAF) may be due to true constitutional mosaicism (which can be confirmed by observing the variant in other non-lymphocyte tissues; in the tumor at higher VAF; and/or segregating in other family members); technical assay issues; a clone driven by underlying malignancy or previous treatment with chemotherapy; or clonal hematopoiesis of indeterminate potential (CHIP). \n\nPositive selection has been proposed to be a mechanism driving clonal hematopoiesis (CH). Fortuno et al., 2022 (PMID: 34906512) demonstrated that the observation of _TP53_ variants at low VAF is a significant predictor of variant pathogenicity. Likelihood ratios toward pathogenicity associated with a VAF 5-25% corresponded to the ACMG-AMP strength level of moderate, and supporting with VAF 25-35%. Code-weighting for this rule was derived from datasets that are equivalent to the information available to diagnostic laboratories with the aim that this would be accurate for interpretation for low VAF variants in a real world testing situation. Uncertainty about the variant truly being the result of CHIP is built into the code strengths assigned, which therefore excludes confirmed constitutional mosaicism. \n\n_Caveats_: This evidence code assumes a somatic origin of the TP53 variant. PP4 and points towards any phenotype-based rule codes (e.g., PS4, PS2, PP1) cannot be applied _in the same individual_ in combination. This code should not be applied if the low VAF TP53 variant has been identified in a patient with blood cancer. Do not apply this code if variant meets BA1 or BS1. Variant must have been detected on MGPT in order for this code to be applied.",
"label": "PP4",
"ns": "009",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "At least 2 independent observations of the variant with VAF 5-25%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Observation of the variant with VAF 5-35% (i.e., once or multiple times with VAF >25-35% and/or once with VAF 5-25%)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639229",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639229",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3bO---"
},
{
"entContent": {
"_uniqueProp": "009_PS4_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "There are two widely used clinical criteria for assessing the likelihood of Li Fraumeni syndrome - Classical and Chompret criteria - with the Chompret criteria being less restrictive. Individuals who meet the Revised Chompret criteria have an estimated ~30% risk of harboring a pathogenic _TP53_ variant (Bougeard et al., 2015; PMID: 26014290). Members of the _TP53_ VCEP calculated likelihood ratios (LRs) for patients meeting Classic LFS or Revised Chompret criteria (excluding confirmed constitutional mosaics and carriers of pathogenic variants in other cancer predisposition genes) using multigene panel testing from Ambry Genetics laboratory. Our data demonstrated that individuals meeting Revised Chompret criteria had a LR of > 2.08 to ≤ 4.3 and individuals meeting Classic LFS criteria had a LR of > 4.3 to ≤ 18.7. Therefore, **we recommend that probands with** _**TP53**_ **germline variants meeting Revised Chompret should be given 0.5 point and probands meeting Classic LFS criteria should be given 1 point.** Do not apply this code for probands with _de novo_ TP53 variants, in which case PS2\\_Variable Weight should be applied instead.\n\nEarly-onset breast cancer is the most common malignancy in women with LFS. Breast tumors from _TP53_ carriers are more likely to be HER2+ than those of non-carriers. Fortuno et al., 2020 (PMID: 32485079) investigated if breast tumor HER2 status has utility as a predictor of _TP53_ germline variant pathogenicity considering age at diagnosis. Their results showed that the identification of HER2+ breast tumors diagnosed before age 40 equated to Supporting level towards pathogenicity and therefore can be incorporated into _TP53_ criteria. **Unrelated probands who are diagnosed with a HER2+ breast cancer below the age of 40 should be conservatively given 0.5 point.** **Do not apply this half point to individuals who have been given points for meeting Classical or Chompret criteria due to breast cancer diagnosis \\<31 years of age.**\n\nPhenotype points in unrelated probands should be tallied using the simplified table for tallying PS4 proband points.\n\n_Caveats_: Points attributed to HER2 status may only be applied in unrelated individuals who underwent multigene panel testing with no other pathogenic/likely pathogenic variants in cancer predisposition genes; individuals who underwent targeted _TP53_ single gene testing may not count towards applied points.Variant must meet PM2\\_Supporting in order for PS4 to be applied at any strength.\n\nSee simplified table for tallying probing points for PS4",
"label": "PS4",
"ns": "009",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 8,
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥ 8 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥ 4-7.5 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "2-3.5 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1-1.5 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639222",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639222",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3a6---"
},
{
"entContent": {
"_uniqueProp": "009_BP3_nuclear_TP53",
"additionalComments": "Not applicable",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "009",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0081",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639218",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639218",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3ei---"
},
{
"entContent": {
"_uniqueProp": "009_BP1_nuclear_TP53",
"additionalComments": "This rule code does not apply to these genes, as truncating variants account for only a portion of disease causing variants.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "009",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639212",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639212",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3bm---"
},
{
"entContent": {
"_uniqueProp": "009_BS1_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BS1",
"ns": "009",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/16644204/"
}
],
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"gene-specific"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Filtering allele frequency (FAF) of ≥ 0.0003 but \\< 0.001 in gnomAD continental subpopulations of a single genetic ancestry group (excluding genetic ancestry groups influenced by founder effects, such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”). Genetic ancestry group must have ≥2,000 alleles tested and a minimum of 2 alleles present. Caution should be exerted if the majority of alleles have a variant allele fraction ( “allele balance” in gnomAD) below 0.35. To set the strong benign FAF cutoff, we used a Whiffin-Ware calculation using prevalence of 1 in 5,000 (Lalloo, et al., 2006 PMID: 16644204). Genetic and allelic heterogeneity were set at 100% and penetrance at 30%. \n\nIn general, the most recent version of gnomAD should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if they are able to provide information the curator deems necessary for optimal variant classification (e.g, they would provide superior information for a particular variant type; have a larger sample size; or better representation for certain subpopulations, etc.)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -1,
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639206",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639206",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3ZO---"
},
{
"entContent": {
"_uniqueProp": "009_PP5_nuclear_TP53",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "009",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432995",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638432995",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3da---"
},
{
"entContent": {
"_uniqueProp": "009_BP6_nuclear_TP53",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "009",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432994",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638432994",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3dC---"
},
{
"entContent": {
"_uniqueProp": "009_PM1_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "There are several known major hotspots for the _TP53_ gene. This code can be used for variants within the following codons using canonical transcript NM\\_000546.4: 175, 245, 248, 249, 273, 282\n\nThis code can also be used for germline missense variants seen in cancerhotspots.org (v2) with ≥ 10 somatic occurrences for the same amino acid change. This follows the recommendation from the ClinGen Germline/Somatic Variant Curation Subcommittee (PMID: 30311369).",
"label": "PM1",
"ns": "009",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense variants within the following codons using transcript NM\\_00546.4: 175, 245, 248, 249, 273, 282. This code weight can also be used for germline missense variants seen in cancerhotspots.org with ≥ 10 somatic occurrences for the same amino acid change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0054",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense variants seen in cancerhotspots.org with 2-9 somatic occurrences for the same amino acid change.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639230",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639230",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3WG---"
},
{
"entContent": {
"_uniqueProp": "009_BP7_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP7",
"ns": "009",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [
"gene-specific"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0065",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "A (synonymous) silent or intronic variant for which RNA splicing assay data demonstrates no splicing aberration, as per recommendations from Walker et al., 2023 (PMID: 37352859).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) outside of the core splice motif (last three nucleotides and first nucleotide of the exon) or intronic variant at or beyond +7 to -21 positions for which SpliceAI predicts no impact to the splice consensus nor the creation of a new splice site (BP4 is met, SpliceAI ≤ 0.1). No requirement to assess for nucleotide conservation for rule application as per evidence and recommendations in Walker et al., 2023 (PMID: 37352859).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639228",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639228",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3Z----"
},
{
"entContent": {
"_uniqueProp": "009_PVS1_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PVS1",
"ns": "009",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 8,
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Please utilize the PVS1 decision tree for application of PVS1 code. The decision tree details the specific strengths each type of null variant may be applied at. Please see below for some additional helpful summary details for application of PVS1 code:\n\n* Initiation codon:\n * PVS1 may be applied to initiation codon variants\n* Nonsense or frameshift variants:\n * PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD) for nonsense variants upstream of p.Lys351 and for frameshift induced premature termination codon (PTC) upstream of p.Lys351\n * PVS1\\_Strong applies to variants not predicted to undergo NMD (nonsense variants downstream of codon 350 or frameshift induced PTC in exon 11 or in the 3’ most 50 nucleotides of exon 10) in variants located in the p.Lys351 to p.Ala 355 range\n * PVS1\\_Moderate applies to variants not predicted to undergo NMD (nonsense variants downstream of codon 350 or frameshift induced PTC in exon 11 or in the 3’ most 50 nucleotides of exon 10) in variants located in the p.Gly356 to p.Asp393 range\n * PVS1\\_Moderate may also be applied to frameshift induced PTC downstream of the natural stop codon\n* Canonical splice variants (+/- 1,2 intronic positions): \n * PVS1 applies to predicted splicing alterations that are PTC resulting in NMD (or in-frame but targeting critical domains or residues)\n * PVS1 applies to predicted splicing alterations that target the start codon (Exon 2 donor)\n * PVS1\\_Moderate applied to splicing alterations that are predicted to shorten (\\<10% of the protein removed) or expand a _TP53_ C-terminal end of unknown function (E10 donor or E11 acceptor)\n* Deletions\n * Full gene deletions: PVS1\n * Single- to multi-exon deletions that target the initiation codon, preserving the potential rescue ATG (p.Met40) in exon 4: PVS1\n * Single- to multi-exon deletions that target the initiation codon and the potential rescue ATG (p.Met40) in exon 4: PVS1\n * Single- to multi-exon deletion that disrupts the reading frame and is predicted to undergo NMD (nonsense or frameshift induced PTC upstream of p.Lys351): PVS1\n * Single- to multi-exon deletion that disrupts the reading frame and is **NOT** predicted to undergo NMD (nonsense or frameshift inducted PTC downstream of p.Leu350): PVS1\n * Single- to multi-exon deletion including the last exon where the truncated/altered region is critical to protein function (any multi-exon combination targeting exon 11): PVS1\n * If the role of the region in protein function is unknown, if the variant removed \\< 10% of the protein (deletion of exon 11): PVS1\\_Moderate\n * Single- to multi-exon deletion that preserves the reading frame where the truncated/altered region is critical to protein function: PVS1\n* Duplications (≥1 exon in size and must be completely contained within the _TP53_ gene)\n * Proven in tandem. Reading frame is disrupted and NMD predicted to occur (nonsense upstream of p.Lys351 or frameshift-induced PTC upstream of p.Lys351): PVS1\n * Presumed in tandem. Reading frame presumed disrupted and NMD predicted to occur (nonsense upstream of p.Lys351 or frameshift-induced PTC upstream of p.Lys351): PVS1\\_Strong\n\nFor variants inducing aberrant transcripts identified via mRNA assay, apply as PVS1\\_Variable Weight (RNA) following recommendations from Walker et al., 2023 (PMID: 37352859), downgrading one strength level if the assay data indicates leakiness.\n\n_Caveats_: PS3 should not be applied at any strength if PVS1 is applied at full strength. PP3 should not be used in combination with PVS1.\n\nFor the purposes of unified curation, the TP53 domains/important motifs by amino acid range are defined as:\n\n**TAD1**: aa 17-25\n\n**TAD2**: aa 48-56\n\n**Proline residues**: aa 64-92\n\n**DNA binding domain**: aa 100-292\n\n**Hinge domain**: aa 293-324\n\n**Oligomerization domain**: aa 325-356\n\n**C-terminal domain (Basic domain)**: aa 368-387\n\nA disease-specific PVS1 decision tree incorporating the above bullets as well as a supplemental file for _TP53_ PVS1 Splicing Worksheet is also included as an additional curation tool and has more granular details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "See PVS1 flowchart for code application",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See PVS1 flowchart for code application",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639223",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639223",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3Z2---"
},
{
"entContent": {
"_uniqueProp": "009_PS2_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "_De novo_ points should be tallied using the table for tallying proband points based on whether maternity and paternity have been confirmed and the type of cancer(s) seen in the proband. This includes probands that are confirmed constitutional mosaics (low _TP53_ VAF on blood or buccal testing with the mutation detected in non-lymphocyte tissue and/or segregating in children) which may be counted as a confirmed _de novo_ case. For probands with multiple cancers, use the most specific/highest weight cancer to determine point application for that proband. Points for all probands should be tallied to determine the strength of PS2 code application, consistent with SVI guidance. To avoid redundancy and increase consistency, the _TP53_ VCEP has opted to drop PM6 and use PS2 exclusively for _de novo_ evidence.\n\nA Table for LFS Cancers for PS2 (and PP1) code application is included below",
"label": "PS2",
"ns": "009",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 8,
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥ 8 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "4-7 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "2-3 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1 point",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639217",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639217",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3W2---"
},
{
"entContent": {
"_uniqueProp": "009_BP6_nuclear_TP53",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "009",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432994",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638432994",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3dC---"
},
{
"entContent": {
"_uniqueProp": "009_PP2_nuclear_TP53",
"additionalComments": "Not applicable",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "009",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639226",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639226",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3Vm---"
},
{
"entContent": {
"_uniqueProp": "009_BP2_nuclear_TP53",
"additionalComments": "Not applicable",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": [
"Evidence code can be applied in either scenario: Variant is observed in trans with a pathogenic or likely pathogenic TP53 variant (phase confirmed) OR when there are 3 or more observations with a pathogenic or likely pathogenic variant when phase is unknown. In this scenario, the variant must be seen with at least two differemt pathogenic or likely pathogenic TP53 variants."
],
"label": "BP2",
"ns": "009",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"gene-specific"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639216",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639216",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3Xy---"
},
{
"entContent": {
"_uniqueProp": "009_PS1_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "This rule code can only be used to compare variants asserted as pathogenic or likely pathogenic following the ClinGen _TP53_ VCEP’s specifications. Must confirm there is no difference using RNA data or SpliceAI (SpliceAI \\< 0.2). Caveat: If both PS1 and PM5 are met, apply the strongest weight possible for each rule code not to exceed a combined strength of strong (4 points in total).",
"label": "PS1",
"ns": "009",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Can be applied to variants asserted as Pathogenic following the _TP53_ VCEP’s specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Can be applied to variants asserted as Likely Pathogenic following the _TP53_ VCEP’s specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639215",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639215",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3Xi---"
},
{
"entContent": {
"_uniqueProp": "009_PM3_nuclear_TP53",
"additionalComments": "This rule does not apply to TP53/Li-Fraumeni syndrome.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "009",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 8,
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 4,
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 2,
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639207",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639207",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3dq---"
},
{
"entContent": {
"_uniqueProp": "009_BA1_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BA1",
"ns": "009",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"gene-specific"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"defaultPoint": "Not Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Filtering allele frequency (FAF) of ≥ 0.001 or 0.1% in gnomAD continental subpopulations of a single genetic ancestry group (excluding genetic ancestry groups influenced by founder effects, such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”). Genetic ancestry group must have ≥2,000 alleles tested and a minimum of 2 alleles present. Caution should be exerted if the majority of alleles have a variant allele fraction (\"allele balance\" in gnomAD) below 0.35. To set the stand-alone benign FAF cutoff, we used the FAF cutoff established for BS1 (0.0003) and increased this cutoff by one order of magnitude to come to a value of 0.001. \n\nIn general, the most recent version of gnomAD should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if they are able to provide information the curator deems necessary for optimal variant classification (e.g, they would provide superior information for a particular variant type; have a larger sample size; or better representation for certain subpopulations, etc.)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639225",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639225",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3Yq---"
},
{
"entContent": {
"_uniqueProp": "009_PM6_nuclear_TP53",
"additionalComments": "Combined with PS2. Use PS2 instead of PM6.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": [
"See above for PS2_PM6 combined rule"
],
"label": "PM6",
"ns": "009",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 8,
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 4,
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 2,
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639214",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639214",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3c----"
},
{
"entContent": {
"_uniqueProp": "009_BS4_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BS4",
"ns": "009",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"gene-specific"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected family members (i.e. family members diagnosed with LFS-associated cancers as described in Table of LFS Cancers and Points for PS2 and PP1 Code Application).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -1,
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639213",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639213",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3aS---"
},
{
"entContent": {
"_uniqueProp": "009_PM5_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "This code can be applied for a missense change at an amino acid residue where one or more pathogenic/likely pathogenic variants have been identified. The other variant must be interpreted as pathogenic or likely pathogenic following the ClinGen _TP53_ VCEP’s specifications. The previously established pathogenic/likely pathogenic variant must reach a classification of pathogenicity without PM5. \n\nGrantham should be used to compare the variants. The variant being evaluated must be equal or worse (value is greater than) than the known pathogenic variant (i.e. the variant residue should be equally chemically different or more chemically different than the known pathogenic residue in comparison to the wild type residue). Splicing should be ruled out with either RNA data or SpliceAI (SpliceAI \\< 0.2).\n\nCaveats: If both PS1 and PM5 are met, apply the strongest weight possible for each rule code not to exceed a combined strength of strong (4 points in total).",
"label": "PM5",
"ns": "009",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense variant at an amino acid residue where ≥2 different missense variants previously determined to be pathogenic according to the _TP53_ VCEP’s specifications have been seen before.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense variant at an amino acid residue where 1 different missense variant previously determined to be pathogenic according to the _TP53_ VCEP’s specifications has been seen before.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense variant at an amino acid residue where 1 different missense variant previously determined to be likely pathogenic according to the _TP53_ VCEP’s specifications has been seen before. **The previously seen likely pathogenic variant must have clinical data that demonstrates pathogenicity (i.e. PS2, PS4, PP1) in order for it to count towards PM5\\_Supporting code application.**",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639211",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639211",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3eO---"
},
{
"entContent": {
"_uniqueProp": "009_BS3_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "This rule should be used and weighted appropriately for variants with functional evidence of loss of function. Follow SVI guidance regarding control numbers for functional studies. _Caveat:_ Do not apply BS3 at any weight for “missense” variants using assays done at the protein level (such as Kato et al. or Giacomelli et al.) if PP3 is applied based on SpliceAI. If there is any laboratory evidence, including RNA-seq data, of splicing aberration for the genetic variant being assessed, for which PVS1\\_Variable Weight (RNA) might be considered instead. Functional missense codes should not be applied if PVS1 is applied for splicing. See flowchart for functional rule codes and spreadsheet of functional results for selected assays in Files & Images section.\n\n**Data Supporting Functional Classes:**\n\n**Kato et al. 2003 (PMID: 12826609) Transactivation Class:** Classification based on the median transactivation activity using eight promoters in yeast. Values can be found in the NCI TP53 Database.\n\nNon-functional: ≤ 20% activity\n\nPartially-functional: > 20% and ≤ 75% activity\n\nFunctional : > 75% activity (variants showing supertransactivation are treated as Functional)\n\n**Giacomelli et al., 2018 (PMID: 30224644):** Classification based on results from growth suppression assays in A549 human cells.\n\nLOF: Etoposide Z-score ≤ -0.21\n\nNo LOF: Etoposide Z-score > -0.21 \n\n**Kawaguchi et al., 2005 (PMID: 16007150):** Classification based on the ability to form an oligomer in yeast.\n\nAbnormal: Monomer/dimer\n\nNormal: Tetramer\n\n**Kotler et al., 2018 (PMID: 29979965):** Classification based on relative fitness scores (RFS) from in vitro growth assays in H1299 human cells\n\nLOF: RFS ≥ -1.0\n\nNo LOF: RFS \\< -1.0\n\n**Funk et al., 2025 (PMID: 39774325):** Classification based on relative fitness scores (RFS) from CRISPR-mediated saturation mutagenesis in human cancer cells\n\nLOF: RFS ≥ 0\n\nNo LOF: EFS \\<0\n\n**Other assays:** Colony formation assays, growth suppression assays, apoptosis assays, tetramer assays, or knock-in mouse models may be considered.\n\nNon-systematic assays are harder to calibrate, but if they meet Brnich et al., 2019 (PMID: 31892348) recommendations for the application of functional evidence and they are in agreement with Kato et al., 2003 , they should be taken into account. A large proportion of these assays are documented in the NCI TP53 database and thus can easily be found by curators. Second assays that may be considered include colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models, and growth suppression assays.\n\nSee Functional Flowchart for more information and guidance on application of functional rule codes",
"label": "BS3",
"ns": "009",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Functional on Kato et al. data **AND** no loss of function (LOF) by the majority of available eligible assays",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Partially functional on Kato et al. data **AND** no evidence of loss of function (LOF) by **all** available assays\n\nBS3\\_Supporting may also be applied to small deletions with available Kotler et al. data that are loss of function (LOF) by the majority of available assays",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639210",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639210",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3Zi---"
},
{
"entContent": {
"_uniqueProp": "009_BP6_nuclear_TP53",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "009",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432994",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638432994",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3dC---"
},
{
"entContent": {
"_uniqueProp": "009_PM2_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PM2",
"ns": "009",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This rule should be applied at supporting level. Variant should have an allele frequency of less than 0.00003 (0.003%) in gnomAD or another large sequenced population. If multiple alleles are present within any genetic ancestry group, allele frequency in that group must be \\<0.00004 (0.004%). Genetic ancestry groups influenced by founder effects (such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”) should be ignored. \n\nIf the variant being assessed does not meet any population rule codes (PM2, BA1, BS1) **AND** has a total allele frequency >0.00003 with no single genetic ancestry group having multiple alleles with a frequency >0.00004, curators should recalculate the total allele frequency based on the number of alleles with variant allele fraction (VAF) >0.35 to assess whether PM2 may be met after excluding the low VAF alleles which are likely to represent clonal hematopoiesis of indeterminant potential (CHIP) contamination in the database. This can be done by visualizing the “allele balance” for heterozygotes under the genotype quality metrics for a given variant. By hovering over the histogram bars, the number of variant carriers for each bar between 0.35 and 0.65 can be totaled and this can be used to revise the allele count to determine the allele frequency that can be used to assess if PM2\\_Supporting can be met.\n\nIn general, the most recent version of gnomAD should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if they are able to provide information the curator deems necessary for optimal variant classification (e.g, they would provide superior information for a particular variant type; have a larger sample size; or better representation for certain subpopulations, etc.)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639231",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639231",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3Wa---"
},
{
"entContent": {
"_uniqueProp": "009_PP3_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "According to the published study by Fortuno et al., 2018 (PMID: 29775997) comparing the performance of different bioinformatics tools for _TP53_, the tools selected are aGVGD (not available for single amino acid in-frame deletions) and BayesDel. To investigate potential effects on splicing for intronic, synonymous (silent), and apparent missense variants, the SpliceAI tool was selected based on recommendations from the ClinGen SVI Splicing Subgroup. All variants should be assessed to consider if there are splicing effects predicted. PP3 should not be used in combination with PVS1.\n\n**Missense variants** _(See Flowchart for application of PP3 and BP4 rule codes for missense variants and spreadsheet of bioinformatics predictions and corresponding preliminary PP3 and BP4 codes in Files & Images section below)_\n\n* **PP3\\_Moderate:** aGVGD Class C65 and BayesDel score ≥ 0.16\n* **PP3:** aGVGD class C25-C55 and BayesDel score ≥ 0.16\n\n**Single amino acid in-frame deletions** _(See single aa BayesDel spreadsheet)_\n\n* **PP3**: BayesDel score ≥ 0.16\n\n**Exonic (including synonymous (silent) variants and apparent “missense” variants or “single amino acid in-frame deletions” for which there is a predicted splice effect) or Intronic Splice Variants (excluding ± 1,2 positions):**\n\n* **PP3:** SpliceAI ≥ 0.2",
"label": "PP3",
"ns": "009",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29775997/"
}
],
"sepioID": "SEPIO-CG:99035",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**Missense variants** _(See flowchart for application of PP3 and BP4 rules for missense variants)_\n\naGVGD Class C65 and BayesDel score ≥ 0.16",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**Missense variants** _(See flowchart for application of PP3 and BP4 rules for missense variants)_\n\naGVGD class C25-C55 and BayesDel score ≥ 0.16\n\n**Single amino acid inframe deletions** _(See single aa BayesDel spreadsheet)_\n\nBayesDel score ≥ 0.16\n\n**Exonic (including silent variants and apparent “missense” variants or “single amino acid inframe deletions” for which there is a predicted splice effect) or Intronic Splice Variants (excluding ± 1,2 positions):**\n\nSpliceAI ≥ 0.2",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639227",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639227",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3cq---"
},
{
"entContent": {
"_uniqueProp": "009_BP5_nuclear_TP53",
"additionalComments": "Not applicable",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "009",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0078",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639224",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639224",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3ai---"
},
{
"entContent": {
"_uniqueProp": "009_PP1_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "Meioses should be counted for individuals who both carry the variant and have a relevant cancer (see LFS cancers table). Meioses can be counted through unaffected obligate carriers. Caution should be used in counting meioses across many families where breast cancer is the only cancer present as this is a common cancer type. It is preferable that breast cancer predisposition syndromes have been ruled out with genetic testing, but this is not required to apply meioses.\n\nIn cases where multiple individuals in a family have a relevant cancer and only tumor testing demonstrating the variant (no germline data), meioses may be applied if the variant has been demonstrated in the germline in at least one individual in the family. (Caveat: Positive tumor testing must exist in multiple family members; meioses should not be applied if there is only positive tumor testing in a single individual. If the variant allele fraction in the tumor is not consistent with the variant being heterozygous it should not count towards meioses. Use caution if the family does not meet Classic LFS criteria). \n\nDo not apply PP1 if variant meets BA1/BS1 criteria.\n\nSee Table of LFS cancers for PP1 (and PS2) code application.",
"label": "PP1",
"ns": "009",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Cosegregation must be observed in ≥ 7 meioses across > 1 family",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Cosegregation must be observed in 5-6 meioses in/across 1 or more families",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Cosegregation must be observed in 3-4 meioses in/across 1 or more families",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639221",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639221",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3Ye---"
},
{
"entContent": {
"_uniqueProp": "009_BP4_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "\\-According to the published study by Fortuno et al., 2018 (PMID: 29775997) comparing the performance of different bioinformatics tools for _TP53_, the tools selected are aGVGD (not available for single amino acid in-frame deletions) and BayesDel. To investigate potential effects on splicing for intronic, synonymous (silent), and apparent missense variants, the SpliceAI tool was selected based on recommendations from the ClinGen SVI Splicing Subgroup. All variants should be assessed to consider if there are splicing effects predicted.\n\n**Missense Variants** _(See Flowchart for application of PP3 and BP4 rule codes for missense variants and spreadsheet of bioinformatics predictions and corresponding preliminary PP3 and BP4 codes in FIles & Images below):_\n\n**BP4\\_Moderate:** BayesDel ≤ -0.008 irrespective of aGVGD score (except C65, in this case do not apply BP4\\_Moderate) AND no predicted differences in splicing (SpliceAI \\< 0.2)\n\n**BP4:** BayesDel \\< 0.16 and > -0.008 irrespective of aGVGD score (except C65, this case do not apply BP4) AND no predicted differences in splicing (SpliceAI \\< 0.2)\n\n**Single amino acid in-frame deletions** (_See single aa BayesDel spreadsheet):_\n\n**BP4**: BayesDel score \\< 0.16 AND no predicted splicing impact (Splice AI \\< 0.2)\n\n**Synonymous (silent) or Intronic Variants (outside ± 1,2 positions):**\n\n**BP4:** SpliceAI ≤ 0.1",
"label": "BP4",
"ns": "009",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29775997/"
}
],
"sepioID": "SEPIO-CG:99046",
"specificationType": [
"gene-specific"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -4,
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -2,
"id": "0214",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "**Missense variants** _(See flowchart for application of PP3 and BP4 rules for missense variants):_\n\nBayesDel ≤ -0.008 irrespective of aGVGD score (except C65, in this case do not apply BP4\\_Moderate) AND no predicted differences in splicing (SpliceAI \\< 0.2)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "**Missense variants** _(See flowchart for application of PP3 and BP4 rules for missense variants):_\n\nBayesDel \\< 0.16 and > -0.008 irrespective of aGVGD score (except C65, this case do not apply BP4) AND no predicted differences in splicing (SpliceAI \\< 0.2)\n\n**Single amino acid inframe deletions** _(See single aa BayesDel spreadsheet):_\n\nBayesDel score \\< 0.16 AND no predicted splicing impact (Splice AI \\< 0.2)\n\n**Silent or Intronic Variants (outside ± 1,2 positions):**\n\nSpliceAI ≤ 0.1",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639220",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639220",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3YG---"
},
{
"entContent": {
"_uniqueProp": "009_PS3_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "Kato et al., 2003 (PMID: 12826609) systematic data performed best on our test set of reference variants. These data thus remain the primary functional assay underlying the classification. Giacomelli et al., 2018 (PMID: 30224644) assays are also systematic and are available for all p53 missense variants. When using cut-offs derived from original publication data (optimal cut-offs separating silent and common cancer variants), they show good concordance with other assays. Giacomelli LOF class can thus be used to support and complement Kato data. If Kato data is supported by Kawaguchi et al., 2005 (PMID: 16007150) in the tetramerization domain and tetramerization is affected, this can be used to apply PS3\\_Supporting. Both Kato and Giacomelli assays have results available for every possible missense variant. Kotler et al., 2018 (PMID: 29979965) data are available for a large number of variants with different effects, but only for those within the DNA binding domain. They may be used as an additional non-systematic missense LOF assay or for small deletions. The recently published CRISPR-based Funk et al. assay (PMID: 39774325) has results for a limited number of exons. _Caveat:_ Do not apply PS3 at any weight for “missense” variants using assays done at the protein level (such as Kato et al. or Giacomelli et al.) if PP3 is applied based on SpliceAI. If there is any laboratory evidence, including RNA-seq data, of splicing aberration for the genetic variant being assessed, for which PVS1\\_Variable Weight (RNA) might be considered instead. Functional missense codes should not be applied if PVS1 is applied for splicing. See flowchart for functional rule codes and spreadsheet of functional results for selected assays in Files & Images section.\n\n**Data Supporting Functional Classes:**\n\n**Kato et al. 2003 (PMID: 12826609) Transactivation Class:** Classification based on the median transactivation activity using eight promoters in yeast. Values can be found in the NCI TP53 Database.\n\nNon-functional: ≤ 20% activity\n\nPartially-functional: > 20% and ≤ 75% activity\n\nFunctional : > 75% activity (variants showing supertransactivation are treated as Functional)\n\n**Giacomelli et al., 2018 (PMID: 30224644):** Classification based on results from growth suppression assays in A549 human cells.\n\nLOF: Etoposide Z-score ≤ -0.21\n\nNo LOF: Etoposide Z-score > -0.21\n\n**Kawaguchi et al., 2005 (PMID: 16007150):** Classification based on the ability to form an oligomer in yeast.\n\nAbnormal: Monomer/dimer\n\nNormal: Tetramer\n\n**Kotler et al., 2018 (PMID: 29979965):** Classification based on relative fitness scores (RFS) from in vitro growth assays in H1299 human cells\n\nLOF: RFS ≥ -1.0\n\nNo LOF: RFS \\< -1.0\n\n**Funk et al., 2025 (PMID: 39774325):** Classification based on relative fitness scores (RFS) from CRISPR-mediated saturation mutagenesis in human cancer cells\n\nLOF: RFS ≥ 0\n\nNo LOF: EFS \\<0\n\n**Other assays:** Colony formation assays, growth suppression assays, apoptosis assays, tetramer assays, or knock-in mouse models may be considered.\n\nNon-systematic assays are harder to calibrate, but if they meet Brnich et al., 2019 (PMID: 31892348) recommendations for the application of functional evidence and they are in agreement with Kato et al., 2003 , they should be taken into account. A large proportion of these assays are documented in the NCI TP53 database and thus can easily be found by curators. Second assays that may be considered include colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models, and growth suppression assays.\n\nThis rule should be used and weighted appropriately for variants with functional evidence of loss of function. Follow SVI guidance regarding control numbers for functional studies. Downgrade to PS3\\_Moderate if PVS1\\_Strong is applied. Do not apply PS3 at any strength if PVS1 is applied at full strength.\n\nSee Functional Flowchart for more information and guidance on application of functional rule codes",
"label": "PS3",
"ns": "009",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 8,
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Non-functional on Kato et al. data **AND** loss of function (LOF) by the majority of other eligible assays",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Partially functional on Kato et al. data **AND** loss of function (LOF) by the majority of other available assays",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Non-functional on Kato et al. data **AND** abnormal on Kawaguchi et al. data regardless of other assays\n\nPS3\\_Supporting may also be applied to small deletions that demonstrate LOF on the majority of available assays",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639219",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639219",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3cW---"
},
{
"entContent": {
"_uniqueProp": "009_PM4_nuclear_TP53",
"additionalComments": "Not applicable",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "009",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 4,
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
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{
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{
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{
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],
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"notes": "CAVEAT: A final point value of -1 may be overridden to Likely Benign in cases where at least 2 benign evidence codes are applied AND PM2_Supporting is the only pathogenic code applied."
}
},
"type": "Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015"
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},
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"shortTitle": "TP53 VCEP",
"title": "TP53 Variant Curation Expert Panel",
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"releaseNotes": "\n * Specifications for PS3 and BS3 have been revised and the strength has been downgraded.\n * PM2 has been downgraded to PM2_Supporting.\n * PP4 has been revised to allow the use of additional evidence types with strength of evidence based on a points system.\n * Cases are no longer required to meet the strict PP4 criterion in order to be counted for PM3.\n * Specifications for PM1 and BS2 are now included.\n * The tools used for in silico prediction of the impact of splice variants and in frame insertions and deletions for PP3 and BP4 have been revised.",
"shortTitle": "LSD VCEP ACMG/AMP Specifications",
"specificationSource": "https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/",
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{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-06-02T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
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],
"title": "ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2",
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},
"entId": "GN010",
"entType": "SequenceVariantInterpretation",
"ld": {
"Assertion": [
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Insufficient Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642235",
"ldhIri": "https://cspec.genome.network/cspec/Assertion/id/135642235",
"modified": null,
"rev": "_inf5Ale--_"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Pathogenic",
"sepioId": "LN:LA26332-9"
},
"entType": "Assertion",
"ldhId": "135642237",
"ldhIri": "https://cspec.genome.network/cspec/Assertion/id/135642237",
"modified": null,
"rev": "_inf5Alm--B"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance",
"sepioId": "LN:LA26333-7"
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"entType": "Assertion",
"ldhId": "135642234",
"ldhIri": "https://cspec.genome.network/cspec/Assertion/id/135642234",
"modified": null,
"rev": "_inf5Ale--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Pathogenic",
"sepioId": "LN:LA6668-3"
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"entType": "Assertion",
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"ldhIri": "https://cspec.genome.network/cspec/Assertion/id/135642233",
"modified": null,
"rev": "_inf5Alm--_"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Benign",
"sepioId": "LN:LA6675-8"
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"entType": "Assertion",
"ldhId": "135642236",
"ldhIri": "https://cspec.genome.network/cspec/Assertion/id/135642236",
"modified": null,
"rev": "_inf5Alm--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Conflicting Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642231",
"ldhIri": "https://cspec.genome.network/cspec/Assertion/id/135642231",
"modified": null,
"rev": "_inf5Ale--_"
},
{
"entContent": {
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"label": "Likely Benign",
"sepioId": "LN:LA26334-5"
},
"entType": "Assertion",
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"ldhIri": "https://cspec.genome.network/cspec/Assertion/id/135642232",
"modified": null,
"rev": "_inf5Ale---"
}
],
"CriteriaCode": [
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
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],
"evidenceCategory": "Functional Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PM1",
"ns": "010",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/1856189/"
}
],
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation.\n * Missense substitution or in frame deletion of residues important in the active site architecture and substrate binding of GAA:- D282, W376, D404, L405, I441, W481, W516, D518, M519, R600, W613, D616, W618, F649, L650, H674.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639311",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639311",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--H"
},
{
"entContent": {
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"additionalComments": "There are no known repetitive regions without known function in GAA.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BP3",
"ns": "010",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0081",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639299",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639299",
"modified": "2022-01-19T20:33:34.305Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--Z"
},
{
"entContent": {
"_uniqueProp": "010_BS4_nuclear_GAA",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Segregation Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "010",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0071",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639294",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639294",
"modified": "2022-01-19T20:33:34.305Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--X"
},
{
"entContent": {
"_uniqueProp": "010_PM5_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "010",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense change at an amino acid residue where a different missense change determined to be 'likely pathogenic' has been seen before.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639292",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639292",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_inf5Apa--C"
},
{
"entContent": {
"_uniqueProp": "010_PM4_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "010",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a nonrepeat region or stop-loss variants.\n * In frame deletion/insertions of two or more amino acids but less than one exon.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a nonrepeat region or stop-loss variants.\n * In frame deletion/insertions of one amino acid.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639290",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639290",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--E"
},
{
"entContent": {
"_uniqueProp": "010_PM3_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Allelic Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "010",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Detected in trans with a pathogenic variant. Points-based system. See main specifications document.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Detected in trans with a pathogenic variant. Points-based system. See main specifications document.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Detected in trans with a pathogenic variant. Points-based system. See main specifications document.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Detected in trans with a pathogenic variant. Points-based system. See main specifications document.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639288",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639288",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--D"
},
{
"entContent": {
"_uniqueProp": "010_PP3_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "010",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "PP3 upgraded in strength to Moderate",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.\n * REVEL score >0.7 for missense variants.\n * In frame deletion or insertion predicted deleterious by 2 out of 3 tools (PROVEAN, MutationTaster, MutPred-InDel).\n * Predicted impact on splicing by SpliceAI (score >0.5).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639308",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639308",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--E"
},
{
"entContent": {
"_uniqueProp": "010_BP4_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "010",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Multiple lines of computational evidence suggest no impact on gene or gene product.\n * REVEL score <0.5 for missense variants.\n * In frame deletion or insertion predicted benign by PROVEAN, MutationTaster, and MutPred-InDel.\n * No predicted impact on splicing by SpliceAI (score <0.2)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639301",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639301",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_inf5Api--F"
},
{
"entContent": {
"_uniqueProp": "010_PS3_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Functional Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
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{
"source": "PubMed",
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{
"source": "PubMed",
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{
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"specificationType": [
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{
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"text": "",
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{
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{
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{
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{
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{
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"id": "0225",
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"strength": "Very Strong",
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"text": "",
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{
"applicability": "Not applicable",
"id": "0072",
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"status": "approved",
"strength": "Strong",
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"text": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function.\n * >60% normal GAA activity when the variant is expressed in a heterologous cell type.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
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"strengthSepioID": "SEPIO:0001327",
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"specificationType": [
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"strength": "Supporting",
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"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n * >50% activity when the variant is expressed in a heterologous cell type, or >30% activity if there is also evidence of normal synthesis and processing.",
"type": "EvidenceLineStrength"
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},
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"modifier": "genbadmin",
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{
"entContent": {
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"applicability": "Not applicable",
"id": "0090",
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"text": "",
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{
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"id": "0222",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"specificationType": [
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],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease.\n * Highest minor allele frequency >0.005 (>0.5%) in any continental population in gnomAD with >2000 alleles.",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
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"text": "",
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{
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"id": "0086",
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"text": "",
"type": "EvidenceLineStrength"
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"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
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},
{
"entContent": {
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"strengthDescriptor": [
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"strength": "Stand Alone",
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"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
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"type": "EvidenceLineStrength"
},
{
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"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
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{
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"strength": "Supporting",
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"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
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"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
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"ldhId": "638433025",
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"modified": "2022-01-19T20:31:31.320Z",
"modifier": "genbadmin",
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{
"entContent": {
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"strengthDescriptor": [
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"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
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},
{
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"strength": "Very Strong",
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"type": "EvidenceLineStrength"
},
{
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"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
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{
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"strength": "Supporting",
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"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
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"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
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]
},
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},
{
"entContent": {
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0219",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0065",
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"text": "",
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{
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"specificationType": [
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]
},
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},
{
"entContent": {
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"id": "0218",
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"text": "",
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{
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"text": "",
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{
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"id": "0073",
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"text": "",
"type": "EvidenceLineStrength"
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"id": "0217",
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{
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"id": "0078",
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"text": "",
"type": "EvidenceLineStrength"
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{
"entContent": {
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"applicability": "Not applicable",
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"text": "",
"type": "EvidenceLineStrength"
},
{
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"text": "",
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{
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"specificationType": [
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"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
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{
"applicability": "Not applicable",
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"status": "not approved",
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
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"text": "",
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}
]
},
"entType": "CriteriaCode",
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"modifier": "genbadmin",
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},
{
"entContent": {
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"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "010",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639293",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639293",
"modified": "2022-01-19T20:33:34.305Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--m"
},
{
"entContent": {
"_uniqueProp": "010_BS2_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Population Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "010",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the homozygous state in a healthy adult.\n * Homozygous individual of any age with normal GAA activity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0076",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639289",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639289",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--E"
},
{
"entContent": {
"_uniqueProp": "010_PM2_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Population Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "010",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0011",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Low frequency in population databases.\n * Minor allele frequency <0.1% (0.001) in all continental populations with >2000 alleles in gnomAD.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0030",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639312",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639312",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--H"
},
{
"entContent": {
"_uniqueProp": "010_BA1_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Population Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "010",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Common in population databases.\n * Highest minor allele frequency >0.01 (>1%) in any continental population in gnomAD with >2000 alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639306",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639306",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--G"
},
{
"entContent": {
"_uniqueProp": "010_PVS1_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "010",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/1856189/"
}
],
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease or in frame loss of an exon that contains residues involved in the active site of GAA.\n * Any nonsense, frameshift, or splice variant creating a premature stop codon before codon 916.\n * In frame deletions of an entire exon containing critical active site/substrate binding residues (exons 8 and 10), or for which another variant removing the exon is known to be pathogenic (exons 2 and 18).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n * In frame loss of an exon which is part of the catalytic barrel domain and contains pathogenic/likely pathogenic nontruncating variants (exons 6 and 9).\n * Initiator codon variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n * Premature termination codon in the 3’ end of GAA (3’ to codon 916), not predicted to be detected by nonsense-mediated decay.\n * Predicted exon-skipping due to canonical splice variant or exon deletion resulting in an in frame deletion of <10% of the gene product (exons 17, 19, and 20).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639304",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639304",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--F"
},
{
"entContent": {
"_uniqueProp": "010_PS4_nuclear_GAA",
"additionalComments": "There are no case-control studies for Pompe disease. As this is a recessive disorder, the prevalence of the variant in affected individuals may not be increased compared to controls (who could be heterozygous carriers). The number of patients with the variant will be addressed by the PM3 evidence code.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Population Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "010",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0053",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0057",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0032",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639303",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639303",
"modified": "2022-01-19T20:33:34.305Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--j"
},
{
"entContent": {
"_uniqueProp": "010_PP1_nuclear_GAA",
"additionalComments": "Sib-ships large enough to meet this criterion are extremely rare. In addition, because GAA is the only gene involved in Pompe disease, all patients are expected to be bi-allelic, regardless of whether the pathogenic variants can be, or have been, detected. A variant under assessment may not be the true pathogenic variant but instead in linkage disequilibrium with an unidentified pathogenic variant. For this reason, this criterion does not facilitate assessment of pathogenicity.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Segregation Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "010",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0023",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0040",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0060",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639302",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639302",
"modified": "2022-01-19T20:33:34.305Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--P"
},
{
"entContent": {
"_uniqueProp": "010_PS2_nuclear_GAA",
"additionalComments": "De novo variants are rarely reported in GAA (PMIDs 7981676, 27142047). The occurrence of de novo variants in GAA is not a mechanism of disease for Pompe disease, and the observation that a variant in GAA has arisen de novo does not support its causality. Any de novo variants will be assessed based on the variant type, functional evidence, and in trans data as described in these guidelines.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "De novo Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "010",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0016",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0051",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639298",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639298",
"modified": "2022-01-19T20:33:34.305Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--Y"
},
{
"entContent": {
"_uniqueProp": "010_PP4_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Other Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "010",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Phenotype specific for disease with single genetic etiology.\n * Points-based system. See main specifications document",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n * Points-based system. See main specifications document",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639310",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639310",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--G"
},
{
"entContent": {
"_uniqueProp": "010_PP2_nuclear_GAA",
"additionalComments": "Does not apply; there are benign and pathogenic missense variants in GAA.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Functional Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "010",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0033",
"instructionsToUse": "",
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{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433055",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433055",
"modified": "2022-01-19T20:31:31.552Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--W"
},
{
"entContent": {
"_uniqueProp": "011_PP3_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "011",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "REVEL score of ≥ 0.7\n OR\n>2 independent in silico missense predictors predict a damaging impact",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639389",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639389",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--D"
},
{
"entContent": {
"_uniqueProp": "011_PP2_nuclear_ITGA2B_ITGB3",
"additionalComments": "This rule does not apply because benign missense variants are not rare. This rule does not apply to GT due to the fact that these genes are thought to be highly polymorphic (PMID: 25827233).",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Functional Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "011",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This rule does not apply because benign missense variants are not rare.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639388",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639388",
"modified": "2022-01-19T20:33:34.409Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--Q"
},
{
"entContent": {
"_uniqueProp": "011_BA1_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Population Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "011",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Frequency cutoff of 0.24% (>0.0024 at 99.99% CI w/subpopulation w/min of 5 alleles).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639387",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639387",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--D"
},
{
"entContent": {
"_uniqueProp": "011_PM6_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "De novo Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "011",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use proposed SVI point recommendations.\n* Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use proposed SVI point recommendations.\n * Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use proposed SVI point recommendations.\n * Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0022",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use proposed SVI point recommendations.\n * Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639376",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639376",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--_"
},
{
"entContent": {
"_uniqueProp": "011_PM5_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "011",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use with no specification.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0048",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use at adjusted strength.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639373",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639373",
"modified": "2021-11-05T21:11:44.828Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--Y"
},
{
"entContent": {
"_uniqueProp": "011_BS1_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Population Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "011",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Frequency cutoff of 0.158% (>0.00158 at 99.99% CI w/subpopulation w/min of 5 alleles)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639368",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639368",
"modified": "2021-11-05T21:11:44.828Z",
"modifier": "genbadmin",
"rev": "_inf5Apy---"
},
{
"entContent": {
"_uniqueProp": "011_BP6_nuclear_ITGA2B_ITGB3",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"ITGA2B",
"ITGB3"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "011",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433054",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433054",
"modified": "2022-01-19T20:31:31.552Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--M"
},
{
"entContent": {
"_uniqueProp": "011_PVS1_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "011",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use decision tree as per SVI WG with specified “regions critical to protein function”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "PVS1 downgraded in strength to Strong",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "PVS1 downgraded in strength to Moderate",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639385",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639385",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--C"
},
{
"entContent": {
"_uniqueProp": "011_PS2_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "De novo Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "011",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use proposed SVI point recommendations.\n* Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "004",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use proposed SVI point recommendations.\n * Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639379",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639379",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--A"
},
{
"entContent": {
"_uniqueProp": "011_BS3_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Functional Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "011",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "* Must demonstrate normal aggregometry in a transgenic mouse model.\n OR\n* In a heterologous cell line, must demonstrate BOTH normal expression and normal protein function",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639372",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639372",
"modified": "2021-11-05T21:11:44.828Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--X"
},
{
"entContent": {
"_uniqueProp": "011_PM3_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Allelic Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "011",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639369",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639369",
"modified": "2021-11-05T21:11:44.828Z",
"modifier": "genbadmin",
"rev": "_inf5Ape---"
},
{
"entContent": {
"_uniqueProp": "011_BP5_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Other Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "011",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Do not use this rule as an individual can be a carrier of an unrelated pathogenic variant for a recessive disorder.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639386",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639386",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--C"
},
{
"entContent": {
"_uniqueProp": "011_PP1_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Segregation Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "011",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Segregations in proband plus >2 affected relatives.\n * Affected relatives must have both variants identified in proband.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Segregation in proband plus 2 affected relatives.\n * Affected relatives must have both variants identified in proband.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Segregation in proband plus 1 affected relative.\n * Affected relatives must have both variants identified in proband.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639383",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639383",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--Q"
},
{
"entContent": {
"_uniqueProp": "011_BP4_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "011",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "REVEL score of < 0.25",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639382",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639382",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--D"
},
{
"entContent": {
"_uniqueProp": "011_BP1_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "011",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Rule does not apply as truncating variants do not predominate and missense variants are a known cause of disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639374",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639374",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--_"
},
{
"entContent": {
"_uniqueProp": "011_PM2_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Population Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "011",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0030",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Prevalence <1/10,000 (<0.0001) alleles in gnomAD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639393",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639393",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--a"
},
{
"entContent": {
"_uniqueProp": "011_PM1_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Functional Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "011",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Rule does not apply due to genes being highly polymorphic.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639392",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639392",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--E"
},
{
"entContent": {
"_uniqueProp": "011_BP7_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "011",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use with no specification.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639390",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639390",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--R"
},
{
"entContent": {
"_uniqueProp": "011_PS4_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Population Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "011",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Rule does not apply due to rarity of disorder and lack of appropriate studies.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0057",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0032",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639384",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639384",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--B"
},
{
"entContent": {
"_uniqueProp": "011_BP2_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Allelic Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "011",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
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"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 2-6 MH case points. Probands with a personal or family history of an MH event are awarded 0.5 points, probands with a personal or family history of a positive (MHS) IVCT/CHCT are awarded an additional 0.5 points. Probands with multiple variants in RYR1 classified as VUS, likely pathogenic or pathogenic are not considered. Popmax in gnomAD ≤0.00006.\n* For variants with popmax MAF in gnomAD >0.00006, an odds ratio of ≥4.33 when comparing MH case points to allele count in gnomAD can qualify. Popmax in gnomAD must be <0.0038.",
"type": "EvidenceLineStrength"
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"id": "0032",
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"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared withthe prevalence in controls.\n* 1 MH case point. Probands with a personal or family history of an MH event are awarded 0.5 points, probands with a personal or family history of a positive (MHS) IVCT/CHCT are awarded an additional 0.5 points. Probands with multiple variants in RYR1 classified as VUS, likely pathogenic or pathogenic are not considered. Popmax in gnomAD ≤0.00006.\nFor variants with popmax MAF in gnomAD >0.00006, an odds ratio of ≥2.08 when comparing MH case points to allele count in gnomAD can qualify. Popmax in gnomAD must be <0.0038.",
"type": "EvidenceLineStrength"
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},
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639465",
"modified": "2022-05-12T15:33:55.804Z",
"modifier": "neethus",
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},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Benign",
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"disease": [
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],
"evidenceCategory": "Allelic Data",
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],
"geneType": "nuclear",
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"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"strengthDescriptor": [
{
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"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in cis with a pathogenic variant in any inheritance pattern",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639459",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639459",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--U"
},
{
"entContent": {
"_uniqueProp": "012_BS1_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Benign",
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"disease": [
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"evidenceCategory": "Population Data",
"gene": [
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"geneType": "nuclear",
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"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Popmax allele frequency >0.0008 (0.08%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639449",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639449",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--n"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Functional Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "012",
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"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Applicable with VCEP specification",
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"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
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"type": "EvidenceLineStrength"
},
{
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"id": "0054",
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"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Located in a mutational hot spot and/or critical and well established functional domain.\n* Residues 1-552 (N-terminal region) and 2,101-2,458 (central region), if PS1/PM5 applicable then PM1 should be used at supporting \n* Residues 4,631-4,991 (C-terminal region).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639473",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639473",
"modified": "2022-05-12T15:33:55.804Z",
"modifier": "neethus",
"rev": "_inf5Ap6--P"
},
{
"entContent": {
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"additionalComments": "",
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"gene": [
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],
"geneType": "nuclear",
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"sepioID": "SEPIO-CG:99038",
"specificationType": [],
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"id": "0087",
"instructionsToUse": "",
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"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Popmax allele frequency >0.0038 (0.38%)",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639468",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639468",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--o"
},
{
"entContent": {
"_uniqueProp": "012_PP1_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Segregation Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "012",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in ≥7 reported meioses",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in 5-6 reported meioses",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in 3-4 reported meioses",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639464",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639464",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--W"
},
{
"entContent": {
"_uniqueProp": "012_BP3_nuclear_RYR1",
"additionalComments": "BP3 is not applicable. RYR1 does not have repetitive regions without known function.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "012",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639461",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639461",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--V"
},
{
"entContent": {
"_uniqueProp": "012_PS2_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "De novo Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "012",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, ≥8 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 4-7 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 2-3 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 1 point",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639460",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639460",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--o"
},
{
"entContent": {
"_uniqueProp": "012_PS1_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "012",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change\n * Previously established pathogenic variant must reach a classification of pathogenic without PS1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Same amino acid change as a previously established likely pathogenic variant regardless of nucleotide change.\n* Previously established likely pathogenic variant must reach a classification of likely pathogenic without PS1.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639458",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639458",
"modified": "2022-05-12T15:33:55.804Z",
"modifier": "neethus",
"rev": "_inf5Ap6--c"
},
{
"entContent": {
"_uniqueProp": "012_PM5_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "012",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense varaint previously determined to be pathogenic\n * Previously established pathogenic variant must reach a classification of pathogenicity without PM5\n * Grantham score for alternate pathogenic variant must be less than for variant being assessed",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense change at an amino acid residue where a different missense variant previously determined to be pathogenic.\n * Previously established likely pathogenic variant can be considered supporting evidence, must reach a classification of likely pathogenic without PM5.\n* Grantham score for alternate likely pathogenic variant must be less than for variant being assessed.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639454",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639454",
"modified": "2022-05-12T15:33:55.804Z",
"modifier": "neethus",
"rev": "_inf5Ap2--W"
},
{
"entContent": {
"_uniqueProp": "012_BS3_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Functional Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "012",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0100",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "Well-established functional studies show no damaging effect on protein function\n * Three or more independent ex vivo studies, NO significant release of Ca2+ in response to agonist",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Strength, Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Well-established functional studies show no damaging effect on protein function\n * No significant increased sensitivity to RYR1 agonist in an approved in vitro assay, Ca2+ release measured, n≥3\n * One or two independent ex vivo studies, NO significant release of Ca2+ in response to agonist\n * Knock-in mouse showing no MH reaction in response to RYR1 agonist AND no increased sensitivity to RYR1 agonists in ex vivo tissue/cells",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639453",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639453",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--X"
},
{
"entContent": {
"_uniqueProp": "012_BS2_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Population Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "012",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.\n * Two or more variant positive individuals with a negative IVCT/CHCT test",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0098",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.\n * One variant positive individual with a negative IVCT/CHCT test",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0076",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639451",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639451",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--W"
},
{
"entContent": {
"_uniqueProp": "012_BP6_nuclear_RYR1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"RYR1"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "012",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433084",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433084",
"modified": "2022-01-19T20:31:31.799Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--L"
},
{
"entContent": {
"_uniqueProp": "012_PP4_nuclear_RYR1",
"additionalComments": "PP4 is not applicable, variants in CACNA1S also result in MHS.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Other Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "012",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639472",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639472",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--p"
},
{
"entContent": {
"_uniqueProp": "012_PS3_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Functional Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "012",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established functional studies supportive of a damaging effect on protein function\n * Knock-in mouse showing MH reaction in response to RYR1 agonist AND increased sensitivity to RYR1 agonists in ex vivo tisue/cells",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Well-established functional studies supportive of a damaging effect on protein function\n * Increased sensitivity to RYR1 agonist in HEK293 in vitro assay, Ca2+ release significantly increased compared to WT, controls to include known pathogenic and benign variants, n≥3.\n * Three or more independent ex vivo studies all showing release of Ca2+ in response to RYR1 agonist\n * Knock-in mouse showing MH reaction in response to RYR1 agonist OR increased sensitivity to RYR1 agonists in ex vivo tissue/cells (but not both, which would be PS3_strong)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established functional studies supportive of a damaging effect on protein function\n * Two independent ex vivo studies all showing release of Ca2+ in response to RYR1 agonist",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639462",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639462",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--p"
},
{
"entContent": {
"_uniqueProp": "012_PM3_nuclear_RYR1",
"additionalComments": "PM3 is not applicable. MHS is inherited as an autosomal dominant trait with reduced penetrance.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Allelic Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "012",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639450",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639450",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--R"
},
{
"entContent": {
"_uniqueProp": "012_PM2_nuclear_RYR1",
"additionalComments": "PM2 is not used alone.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Population Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "012",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0030",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639474",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639474",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--q"
},
{
"entContent": {
"_uniqueProp": "012_PVS1_nuclear_RYR1",
"additionalComments": "PVS1 is not applicable. MHS is due to gain of function variants in RYR1.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "012",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0244",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639466",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639466",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--n"
},
{
"entContent": {
"_uniqueProp": "012_PM6_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "De novo Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "012",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, ≥8 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 4-7 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 2-3 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 1 point",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639457",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639457",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--l"
},
{
"entContent": {
"_uniqueProp": "012_PP5_nuclear_RYR1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"RYR1"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "012",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433085",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433085",
"modified": "2022-01-19T20:31:31.799Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--N"
},
{
"entContent": {
"_uniqueProp": "012_PP3_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "012",
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{
"applicability": "Not applicable",
"id": "0238",
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"status": "not approved",
"strength": "Stand Alone",
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"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product\n * Use REVEL score of >0.85",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0062",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
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"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--d"
},
{
"entContent": {
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"applicability": "Not Applicable for this VCEP",
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"disease": [
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],
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"applicability": "Not applicable",
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"status": "not approved",
"strength": "Stand Alone",
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0034",
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"status": "not approved",
"strength": "Moderate",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0061",
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"status": "not approved",
"strength": "Supporting",
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"text": "",
"type": "EvidenceLineStrength"
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},
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"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--c"
},
{
"entContent": {
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"additionalComments": "BP5 is not applicable as individuals have been described with MHS and two pathogenic variants in RYR1.",
"applicability": "Not Applicable for this VCEP",
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"disease": [
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],
"evidenceCategory": "Other Data",
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],
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"ns": "012",
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"id": "0218",
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"status": "not approved",
"strength": "Stand Alone",
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"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639467",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639467",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--b"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
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],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BP4",
"ns": "012",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Computational evidence suggest no impact on gene or gene product, REVEL score of <0.5",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639463",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639463",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--m"
},
{
"entContent": {
"_uniqueProp": "012_BS4_nuclear_RYR1",
"additionalComments": "BS4 is not applicable. Phenotype for MHS is routinely determined based on the vitro contraction test (IVCT) that has a false positive rate of approximately 6% (PP1) or the caffeine-halothane contracture test (CHCT). As the phenotype in individuals who have not experienced an MH crisis cannot be reliably determined BS4 is not utilized.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
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],
"evidenceCategory": "Segregation Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BS4",
"ns": "012",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
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"id": "0229",
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0071",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639456",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639456",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--T"
},
{
"entContent": {
"_uniqueProp": "012_BP1_nuclear_RYR1",
"additionalComments": "BP1 is not applicable. MH is caused primarily by missense variants in RYR1.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
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],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BP1",
"ns": "012",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639455",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639455",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--Y"
},
{
"entContent": {
"_uniqueProp": "012_PM4_nuclear_RYR1",
"additionalComments": "PM4 is not applicable. The majority of RYR1 variants that are causative for MHS are missense variants.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
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],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PM4",
"ns": "012",
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"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "009",
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"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639452",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639452",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--S"
}
],
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{
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"basicPropertyValues": [
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"val": "https://www.malacards.org/card/malignant_hyperthermia"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0002254"
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{
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"val": "http://identifiers.org/meddra/10020844"
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{
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{
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"val": "http://identifiers.org/snomedct/405501007"
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{
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"val": "http://linkedlifedata.com/resource/umls/id/C0024591"
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{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_8545"
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{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C84869"
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{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_423"
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],
"definition": {
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"subsets": [
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{
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{
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{
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},
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{
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{
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},
{
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},
{
"val": "MEDGEN:9867"
},
{
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{
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{
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{
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},
{
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{
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]
},
"type": "CLASS"
},
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"name": "malignant hyperthermia of anesthesia"
},
"entId": "MONDO:0018493",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0018493",
"entType": "Disease",
"ldhId": "135642187",
"ldhIri": "https://cspec.genome.network/cspec/Disease/id/135642187",
"modified": "2025-10-07T16:15:01.878Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7yZ-q---"
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],
"EvidenceCategory": [
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"entContent": {
"label": "Other Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642490",
"ldhIri": "https://cspec.genome.network/cspec/EvidenceCategory/id/135642490",
"modified": null,
"rev": "_inf5Asm--r"
},
{
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"label": "Other Database",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642489",
"ldhIri": "https://cspec.genome.network/cspec/EvidenceCategory/id/135642489",
"modified": null,
"rev": "_inf5Asm--o"
},
{
"entContent": {
"label": "De novo Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642492",
"ldhIri": "https://cspec.genome.network/cspec/EvidenceCategory/id/135642492",
"modified": null,
"rev": "_inf5Asm--t"
},
{
"entContent": {
"label": "Population Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642486",
"ldhIri": "https://cspec.genome.network/cspec/EvidenceCategory/id/135642486",
"modified": null,
"rev": "_inf5AsS--_"
},
{
"entContent": {
"label": "Allelic Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642488",
"ldhIri": "https://cspec.genome.network/cspec/EvidenceCategory/id/135642488",
"modified": null,
"rev": "_inf5Asi--A"
},
{
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},
"entType": "EvidenceCategory",
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"ldhIri": "https://cspec.genome.network/cspec/EvidenceCategory/id/135642491",
"modified": null,
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},
{
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},
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"ldhIri": "https://cspec.genome.network/cspec/EvidenceCategory/id/135642487",
"modified": null,
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},
{
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},
"entType": "EvidenceCategory",
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"ldhIri": "https://cspec.genome.network/cspec/EvidenceCategory/id/135642485",
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"strengthSepioID": "SEPIO:0000216",
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"type": "EvidenceLineStrength"
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"text": "",
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"strength": "Strong",
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"text": "Variant meets Level 1 pathogenic functional study criteria. See Table 3.\n(1) Study of the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding, and LDL internalization) performed in heterologous cells (with noendogenous LDLR) transfected with mutant plasmid. Assay result of <70% ofwild-type activity in either expression/biosynthesis, binding OR internalization.",
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],
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"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
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"text": "",
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"strengthSepioID": "SEPIO:0000216",
"text": "See PS2 above.",
"type": "EvidenceLineStrength"
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"strength": "Supporting",
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"text": "",
"type": "EvidenceLineStrength"
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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"geneType": "nuclear",
"label": "PM5",
"ns": "013",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
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"applicability": "Not applicable",
"id": "0234",
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0047",
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"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Applicable as originally described",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense variant at a codon with ≥2 missense variants classified pathogenic (by these guidelines), and predicts a different amino acid change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationtype": [
"Clarification"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense variant at the same codon as a variant classified pathogenic (by these guidelines), and predicts a different amino acid change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637696",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637696",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_inf5Apa---"
},
{
"entContent": {
"_uniqueProp": "013_PM3_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Allelic Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "013",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion can be used for a candidate LDLR variant observed in an individual with a homozygous FH phenotype when there is only one other pathogenic or likely pathogenic variant in LDLR (in trans), APOB or PCSK9. Caveat: variant must also meet PM2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637692",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637692",
"modified": "2021-11-12T23:33:06.714Z",
"modifier": "neethus",
"rev": "_inf5Apy--E"
},
{
"entContent": {
"_uniqueProp": "013_PM2_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Population Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "013",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0011",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant has a PopMax MAF ≤0.0002 (0.02%) in gnomAD. Consider exceptions for known founder variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0030",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637716",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637716",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--A"
},
{
"entContent": {
"_uniqueProp": "013_BP7_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "013",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant is synonymous.\nCaveat: variant must also meet BP4 (i.e. no predicted impact on splicing).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637713",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637713",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--C"
},
{
"entContent": {
"_uniqueProp": "013_BA1_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Population Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "013",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Variant has a PopMax FAF ≥0.005 (0.5%) in gnomAD.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637710",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637710",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--B"
},
{
"entContent": {
"_uniqueProp": "013_PVS1_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "013",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "See PVS1 flow diagram (Figure 1).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "See PVS1 flow diagram (Figure 1).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See PVS1 flow diagram (Figure 1).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637708",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637708",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--_"
},
{
"entContent": {
"_uniqueProp": "013_BS1_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Population Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "013",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant has a PopMax FAF ≥0.002 (0.2%) in gnomAD.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637691",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637691",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_inf5Apu---"
},
{
"entContent": {
"_uniqueProp": "013_PP3_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "013",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "REVEL score ≥0.75 (missense variants), or predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637712",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637712",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_inf5Apa--B"
},
{
"entContent": {
"_uniqueProp": "013_PP2_nuclear_LDLR",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Functional Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "013",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637711",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637711",
"modified": "2022-01-19T20:33:34.697Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--f"
},
{
"entContent": {
"_uniqueProp": "013_BP5_nuclear_LDLR",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Other Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "013",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637709",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637709",
"modified": "2022-01-19T20:33:34.697Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--r"
},
{
"entContent": {
"_uniqueProp": "013_PP1_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Segregation Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "013",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Variant segregates with phenotype in ≥6 informative meioses in ≥1 family. Must include ≥2 affected relatives (LDL-C >75th centile) with the variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant segregates with phenotype in 4-5 informative meioses in ≥1 family. Must include ≥2 affected relatives (LDL-C >75th centile) with the variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Variant segregates with phenotype in 2-3 informative meioses in ≥1 family. Must include ≥1 affected relative (LDL-C >75th centile) with the variant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637706",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637706",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_inf5Apy---"
},
{
"entContent": {
"_uniqueProp": "013_BP4_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "013",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "REVEL score ≤0.5 (missense variants), or no predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637705",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637705",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--A"
},
{
"entContent": {
"_uniqueProp": "013_BP3_nuclear_LDLR",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "013",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637703",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637703",
"modified": "2022-01-19T20:33:34.697Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--e"
},
{
"entContent": {
"_uniqueProp": "013_PS1_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "013",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Clarification"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense variant at the same codon as a variant classified pathogenic (by these guidelines), and predicts the same amino acid change.\nCaveat: there is no in silico predicted splicing impact for either variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637700",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637700",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_inf5Api--B"
},
{
"entContent": {
"_uniqueProp": "013_BP1_nuclear_LDLR",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "013",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Missense variant in gene where only LOF causes disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637697",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637697",
"modified": "2022-01-19T20:33:34.697Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--X"
},
{
"entContent": {
"_uniqueProp": "013_BS3_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Functional Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "013",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant meets Level 1 benign functional study criteria. See Table 3.\n(1) Study of the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding, and LDL internalization) performed in heterologous cells (with no endogenous LDLR) transfected with mutant plasmid. Assay result of >90% of wild-type activity in expression/biosynthesis, binding AND internalization.\nNote: studies of only part of the LDLR cycle are not eligible for BS3 or BS3_Supporting. ",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant meets Level 3 benign functional study criteria. See Table 3.\n(1) Study of whole LDLR cycle in a) true homozygous patient cells, with assay result of >90% of wild-type activity in biosynthesis, binding AND internalization; or in b) heterozygous patient cells with assay result of >95% of wild-type activity in biosynthesis, binding AND internalization.\n(2) Luciferase studies with transcription levels of >90% when compared to wild-type (applicable to 5’UTR/promoter variants).\n(3) RNA studies, using RNA extracted from heterozygous or homozygous patientcells, with a) aberrant transcripts quantification, where aberrant transcript is<10% of total transcript OR b) without transcript quantification where noaberrant transcript is confirmed by sequencing.\n(4) Minigene splicing assay where only wild-type transcript is present and confirmed by sequencing.\n(5) High-throughput assays as defined above; only applicable when assay canindicate the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding AND internalization) is unaffected.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637695",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637695",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_inf5Apu---"
},
{
"entContent": {
"_uniqueProp": "013_BS2_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Population Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "013",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant is identified in ≥3 heterozygous or ≥1 homozygous well-phenotyped, untreated, normolipidemic adults (unrelated).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0076",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637693",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637693",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_inf5Api--_"
},
{
"entContent": {
"_uniqueProp": "013_PP5_nuclear_LDLR",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"LDLR"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "013",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433115",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433115",
"modified": "2022-01-19T20:31:32.045Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--P"
},
{
"entContent": {
"_uniqueProp": "013_PM1_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Functional Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "013",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense variant located in exon 4, or a missense change in one of 60 highly conserved cysteine residues (listed in Supp. Table 4). Caveat: variant must also meet PM2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637715",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637715",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_inf5Api--D"
},
{
"entContent": {
"_uniqueProp": "013_PP4_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Other Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "013",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Any LDLR variant identified in an FH patient [diagnosis based on validated clinical criteria, e.g. Dutch Lipid Clinic Network (≥6), Simon Broome possible/definite), MEDPED], after alternative causes of high cholesterol are excluded.\nCaveat: variant must also meet PM2.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637714",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637714",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_inf5Api--C"
},
{
"entContent": {
"_uniqueProp": "013_PS2_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "De novo Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "013",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
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"text": "",
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{
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"strength": "Supporting",
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"type": "EvidenceLineStrength"
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"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
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{
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"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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{
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"strength": "Strong",
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"text": "",
"type": "EvidenceLineStrength"
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"id": "0078",
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{
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"id": "0210",
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"status": "not approved",
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"text": "",
"type": "EvidenceLineStrength"
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"applicability": "Not applicable",
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"id": "0081",
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"strength": "Supporting",
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]
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"modifier": "genbadmin",
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{
"entContent": {
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"applicability": "Not applicable",
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"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
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"text": "",
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{
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "001",
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"status": "not approved",
"strength": "Supporting",
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"text": "",
"type": "EvidenceLineStrength"
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"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
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},
{
"entContent": {
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"applicability": "Not applicable",
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{
"applicability": "Not applicable",
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"text": "",
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{
"applicability": "Not applicable",
"id": "004",
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"status": "not approved",
"strength": "Moderate",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0043",
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"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
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]
},
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"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
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{
"entContent": {
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"id": "0209",
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0207",
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"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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"id": "0068",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
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"id": "0208",
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"status": "not approved",
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"text": "",
"type": "EvidenceLineStrength"
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"id": "0084",
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"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern",
"type": "EvidenceLineStrength"
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]
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"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
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"applicability": "Not applicable",
"id": "0240",
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"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0021",
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"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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"id": "0050",
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"status": "approved",
"strength": "Strong",
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"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change",
"type": "EvidenceLineStrength"
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"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
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]
},
"entType": "CriteriaCode",
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"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_inf5Api--S"
},
{
"entContent": {
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"id": "0091",
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"strength": "Stand Alone",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0224",
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"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0069",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in a healthy adult individual in the homozygous state AND/OR Normal mtDNA content (1. Must be performed in muscle and/or liver; blood, fibroblast, and buccal not acceptable; 2. Must be performed in children only - defined as <18 years old; 3. A normal level is defined as >50%.)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0076",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of COX negative fibers in muscle (children and adults)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637907",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637907",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--R"
},
{
"entContent": {
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"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
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"evidenceCategory": "Population Data",
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"geneType": "nuclear",
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"ns": "014",
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"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
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},
{
"applicability": "Not applicable",
"id": "0048",
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}
]
},
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"modifier": "genbadmin",
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},
{
"entContent": {
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"evidenceCategory": "Other Database",
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],
"instructionsToUse": "",
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"references": [
{
"id": "29543229",
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],
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{
"applicability": "Not applicable",
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},
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},
{
"entContent": {
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"text": "",
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{
"applicability": "Not applicable",
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"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0028",
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"strengthSepioID": "SEPIO:0000330",
"text": "",
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"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
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"applicability": "Not applicable",
"id": "0054",
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"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
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]
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"entType": "CriteriaCode",
"ldhId": "135637955",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637955",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--i"
},
{
"entContent": {
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"additionalComments": "",
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"disease": [
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"evidenceCategory": "De novo Data",
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"geneType": "nuclear",
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"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0235",
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo in a patient with the disease and no family history",
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{
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"id": "0010",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of paternity and maternity",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637939",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637939",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--U"
},
{
"entContent": {
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"additionalComments": "",
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"sepioID": "SEPIO-CG:99029",
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{
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"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use per SVI guidance",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637932",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637932",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_inf5Apa--b"
},
{
"entContent": {
"_uniqueProp": "014_BS1_nuclear_ETHE1",
"additionalComments": "MAF - >0.01(>1.0%), Prevalence - <1/1,000,000, Allelic Heterogeneity - 20% (estimated), Penetrance - 100%. ",
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"specificationType": [],
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{
"applicability": "Not applicable",
"id": "0090",
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": ">0.0002 (>0.020%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637931",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637931",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--M"
},
{
"entContent": {
"_uniqueProp": "014_PM2_nuclear_POLG",
"additionalComments": "Per SVI: Use a threshold an order of magnitude below BS1 threshold",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
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],
"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PM2",
"ns": "014",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "<0.0005 (<0.05% )",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0030",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637930",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637930",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_inf5Apm---"
},
{
"entContent": {
"_uniqueProp": "014_PM1_nuclear_POLG",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Functional Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "014",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637929",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637929",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--g"
},
{
"entContent": {
"_uniqueProp": "014_PP4_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Other Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PP4",
"ns": "014",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0018",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1. Mitochondrial DNA depletion showing ≤ 20% of controls, OR \n2. Multiple mitochondrial DNA deletions (NOTE:depletion and/or deletion analysis must be performed in muscle and/or liver; other tissues such as blood, fibroblast, and buccal are not acceptable; Must be performed in child, as defined as <18 years old) \nNote: For both scenarios 1 and 2, will only apply if other mtDNA maintenance disorders have been excluded (exome sequencing or comprehensive panel-based testing)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1. Mitochondrial DNA depletion showing 20-50% of controls in children (< 18 years of age), AND/OR \n2. COX negative fibers in muscle in children and/or adults\nNote: Will only apply if other mtDNA maintenance disorders have been excluded (exome sequencing or comprehensive panel-based testing)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637928",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637928",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--L"
},
{
"entContent": {
"_uniqueProp": "014_PP1_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
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],
"evidenceCategory": "Segregation Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PP1",
"ns": "014",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0023",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0040",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Further define “affected” as an individual in whom there is objective evidence of manifestations consistent with POLG-related disorders spectrum: Alpers-Huttenlocher syndrome (AHS), childhood myocerebrohepatopathy spectrum (MCHS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), and/or progressive external ophthalmoplegia (PEO)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637920",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637920",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--J"
},
{
"entContent": {
"_uniqueProp": "014_BS1_nuclear_POLG",
"additionalComments": "MAF - >0.005 (>0.5%), Prevalence - 1/10,000 , Allelic Heterogeneity - 50% (estimated), Penetrance - 100%. ",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
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],
"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BS1",
"ns": "014",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": ">0.005 (>0.5% - AR)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637905",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637905",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--N"
},
{
"entContent": {
"_uniqueProp": "014_BP7_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0019169"
],
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{
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{
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{
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{
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{
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{
"applicability": "Not applicable",
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{
"applicability": "Not applicable",
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{
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"strength": "Very Strong",
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{
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{
"applicability": "Not applicable",
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{
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{
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"text": "",
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{
"applicability": "Not applicable",
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"strengthSepioID": "SEPIO:0000329",
"text": "",
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{
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"text": "",
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{
"applicability": "Not applicable",
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"text": "",
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{
"applicability": "Not applicable",
"id": "0033",
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"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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"applicability": "Not applicable",
"id": "0034",
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"text": "",
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"applicability": "Not applicable",
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"text": "",
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"modified": "2022-01-19T20:33:34.959Z",
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{
"entContent": {
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"applicability": "Not applicable",
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"text": "",
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{
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0052",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0039",
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"strength": "Moderate",
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"text": "",
"type": "EvidenceLineStrength"
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"id": "0045",
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"status": "approved",
"strength": "Supporting",
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}
]
},
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"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
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},
{
"entContent": {
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"applicability": "Not applicable",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0016",
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"status": "not approved",
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"text": "",
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{
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"id": "0051",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
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"text": "De novo in a patient with the disease and no family history",
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{
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"id": "004",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0043",
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"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
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"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--R"
},
{
"entContent": {
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"text": "",
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{
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"id": "0227",
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"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0071",
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"id": "0228",
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"text": "",
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"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
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}
]
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"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--_"
},
{
"entContent": {
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0225",
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"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0072",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
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]
},
"entType": "CriteriaCode",
"ldhId": "135637935",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637935",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--b"
},
{
"entContent": {
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"additionalComments": "",
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{
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"id": "0215",
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"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0080",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively. Will also utilize POLG pathogenicity prediction server if/when live again (PMID: 28480171); both tools (REVEL and server) will have to be in agreement to score",
"type": "EvidenceLineStrength"
}
]
},
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637919",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--S"
},
{
"entContent": {
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"baseStrength": "Benign",
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"disease": [
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],
"evidenceCategory": "Segregation Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BS4",
"ns": "014",
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"status": "not approved",
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"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0071",
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"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected and/or treated members of a family.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637912",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637912",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
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{
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{
"entContent": {
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"applicability": "Not applicable",
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"id": "0052",
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{
"entContent": {
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"id": "0240",
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{
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"id": "0021",
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"text": "",
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"id": "0050",
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"id": "0046",
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"status": "not approved",
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"applicability": "Not applicable",
"id": "0036",
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"text": "",
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"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--K"
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{
"entContent": {
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"id": "0235",
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"text": "",
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{
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"id": "0014",
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"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0037",
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"id": "0010",
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{
"entContent": {
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"applicability": "Not applicable",
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{
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"id": "0047",
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"text": "",
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{
"applicability": "Not applicable",
"id": "0056",
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"text": "",
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"id": "008",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
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"text": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before",
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{
"applicability": "Not applicable",
"id": "0048",
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"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
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]
},
"entType": "CriteriaCode",
"ldhId": "135637884",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637884",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--L"
},
{
"entContent": {
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"additionalComments": "MAF - ><0.00005 (0.0050%). Notes: Per SVI: Use a threshold an order of magnitude below BS1 threshold",
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"sepioID": "SEPIO-CG:99028",
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"applicability": "Not applicable",
"id": "0231",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0044",
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"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
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{
"applicability": "Not applicable",
"id": "0013",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0011",
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"strengthSepioID": "SEPIO:0000216",
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{
"applicability": "Not applicable",
"id": "0030",
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"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
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]
},
"entType": "CriteriaCode",
"ldhId": "135637878",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637878",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_inf5Api--M"
},
{
"entContent": {
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"sepioID": "SEPIO-CG:99027",
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{
"applicability": "Not applicable",
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"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
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{
"applicability": "Not applicable",
"id": "0028",
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"strength": "Strong",
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"text": "",
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{
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"id": "006",
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"status": "not approved",
"strength": "Moderate",
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"text": "",
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{
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"id": "0054",
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"strength": "Supporting",
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"text": "",
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"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--Y"
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{
"entContent": {
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"applicability": "Not Applicable for this VCEP",
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"instructionsToUse": "",
"label": "PP5",
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"references": [
{
"id": "29543229",
"source": "PubMed",
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],
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{
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"strength": "Very Strong",
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"type": "EvidenceLineStrength"
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{
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"strength": "Strong",
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"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
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"strength": "Supporting",
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"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433199",
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"modified": "2022-01-19T20:31:32.743Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--N"
},
{
"entContent": {
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"id": "0087",
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"strengthSepioID": "SEPIO:0000325",
"text": ">0.001 (>0.1%)",
"type": "EvidenceLineStrength"
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{
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"id": "0201",
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"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0202",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637950",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637950",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--T"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Pathogenic",
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"disease": [
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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"geneType": "nuclear",
"label": "PVS1",
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"sepioID": "SEPIO-CG:99022",
"specificationType": [],
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"applicability": "Not applicable",
"id": "0245",
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0017",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Applied per PVS1 flowsheet of Abou Toyoun et al.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
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"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--W"
},
{
"entContent": {
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"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
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"disease": [
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"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PS4",
"ns": "014",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
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"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0053",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0057",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0032",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637947",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637947",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--h"
},
{
"entContent": {
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"additionalComments": "",
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"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Segregation Data",
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"ETHE1"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "014",
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"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
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"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0023",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0040",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637946",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637946",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--M"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Benign",
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"disease": [
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],
"evidenceCategory": "Allelic Data",
"gene": [
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],
"geneType": "nuclear",
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"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637941",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637941",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--W"
},
{
"entContent": {
"_uniqueProp": "014_PM5_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "014",
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"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637936",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637936",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--T"
},
{
"entContent": {
"_uniqueProp": "014_PM4_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "014",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637934",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637934",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--O"
},
{
"entContent": {
"_uniqueProp": "014_PP3_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "014",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively\n * Will also utilize POLG pathogenicity prediction server if/when live again (PMID: 28480171); both tools (REVEL and server) will have to be in agreement to score",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637926",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637926",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_inf5Apa--J"
},
{
"entContent": {
"_uniqueProp": "014_BP5_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Other Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "014",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637923",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637923",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--Q"
},
{
"entContent": {
"_uniqueProp": "014_PS4_nuclear_POLG",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Population Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "014",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Rarely, pathogenic variants cause disease in an AD manner. For these variants only, presence in: 2 unrelated probands will be considered supporting evidence, 4 unrelated probands will be considered moderate evidence, 16 unrelated probands will be strong evidence.\n * Note: This will only be utilized when there is segregation evidence supporting autosomal dominant inheritance",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0057",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0032",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637921",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637921",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--b"
},
{
"entContent": {
"_uniqueProp": "014_PM6_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "De novo Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "014",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo in a patient with the disease and no family history",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of paternity and maternity",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637913",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637913",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_inf5Api--R"
},
{
"entContent": {
"_uniqueProp": "014_PM3_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Allelic Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "014",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use per SVI guidance.\nNote: T251I and P587L are almost always in cis",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637906",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637906",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--A"
},
{
"entContent": {
"_uniqueProp": "014_PP4_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Other Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "014",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One of the following criteria are met: \n(1) Pyruvate radioactive enzyme assay showing decreased (as defined as <3rd percentile of controls) for PDC, activated and decreased ratios (PDC/E3 and/or PDC/CS) in fibroblasts, muscle, and/or lymphocytes; \n(2) other assays showing decrease in PDC activity (ie: western blot, immunocapture, and activity; commercial kits for research); \n(3) abnormally high pyruvate and/or pyruvate/lactate ratio",
"type": "EvidenceLineStrength"
}
]
},
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637902",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
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},
{
"entContent": {
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"additionalComments": "",
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"applicability": "Not applicable",
"id": "0238",
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"strength": "Stand Alone",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0025",
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"status": "not approved",
"strength": "Moderate",
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"text": "",
"type": "EvidenceLineStrength"
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"id": "0062",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637900",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637900",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--O"
},
{
"entContent": {
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"additionalComments": "",
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"evidenceCategory": "Other Data",
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"geneType": "nuclear",
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"id": "0218",
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"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0073",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
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"status": "not approved",
"strength": "Moderate",
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"text": "",
"type": "EvidenceLineStrength"
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"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease",
"type": "EvidenceLineStrength"
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},
"entType": "CriteriaCode",
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637897",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_inf5Api--O"
},
{
"entContent": {
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"additionalComments": "",
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"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0017",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Applied per PVS1 flowsheet of Abou Toyoun et al.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637896",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637896",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--h"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BP3",
"ns": "014",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637891",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637891",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--M"
},
{
"entContent": {
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"additionalComments": "Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity",
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"disease": [
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],
"evidenceCategory": "De novo Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PS2",
"ns": "014",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo in a patient with the disease and no family history",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637890",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637890",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--M"
},
{
"entContent": {
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"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
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],
"evidenceCategory": "Allelic Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BP2",
"ns": "014",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0084",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637889",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637889",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--a"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
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],
"evidenceCategory": "Segregation Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BS4",
"ns": "014",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0071",
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"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected and/or treated members of a family.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637886",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637886",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--I"
},
{
"entContent": {
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"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
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],
"evidenceCategory": "Allelic Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PM3",
"ns": "014",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637880",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637880",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--Z"
},
{
"entContent": {
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"additionalComments": "",
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"disease": [
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"evidenceCategory": "Computational And Predictive Data",
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"sepioID": "SEPIO-CG:99049",
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"strengthDescriptor": [
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"id": "0221",
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0079",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637875",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637875",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--L"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
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"evidenceCategory": "Other Data",
"gene": [
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"geneType": "nuclear",
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"ns": "014",
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"sepioID": "SEPIO-CG:99047",
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"strengthDescriptor": [
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"id": "0218",
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
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"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0078",
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"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637871",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637871",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_inf5Api--L"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
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],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
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"label": "BA1",
"ns": "015",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Top-level haplogroup defining variants in individuals that are members of that same top-level haplogroup OR Allele frequency > 0.01 (1%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638268",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638268",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_inf5Apa--N"
},
{
"entContent": {
"_uniqueProp": "015_PP1_mitochondrial",
"additionalComments": "Variant must not only segregate in maternal family members, but the level of heteroplasmy must also segregate with disease manifestations, where those individuals with more mild symptoms or appearing to be healthy have lower to undetectable levels of the variant and those more severely affected individuals and/or tissues have higher levels of the variant.\nThis criterion cannot be applied when a variant is present at homoplasmy in multiple family members.",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "PP1",
"ns": "015",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0023",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in 5+ maternal family members and level of heteroplasmy segregating with disease manifestations",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in 2-4 maternal family members and level of heteroplasmy segregating with disease manifestations",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638264",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638264",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--c"
},
{
"entContent": {
"_uniqueProp": "015_BP3_mitochondrial",
"additionalComments": "There are a few locations in the mtDNA genome where indels within a repetitive region are observed outside of two common locations: one is in the hypervariable region 1 (around position 16,189) and the other in hypervariable region 2 (around position 310). These indels are well-known benign findings.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"geneType": "mitochondrial",
"label": "BP3",
"ns": "015",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638261",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638261",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--j"
},
{
"entContent": {
"_uniqueProp": "015_BS4_mitochondrial",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "BS4",
"ns": "015",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family and/or segregation of disease in paternal family members",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638256",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638256",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--D"
},
{
"entContent": {
"_uniqueProp": "015_PM2_mitochondrial",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"geneType": "mitochondrial",
"label": "PM2",
"ns": "015",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0030",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Frequency <0.00002 (0.002%, 1/50,000) from controls",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638274",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638274",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--W"
},
{
"entContent": {
"_uniqueProp": "015_BP7_mitochondrial",
"additionalComments": "Mitochondrial genes do not undergo splicing. Conservation is included in predictor algorithms used in PP3 and BP4, so conservation will be incorporated in this criterion.",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"geneClass": [
"mRNA"
],
"geneType": "mitochondrial",
"label": "BP7",
"ns": "015",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638271",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638271",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--e"
},
{
"entContent": {
"_uniqueProp": "015_PS2_mitochondrial",
"additionalComments": "Older sequencing techniques such as Sanger sequencing cannot reliably detect heteroplasmy levels below 30-50%. Current NGS techniques can typically detect heteroplasmy levels as low as 1.5%. It is recommended to test several tissues in the mother to fully assess for the presence and level of the mtDNA variant in question. Utilize ClinGen SVI recommendation for applying these criteria (https://clinicalgenome.org/site/assets/files/3461/ svi_proposal_for_de_novo_criteria_v1_0.pdf), the mitochondrial genome would best fit with Table 1 “phenotypic consistency” category of “phenotype consistent with gene but not highly specific.”",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "PS2",
"ns": "015",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0016",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "004",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0043",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638260",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638260",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--e"
},
{
"entContent": {
"_uniqueProp": "015_PM5_mitochondrial",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "PM5",
"ns": "015",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applied per original ACMG/AMP guidelines (protein-coding genes)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0048",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Same nucleotide position as previously established pathogenic variant in a rRNA/tRNA",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638254",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638254",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--V"
},
{
"entContent": {
"_uniqueProp": "015_BS3_mitochondrial",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"geneType": "mitochondrial",
"label": "BS3",
"ns": "015",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0085",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "No evidence of functional effect in cybrid studies or single fiber analysis is present (no statistically significant difference from control; mean values of <2 SD from control mean, or 50% enzyme activity compared to controls).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638253",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638253",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--C"
},
{
"entContent": {
"_uniqueProp": "015_PM3_mitochondrial",
"additionalComments": "mtDNA variants are maternally inherited and not inherited in an autosomal recessive manner.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"geneType": "mitochondrial",
"label": "PM3",
"ns": "015",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638250",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638250",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--d"
},
{
"entContent": {
"_uniqueProp": "015_PM4_mitochondrial",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"geneClass": [
"mRNA"
],
"geneType": "mitochondrial",
"label": "PM4",
"ns": "015",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applied per original ACMG/AMP guidelines",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638252",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638252",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
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},
{
"entContent": {
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"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [],
"instructionsToUse": "",
"label": "BP6",
"ns": "015",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433255",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433255",
"modified": "2022-01-19T20:31:33.145Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--g"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"geneClass": [
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"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "PP3",
"ns": "015",
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"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, etc)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638270",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638270",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--b"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "BP5",
"ns": "015",
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"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Mitochondrial DNA variant found in a case with a nuclear DNA-related disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638267",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638267",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--a"
},
{
"entContent": {
"_uniqueProp": "015_PVS1_mitochondrial",
"additionalComments": "Nonsense mediated decay is not known to occur for mtDNA, however ClinGen SVI PVS1 guidelines (Abou Tayoun et al., 2018) will be utilized when applicable (see figure).",
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"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"geneClass": [
"mRNA"
],
"geneType": "mitochondrial",
"label": "PVS1",
"ns": "015",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Large heteroplasmic mtDNA deletions, where at least one gene is completely deleted",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0020",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Assessment of small deletions, nonsense, and frameshift variants in protein-coding genes should follow established guidelines (Abou Tayoun et al., 2018)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0026",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assessment of small deletions, nonsense, and frameshift variants in protein-coding genes should follow established guidelines (Abou Tayoun et al., 2018)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "001",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Assessment of small deletions, nonsense, and frameshift variants in protein-coding genes should follow established guidelines (Abou Tayoun et al., 2018)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638266",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638266",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--B"
},
{
"entContent": {
"_uniqueProp": "015_PS4_mitochondrial",
"additionalComments": "Individuals are defined as affected if they:\n* meet diagnostic criteria for one of the classic mitochondrial disease clinical syndromes (MELAS, MERRF, MIDD, NARP, Pearson, KSS, CPEO, CPEO plus, Leigh, Alpers, LHON, primary lactic acidosis).\n OR \n* have 1 “red flag” feature with 2 or more nonspecific features (see tables in Haas et al., 2007)\n OR \n* have 3 or more nonspecific features with lab abnormalities (see table in Haas et al., 2008).",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "PS4",
"ns": "015",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Variant present in ≥16 unrelated probands",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0057",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant present in ≥4 unrelated probands",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0032",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Variant present in 2 unrelated probands in different top-level haplogroups",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638265",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638265",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--d"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "BP4",
"ns": "015",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, etc)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638263",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638263",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_inf5Apa--M"
},
{
"entContent": {
"_uniqueProp": "015_BP2_mitochondrial",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "BP2",
"ns": "015",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Other mtDNA variant is observed in individual’s mtDNA that has previously been confirmed to be pathogenic",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638259",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638259",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--Z"
},
{
"entContent": {
"_uniqueProp": "015_PS1_mitochondrial",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"geneClass": [
"mRNA"
],
"geneType": "mitochondrial",
"label": "PS1",
"ns": "015",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applied per original ACMG/AMP guidelines",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638258",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638258",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--F"
},
{
"entContent": {
"_uniqueProp": "015_BP1_mitochondrial",
"additionalComments": "Most variants in protein-coding mtDNA genes are not truncating, but rather missense variants. Even if truncating variants were more common, this would not preclude missense variants from also causing a loss of protein function.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"geneType": "mitochondrial",
"label": "BP1",
"ns": "015",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638255",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638255",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--D"
},
{
"entContent": {
"_uniqueProp": "015_BS2_mitochondrial",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "BS2",
"ns": "015",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"status": "approved",
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"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638557",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638557",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--e"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "De novo Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "016",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0016",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638552",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638552",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_inf5Api--J"
},
{
"entContent": {
"_uniqueProp": "016_PS1_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "016",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638550",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638550",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--K"
},
{
"entContent": {
"_uniqueProp": "016_BS4_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Segregation Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "016",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member, when seen in two or more families.\n* Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member.\n* Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638548",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638548",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--J"
},
{
"entContent": {
"_uniqueProp": "016_BP1_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638547",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638547",
"modified": "2021-11-05T21:07:14.050Z",
"modifier": "genbadmin",
"rev": "_inf5Apa--O"
},
{
"entContent": {
"_uniqueProp": "016_BS2_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Population Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "016",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 4 unaffected (related and maternally inherited or unrelated) Het (UBE3A).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 2 unaffected (related and maternally inherited or unrelated) Het (UBE3A),",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638543",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638543",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--f"
},
{
"entContent": {
"_uniqueProp": "016_PM2_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Population Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "016",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638540",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638540",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Api--H"
},
{
"entContent": {
"_uniqueProp": "016_PP2_nuclear_TCF4",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Functional Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638535",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638535",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--G"
},
{
"entContent": {
"_uniqueProp": "016_PS2_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "De novo Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "016",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638526",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638526",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--X"
},
{
"entContent": {
"_uniqueProp": "016_BS4_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Segregation Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "016",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member, when seen in two or more families.\n* Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member.\n* Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638522",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638522",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--_"
},
{
"entContent": {
"_uniqueProp": "016_PM2_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Population Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "016",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638514",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638514",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--W"
},
{
"entContent": {
"_uniqueProp": "016_BA1_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Population Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "016",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency above 0.05%.\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638508",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638508",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Api--B"
},
{
"entContent": {
"_uniqueProp": "016_BP4_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638503",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638503",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Api--A"
},
{
"entContent": {
"_uniqueProp": "016_PS3_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Functional Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an out-offrame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638502",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638502",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Api--_"
},
{
"entContent": {
"_uniqueProp": "016_BP3_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "016",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638501",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638501",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--Y"
},
{
"entContent": {
"_uniqueProp": "016_PP1_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Segregation Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "016",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members. ≥5 informative meiosis .Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members. 3-4 informative meiosis. Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members. 2 informative meiosis. Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638478",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638478",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--U"
},
{
"entContent": {
"_uniqueProp": "016_BP3_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "016",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638475",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638475",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--O"
},
{
"entContent": {
"_uniqueProp": "016_PS1_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "016",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638472",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638472",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--w"
},
{
"entContent": {
"_uniqueProp": "016_PM6_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "De novo Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "016",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638471",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638471",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--M"
},
{
"entContent": {
"_uniqueProp": "016_PM2_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Population Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "016",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638462",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638462",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--q"
},
{
"entContent": {
"_uniqueProp": "016_PVS1_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "016",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable up to p.S468.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0020",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Strong is applicable for any truncating variant from p.S469 to p.Q480.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Moderate is applicable for any truncating variant distal of p.Q480.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Supporting is applicable for initiation codon variants in CDKL5, FOXG1, SLC9A6 and TCF4.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638454",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638454",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--q"
},
{
"entContent": {
"_uniqueProp": "016_PS1_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "016",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638446",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638446",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--o"
},
{
"entContent": {
"_uniqueProp": "016_PM2_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Population Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "016",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638436",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638436",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--m"
},
{
"entContent": {
"_uniqueProp": "016_PP3_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638432",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638432",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--n"
},
{
"entContent": {
"_uniqueProp": "016_PS3_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Functional Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an out-offrame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638424",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638424",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--i"
},
{
"entContent": {
"_uniqueProp": "016_PP2_nuclear_UBE3A",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Functional Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638561",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638561",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--F"
},
{
"entContent": {
"_uniqueProp": "016_BP4_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638555",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638555",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--h"
},
{
"entContent": {
"_uniqueProp": "016_BS3_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Functional Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638545",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638545",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--I"
},
{
"entContent": {
"_uniqueProp": "016_PM4_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "016",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* PM4_Strong is applicable to stop-loss variants in MECP2 and UBE3A.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638544",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638544",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--a"
},
{
"entContent": {
"_uniqueProp": "016_PM1_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Functional Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "016",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n* (basic Helix-Loop-Helix domain (bHLH): aa 564-617).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638539",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638539",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--D"
},
{
"entContent": {
"_uniqueProp": "016_PP3_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638536",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638536",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--Z"
},
{
"entContent": {
"_uniqueProp": "016_BA1_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Population Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "016",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency above 0.05%.\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638534",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638534",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--d"
},
{
"entContent": {
"_uniqueProp": "016_PVS1_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "016",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable up to p.E643, for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-offrame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 15).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0020",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1 is applicable up to p.E643, for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-of-frame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 15).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Moderate is applicable for any truncating variant distal of p.E643 and for single exon deletions that involve just non-coding exon 20.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Supporting is applicable for initiation codon variants in CDKL5, FOXG1, SLC9A6 and TCF4.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638532",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638532",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--c"
},
{
"entContent": {
"_uniqueProp": "016_BP4_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638529",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638529",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--B"
},
{
"entContent": {
"_uniqueProp": "016_PM5_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "016",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* Applicable to all genes as written.\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638520",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638520",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Api--E"
},
{
"entContent": {
"_uniqueProp": "016_PP3_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638510",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638510",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--5"
},
{
"entContent": {
"_uniqueProp": "016_PP2_nuclear_SLC9A6",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Functional Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638509",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638509",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--V"
},
{
"entContent": {
"_uniqueProp": "016_PVS1_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "016",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable up to p.A563, for canonical splice site variants predicted to result in an out-of-frame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 10).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0020",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Strong is applicable for any truncating variant from p.C564 to p.T601 and for canonical splice site variants that flank exon 3 (in-frame exon).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Moderate is applicable for any truncating variant between p.Y602 to p.A669 and any frameshift variant that results in a read-through of the stop codon.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Supporting is applicable for initiation codon variants in CDKL5, FOXG1, SLC9A6 and TCF4.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638506",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638506",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--A"
},
{
"entContent": {
"_uniqueProp": "016_PS4_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Population Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "016",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638505",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638505",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--3"
},
{
"entContent": {
"_uniqueProp": "016_PP1_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Segregation Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "016",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n* ≥5 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n* 3-4 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n* 2 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638504",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638504",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6---"
},
{
"entContent": {
"_uniqueProp": "016_PS1_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "016",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638498",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638498",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--1"
},
{
"entContent": {
"_uniqueProp": "016_PM6_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "De novo Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "016",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638497",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638497",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--0"
},
{
"entContent": {
"_uniqueProp": "016_BP1_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638495",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638495",
"modified": "2021-11-05T21:07:13.862Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--c"
},
{
"entContent": {
"_uniqueProp": "016_PM5_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "016",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* Applicable to all genes as written.\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638494",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638494",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--z"
},
{
"entContent": {
"_uniqueProp": "016_PM3_nuclear_SLC9A6",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Allelic Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "016",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638490",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638490",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--x"
},
{
"entContent": {
"_uniqueProp": "016_PM1_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Functional Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "016",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n* Methyl-DNA binding (MDB): aa 90-162; Transcriptional repression domain (TRD): aa 302-306.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638487",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638487",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--R"
},
{
"entContent": {
"_uniqueProp": "016_PP4_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Other Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "016",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638486",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638486",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--w"
},
{
"entContent": {
"_uniqueProp": "016_PP2_nuclear_MECP2",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Functional Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638483",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638483",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--V"
},
{
"entContent": {
"_uniqueProp": "016_BP4_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638477",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638477",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--Q"
},
{
"entContent": {
"_uniqueProp": "016_PS2_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "De novo Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "016",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638474",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638474",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--N"
},
{
"entContent": {
"_uniqueProp": "016_PM1_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Functional Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "016",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n* (Forkhead: aa 181-275).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638461",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638461",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--K"
},
{
"entContent": {
"_uniqueProp": "016_BP7_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "016",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638459",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638459",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--o"
},
{
"entContent": {
"_uniqueProp": "016_BA1_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Population Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "016",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency above 0.05%.\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638456",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638456",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--s"
},
{
"entContent": {
"_uniqueProp": "016_PP1_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Segregation Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "016",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n* ≥5 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n* 3-4 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n* 2 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638452",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638452",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--I"
},
{
"entContent": {
"_uniqueProp": "016_PS3_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Functional Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an out-offrame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638450",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638450",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--p"
},
{
"entContent": {
"_uniqueProp": "016_PM3_nuclear_FOXG1",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Allelic Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "016",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638438",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638438",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--K"
},
{
"entContent": {
"_uniqueProp": "016_PM1_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Functional Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "016",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n* (ATP binding region: aa 19-43; TEY phosphorylation site: aa 169-171).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638435",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638435",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--l"
},
{
"entContent": {
"_uniqueProp": "016_PP2_nuclear_CDKL5",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Functional Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
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{
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"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
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"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
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},
{
"entContent": {
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"disease": [
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"text": "",
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{
"applicability": "Not applicable",
"id": "0038",
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"strength": "Very Strong",
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"text": "",
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{
"applicability": "Not applicable",
"id": "0058",
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"text": "",
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{
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{
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"modifier": "genbadmin",
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},
{
"entContent": {
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},
{
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{
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"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
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"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
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"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
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{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
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}
]
},
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"ldhId": "638433420",
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"modifier": "genbadmin",
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{
"entContent": {
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"evidenceCategory": "Other Database",
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{
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"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
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},
{
"applicability": "Not applicable",
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"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
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"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
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}
]
},
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"ldhId": "638433367",
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"modified": "2022-01-19T20:31:34.054Z",
"modifier": "genbadmin",
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},
{
"entContent": {
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"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
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"instructionsToUse": "",
"label": "BP6",
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"references": [
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"strengthDescriptor": [
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"strength": "Stand Alone",
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},
{
"applicability": "Not applicable",
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"strength": "Very Strong",
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"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433339",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433339",
"modified": "2022-01-19T20:31:33.889Z",
"modifier": "genbadmin",
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},
{
"entContent": {
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"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
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"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
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"instructionsToUse": "",
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"references": [
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"id": "29543229",
"source": "PubMed",
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],
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"strengthDescriptor": [
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"applicability": "Not applicable",
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"strength": "Stand Alone",
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"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433286",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433286",
"modified": "2022-01-19T20:31:33.578Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--Y"
},
{
"entContent": {
"_uniqueProp": "016_PVS1_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
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],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PVS1",
"ns": "016",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
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"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0245",
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable up to p.K841, for any frameshift variant that results in a read-through of the stop codon, for initiation codon variants, and for canonical splice site variants predicted to result in an out-of-frame product.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0020",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Strong is applicable for any truncating variant from p.K842 to p.G850 and for canonical splice site variants that flank exons 7, 8 (in-frame exons).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Moderate is applicable for any truncating variant distal of p.G850.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638558",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638558",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--L"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
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"evidenceCategory": "Functional Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
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"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0242",
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an out-offrame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.",
"type": "EvidenceLineStrength"
}
]
},
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"ldhId": "135638554",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638554",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_inf5Api--K"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
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],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BP3",
"ns": "016",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638553",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638553",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--g"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
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],
"evidenceCategory": "Allelic Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "016",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n* BP2 is not applicable for SLC9A6, UBE3A and CDKL5 for in trans state.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638551",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638551",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--c"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "016",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* Applicable to all genes as written.\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638546",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638546",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--b"
},
{
"entContent": {
"_uniqueProp": "016_PP4_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Other Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "016",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638538",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638538",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--e"
},
{
"entContent": {
"_uniqueProp": "016_BP7_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "016",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638537",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638537",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Api--G"
},
{
"entContent": {
"_uniqueProp": "016_BP5_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Other Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "016",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* Do not apply for any gene if variant is de novo.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638533",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638533",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Api--F"
},
{
"entContent": {
"_uniqueProp": "016_PM6_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "De novo Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "016",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638523",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638523",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--a"
},
{
"entContent": {
"_uniqueProp": "016_BS3_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Functional Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638519",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638519",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--D"
},
{
"entContent": {
"_uniqueProp": "016_PM4_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "016",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638518",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638518",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Api--D"
},
{
"entContent": {
"_uniqueProp": "016_BP5_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Other Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "016",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* The variant should be in the hemizygous state in the case with an alternate molecular basis for disease to be used.\n* Do not apply for any gene if variant is de novo.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638507",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638507",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--4"
},
{
"entContent": {
"_uniqueProp": "016_PS2_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "De novo Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "016",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638500",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638500",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--2"
},
{
"entContent": {
"_uniqueProp": "016_BP2_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Allelic Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "016",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n* BP2 is not applicable for SLC9A6, UBE3A and CDKL5 for in trans state.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638499",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638499",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Api---"
},
{
"entContent": {
"_uniqueProp": "016_BS4_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Segregation Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "016",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member, when seen in two or more families.\n* Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member.\n* Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638496",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638496",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--X"
},
{
"entContent": {
"_uniqueProp": "016_BS2_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Population Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "016",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638491",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638491",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--W"
},
{
"entContent": {
"_uniqueProp": "016_BP7_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "016",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638485",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638485",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--y"
},
{
"entContent": {
"_uniqueProp": "016_PP3_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638484",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638484",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--v"
},
{
"entContent": {
"_uniqueProp": "016_BA1_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Population Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "016",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency above 0.05%.\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638482",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638482",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--x"
},
{
"entContent": {
"_uniqueProp": "016_BS4_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Segregation Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "016",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member, when seen in two or more families.\n* Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member.\n* Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638470",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638470",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--S"
},
{
"entContent": {
"_uniqueProp": "016_BP1_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638469",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638469",
"modified": "2021-11-05T21:07:13.769Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--X"
},
{
"entContent": {
"_uniqueProp": "016_BS2_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Population Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "016",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638465",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638465",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--r"
},
{
"entContent": {
"_uniqueProp": "016_PM6_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "De novo Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "016",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638445",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638445",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--M"
},
{
"entContent": {
"_uniqueProp": "016_BS4_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Segregation Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "016",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member, when seen in two or more families.\n* Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member.\n* Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638444",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638444",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--L"
},
{
"entContent": {
"_uniqueProp": "016_BP1_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638443",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638443",
"modified": "2021-11-05T21:07:13.638Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--H"
},
{
"entContent": {
"_uniqueProp": "016_PM4_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "016",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Do not use PM4 for in-frame deletions/insertions in the Histidine-rich region (p.37-p.57), Proline and Glutaminerich region (p.58-p.86) and Proline-rich region (p.105-p.112).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638440",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638440",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--G"
},
{
"entContent": {
"_uniqueProp": "016_BS2_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Population Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "016",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638439",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638439",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--m"
},
{
"entContent": {
"_uniqueProp": "016_BS1_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Population Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "016",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease (0.025%).\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638437",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638437",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--J"
},
{
"entContent": {
"_uniqueProp": "016_BP7_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "016",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638433",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638433",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--I"
},
{
"entContent": {
"_uniqueProp": "016_PP1_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Segregation Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "016",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n* ≥5 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n* 3-4 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n* 2 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638426",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638426",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--E"
},
{
"entContent": {
"_uniqueProp": "016_PM5_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "016",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* Applicable to all genes as written.\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638416",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638416",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--m"
},
{
"entContent": {
"_uniqueProp": "016_PM4_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "016",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Do not use for in-frame deletions/insertions in CDKL5 C-terminus (exons 19-21, or after p.904) when using the NM_003159.2 transcript. ",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638414",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638414",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--g"
},
{
"entContent": {
"_uniqueProp": "016_BS2_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Population Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "016",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638413",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638413",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--D"
},
{
"entContent": {
"_uniqueProp": "016_BP6_nuclear_FOXG1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"FOXG1"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "016",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433312",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433312",
"modified": "2022-01-19T20:31:33.731Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--h"
},
{
"entContent": {
"_uniqueProp": "016_PP3_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638562",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638562",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--j"
},
{
"entContent": {
"_uniqueProp": "016_BA1_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Population Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "016",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency above 0.05%.\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638560",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638560",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--M"
},
{
"entContent": {
"_uniqueProp": "016_BP5_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Other Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "016",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* Variant should also be maternally inherited in the case with an alternate molecular basis for disease for this criteria to be used.\n* Do not apply for any gene if variant is de novo.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638559",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638559",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--i"
},
{
"entContent": {
"_uniqueProp": "016_PM6_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "De novo Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "016",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638549",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638549",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_inf5Api--I"
},
{
"entContent": {
"_uniqueProp": "016_PS4_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Population Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "016",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638531",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638531",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--b"
},
{
"entContent": {
"_uniqueProp": "016_PP1_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Segregation Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "016",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n* ≥5 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n* 3-4 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n* 2 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638530",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638530",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--C"
},
{
"entContent": {
"_uniqueProp": "016_PS3_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Functional Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an out-offrame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638528",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638528",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--A"
},
{
"entContent": {
"_uniqueProp": "016_BS2_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Population Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "016",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638517",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638517",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2---"
},
{
"entContent": {
"_uniqueProp": "016_PM3_nuclear_TCF4",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Allelic Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "016",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638516",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638516",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--6"
},
{
"entContent": {
"_uniqueProp": "016_BS1_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Population Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "016",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease (0.025%).\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638515",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638515",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--C"
},
{
"entContent": {
"_uniqueProp": "016_PM1_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Functional Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "016",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638513",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638513",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Api--C"
},
{
"entContent": {
"_uniqueProp": "016_PP4_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Other Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "016",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638512",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638512",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--Z"
},
{
"entContent": {
"_uniqueProp": "016_BP7_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "016",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638511",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638511",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--B"
},
{
"entContent": {
"_uniqueProp": "016_BS3_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Functional Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638493",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638493",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--y"
},
{
"entContent": {
"_uniqueProp": "016_PM4_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "016",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638492",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638492",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--U"
},
{
"entContent": {
"_uniqueProp": "016_PM2_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Population Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "016",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638488",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638488",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--S"
},
{
"entContent": {
"_uniqueProp": "016_PVS1_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "016",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable up to p.E472, for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-offrame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 3). PVS1 is not applicable for initiation codons.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Moderate is applicable for any truncating variant distal of p.E472.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638480",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638480",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--u"
},
{
"entContent": {
"_uniqueProp": "016_BP2_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Allelic Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "016",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n* BP2 is applicable for MECP2, TCF4, FOXG1 for in trans state.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638473",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638473",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--T"
},
{
"entContent": {
"_uniqueProp": "016_PM5_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "016",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ≥2 different missense changes affecting the amino acid residue. Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Applicable to all genes as written. A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638468",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638468",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--L"
},
{
"entContent": {
"_uniqueProp": "016_PM4_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "016",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* PM4_Strong is applicable to stop-loss variants in MECP2 and UBE3A.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Do not use PM4 for in-frame deletions/insertions in the Proline-rich region of gene p.381-p.405).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638466",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638466",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--s"
},
{
"entContent": {
"_uniqueProp": "016_PM3_nuclear_MECP2",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Allelic Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "016",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638464",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638464",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--u"
},
{
"entContent": {
"_uniqueProp": "016_BS1_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Population Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "016",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease (0.025%).\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638463",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638463",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--Q"
},
{
"entContent": {
"_uniqueProp": "016_PP4_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Other Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "016",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638460",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638460",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--t"
},
{
"entContent": {
"_uniqueProp": "016_PP3_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638458",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638458",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--J"
},
{
"entContent": {
"_uniqueProp": "016_PP2_nuclear_FOXG1",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Functional Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638457",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638457",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--n"
},
{
"entContent": {
"_uniqueProp": "016_PS4_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Population Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "016",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638453",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638453",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--p"
},
{
"entContent": {
"_uniqueProp": "016_BP2_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Allelic Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "016",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n* BP2 is applicable for MECP2, TCF4, FOXG1 for in trans state.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638447",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638447",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--N"
},
{
"entContent": {
"_uniqueProp": "016_PM5_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "016",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* Applicable to all genes as written.\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638442",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638442",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--n"
},
{
"entContent": {
"_uniqueProp": "016_BA1_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Population Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "016",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency above 0.05%.\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638430",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638430",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--k"
},
{
"entContent": {
"_uniqueProp": "016_PS4_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Population Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "016",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638427",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638427",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--H"
},
{
"entContent": {
"_uniqueProp": "016_BP2_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Allelic Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "016",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n* BP2 is not applicable for SLC9A6, UBE3A and CDKL5 for in trans state.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638421",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638421",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--h"
},
{
"entContent": {
"_uniqueProp": "016_PM6_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "De novo Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "016",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638419",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638419",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--h"
},
{
"entContent": {
"_uniqueProp": "016_BS4_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Segregation Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "016",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member, when seen in two or more families.\n* Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member.\n* Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638418",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638418",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--g"
},
{
"entContent": {
"_uniqueProp": "016_BP1_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638417",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638417",
"modified": "2021-11-05T21:07:13.541Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--G"
},
{
"entContent": {
"_uniqueProp": "016_BS1_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Population Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "016",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease (0.025%).\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638411",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638411",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--E"
},
{
"entContent": {
"_uniqueProp": "016_PP5_nuclear_UBE3A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"UBE3A"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "016",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433421",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433421",
"modified": "2022-01-19T20:31:34.350Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--Q"
},
{
"entContent": {
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"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"TCF4"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "016",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433394",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433394",
"modified": "2022-01-19T20:31:34.202Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--Z"
},
{
"entContent": {
"_uniqueProp": "016_BP6_nuclear_CDKL5",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"CDKL5"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "016",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433285",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433285",
"modified": "2022-01-19T20:31:33.578Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--O"
},
{
"entContent": {
"_uniqueProp": "016_PM2_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Population Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "016",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638566",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638566",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--N"
},
{
"entContent": {
"_uniqueProp": "016_PM1_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Functional Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "016",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n* 3’ cysteine binding site: aa 820.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638565",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638565",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--G"
},
{
"entContent": {
"_uniqueProp": "016_PP4_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Other Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "016",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638564",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638564",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_inf5Api--M"
},
{
"entContent": {
"_uniqueProp": "016_BP7_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "016",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638563",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638563",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--k"
},
{
"entContent": {
"_uniqueProp": "016_PP1_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Segregation Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "016",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n* ≥5 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n* 3-4 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n* 2 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638556",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638556",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--d"
},
{
"entContent": {
"_uniqueProp": "016_PM3_nuclear_UBE3A",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Allelic Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "016",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638542",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638542",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--H"
},
{
"entContent": {
"_uniqueProp": "016_BS1_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Population Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "016",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease (0.025%).\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638541",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638541",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--E"
},
{
"entContent": {
"_uniqueProp": "016_BP3_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "016",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638527",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638527",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--Y"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
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],
"evidenceCategory": "Allelic Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "016",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n* BP2 is applicable for MECP2, TCF4, FOXG1 for in trans state.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638525",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638525",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--F"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
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],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "016",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638524",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638524",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--E"
},
{
"entContent": {
"_uniqueProp": "016_BP1_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638521",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638521",
"modified": "2021-11-05T21:07:13.956Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--d"
},
{
"entContent": {
"_uniqueProp": "016_BS1_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Population Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "016",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease (0.025%).\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638489",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638489",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--T"
},
{
"entContent": {
"_uniqueProp": "016_BP5_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Other Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "016",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* Do not apply for any gene if variant is de novo.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638481",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638481",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--p"
},
{
"entContent": {
"_uniqueProp": "016_PS4_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Population Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "016",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638479",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638479",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--t"
},
{
"entContent": {
"_uniqueProp": "016_PS3_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Functional Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an out-offrame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638476",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638476",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--P"
},
{
"entContent": {
"_uniqueProp": "016_BS3_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Functional Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638467",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638467",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--v"
},
{
"entContent": {
"_uniqueProp": "016_BP5_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Other Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "016",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* Do not apply for any gene if variant is de novo.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638455",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638455",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--r"
},
{
"entContent": {
"_uniqueProp": "016_BP4_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638451",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638451",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--P"
},
{
"entContent": {
"_uniqueProp": "016_BP3_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "016",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function.\n* Inframe expansions or deletions in FOXG1 repetitive regions: poly His (p.His47-p.His57), poly Gln (p.Gln70-p.Gln73) and poly Pro (p.Pro58-p.Pro61; p.Pro65-p.Pro69; p.Pro74-p.Pro80).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638449",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638449",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--O"
},
{
"entContent": {
"_uniqueProp": "016_PS2_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "De novo Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "016",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638448",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638448",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--o"
},
{
"entContent": {
"_uniqueProp": "016_BS3_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Functional Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638441",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638441",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--H"
},
{
"entContent": {
"_uniqueProp": "016_PP4_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Other Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "016",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638434",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638434",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--k"
},
{
"entContent": {
"_uniqueProp": "016_BP5_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Other Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "016",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* Do not apply for any gene if variant is de novo.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638429",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638429",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--F"
},
{
"entContent": {
"_uniqueProp": "016_PVS1_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "016",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* Do not use PVS1 for truncating variants in CDKL5 Cterminus (exons 19-21, or after p.P904) when using the historically used transcript (NM_003159.2). PVS1 is applicable up to p.R948 when using the major brain isoform which has an alternative C-terminus (NM_001323289.2), for canonical splice site variants predicted to result in an out-of-frame product, for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exons 7, 10, 13), and for the non-coding CDKL5 exon (exon 1).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Moderate is applicable for any truncating variant distal of p.R948 (when using the major brain isoform, NM_001323289.2) and for canonical splice site variants that flank exon 17 (in-frame exon).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Supporting is applicable for initiation codon variants in CDKL5, FOXG1, SLC9A6 and TCF4.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638428",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638428",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--j"
},
{
"entContent": {
"_uniqueProp": "016_BP4_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638425",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638425",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--j"
},
{
"entContent": {
"_uniqueProp": "016_BP3_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "016",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638423",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638423",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--G"
},
{
"entContent": {
"_uniqueProp": "016_PS2_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "De novo Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "016",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638422",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638422",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--i"
},
{
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"modifiedBy": "cjodarski",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2025-09-19T17:56:01.049Z"
},
"name": "Pilot Rules Submitted"
},
{
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"event": {
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"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
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"name": "Approved For Release"
},
{
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"event": {
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"name": "pilot-rules-withdrawn",
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"timeStamp": "2025-09-12T17:12:29.517Z"
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"event": {
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"timeStamp": "2025-06-29T18:45:57.787Z"
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}
],
"tagNameSpaces": [
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],
"title": "ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF1A Version 3.1.0",
"type": "Richards et.al., 2015 - Combining rules",
"version": "3.1.0",
"versioned": true
},
"entId": "GN017",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
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"entContent": {
"_uniqueProp": "017_BS1_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS1",
"ns": "017",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "gnomAD Grpmax FAF ≥ 1:30,000 (≥0.0033% or 0.000033)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
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]
},
"entType": "CriteriaCode",
"ldhId": "467903888",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903888",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YReC---"
},
{
"entContent": {
"_uniqueProp": "017_PP4_nuclear_HNF1A",
"additionalComments": "Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see rules).\nCertain assumptions can be made in order to use the MODY probability calculator: \n* Specific clinical information about parents not given but lab/literature states “Family history of diabetes”: Click “Parent with diabetes” in calculator. \n* No information about family history of diabetes is provided: Attempt to use the calculator using both possibilities (yes/no). If this makes a difference in the ability to meet the PP4 cutoff (>50%), PP4 cannot be used. \n* Weight/Height/BMI not given but lab/literature states patient is “lean”: Enter BMI of 30. \n* HbA1c is not provided: Attempt to use the calculator using values of 6% and 10%. If this makes a difference in the ability to meet the PP4 cutoff (>50%), PP4 cannot be used. \n* Treatment information is not provided: Cannot use calculator. ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": "Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology: \n\n* One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD)[11](#pmid_21395678),[12](#pmid_28701371),[13](#pmid_30409810),[14](#pmid_31704690)\n* Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (\\<200pmol/L or 0.6ng/mL)[15](#pmid_30225972),[16](#pmid_23771925) or urinary C-peptide/creatinine ratio \\<0.2 nmol/mmol[12](#pmid_28701371),[13](#pmid_30409810)",
"label": "PP4",
"ns": "017",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "MODY Probability Calculator (MPC) result ≥50% chance of testing positive [https://www.diabetesgenes.org/mody-probability-calculator/](https://www.diabetesgenes.org/mody-probability-calculator/)) AND negative HNF4A testing AND presence of at least one additional feature characteristic of HNF1A-MODY:\n\n* Antibody negative and/or persistent C-peptide after five years post-T1DM diagnosis\n* Response to low-dose sulfonyurea (SU) (extreme response- hypoglycemia)\n* Low hsCRP in patient with clinical diagnosis of T2DM\n* Biochemical/Molecular phenotypic evidence from patient cell lines\n* Hepatocellular adenomas",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "MODY Probability Calculator (MPC) result ≥50% chance of testing positive https://www.diabetesgenes.org/mody-probability-calculator/) AND negative HNF4A testing",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903886",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903886",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRlO---"
},
{
"entContent": {
"_uniqueProp": "017_PP1_nuclear_HNF1A",
"additionalComments": "Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see rules).",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": "Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology: \n\n* One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD)[11](#pmid_21395678),[12](#pmid_28701371),[13](#pmid_30409810),[14](#pmid_31704690)\n* Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (\\<200pmol/L or 0.6ng/mL)[15](#pmid_30225972),[16](#pmid_23771925) or urinary C-peptide/creatinine ratio \\<0.2 nmol/mmol[12](#pmid_28701371),[13](#pmid_30409810)",
"label": "PP1",
"ns": "017",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use thresholds suggested by Jarvik and Browning[7](#pmid_27236918)\n\n* Single Family : ≤ 1/32 (5 meioses)\n* \\>1 Family : ≤ 1/16 (4 meioses)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use thresholds suggested by Jarvik and Browning[7](#pmid_27236918)\n\n* Single Family : ≤ 1/16 (4 meioses)\n* \\>1 Family : ≤ 1/8 (3 meioses)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use thresholds suggested by Jarvik and Browning[7](#pmid_27236918)\n\n* Single Family : ≤ 1/8 (3 meioses)\n* \\>1 Family : ≤ ¼ (2 meioses)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903883",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903883",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRf----"
},
{
"entContent": {
"_uniqueProp": "017_PM1_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "017",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion can be used for variants in residues that directly bind DNA: Gln130, Arg131, Glu132, His143, Leu144, Ser145, Gln146, His147, Leu148, Asn149, Lys155, Thr156, Gln157, Lys158, Arg203, Phe204, Lys205, Trp206, Arg263, Val264, Tyr265, Asn270, Arg271, Arg272, Lys273 ",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use for defined regions in the DNA binding and dimerization domains.\n\n* Dimerization: codons 1-32, NM\\_000545.8\n* Subset of DNA binding domains: codons 107-174 and 201-280\n\nIt can also be used for variants within certain transcription factor binding sites of the promoter:\n\n* –c.-187 to c.-195 (AP1 binding site)\n* –c.-209 to c.-227 (Overlapping HNF3 & NF-Y sites)\n* –c.-238 to c.-259 (HNF1A binding site)\n* –c.-276 to c.-288 (HNF4A binding site)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903877",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903877",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRk2---"
},
{
"entContent": {
"_uniqueProp": "017_PVS1_nuclear_HNF1A",
"additionalComments": "Per guidance from ClinGen/SVI, PM2_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": "Use HNF1A PVS1 decision tree.\n\nPer recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",
"label": "PVS1",
"ns": "017",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use HNF1A PVS1 decision tree.\n\n* Apply PVS1 to nonsense or frameshift variants occurring 5' of c.1768. \n * Variants generating PTCs 3’ of c.1714 of NM\\_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD [2](#pmid_24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs.\n* “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”\n * Apply PVS1 for exon skipping or single to multi exon deletion involving exons 1-9\n * Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG\\_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1\\_Strong in this situation.\n* Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118.\n* Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use HNF1A PVS1 decision tree.\n\n* Apply PVS1\\_Strong for nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. \n * The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY.\n* “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”\n * Apply PVS1\\_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10.\n * A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use This specification is in accordance with Tayoun’s recommendation to use PVS1\\_Strong in cases in which the truncated region is critical to protein function.[17](#pmid_30192042)\n\nPer recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use HNF1A PVS1 decision tree.\n\n* Apply PVS1\\_Supporting levels for nonsense variants occurring 3’ of c.1803 (p.601) and frameshift variants occurring 3’ of c.1854 (p.618) as there is limited evidence of patients with MODY phenotype at this time.\n\nPer recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903872",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903872",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRkS---"
},
{
"entContent": {
"_uniqueProp": "017_BP2_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "017",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Also applicable when in cis or trans with a likely pathogenic variant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903893",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903893",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRci---"
},
{
"entContent": {
"_uniqueProp": "017_PP2_nuclear_HNF1A",
"additionalComments": "Missense variants account for 55% of all published pathogenic variants in this gene (Colclough et al 2013), however the constraint score for HNF1A (gene) is 1.07, which is not significant; therefore, we do not support using this criterion at this time. The low constraint score is most likely due to high tolerance for missense variants in the transactivation domain (see PM1 section). There are significantly more pathogenic missense variants in the DNA binding and dimerization domains, which are much less tolerant to missense variation. We may update this in the future if we can generate domain-specific scores.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "017",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903884",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903884",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRee---"
},
{
"entContent": {
"_uniqueProp": "017_PM4_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "017",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "For deletions/insertions of more than one amino acid in a non-repeat region, use as moderate level of evidence.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For single amino acid deletions/insertions, use as supporting level of evidence",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903880",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903880",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRjy---"
},
{
"entContent": {
"_uniqueProp": "017_BP7_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "017",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way \\< 2.0.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903897",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903897",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRhu---"
},
{
"entContent": {
"_uniqueProp": "017_BP4_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "017",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2 [8](#pmid_32123317),[9](#pmid_30661751).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903895",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903895",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRfq---"
},
{
"entContent": {
"_uniqueProp": "017_BS4_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "017",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applicable to family members without variant who have MPC score >50% (i.e., genotype negative, phenotype positive).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903891",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903891",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRki---"
},
{
"entContent": {
"_uniqueProp": "017_PS4_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": "Variant should meet PM2\\_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region). \n\nPhenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology: \n\n* One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD)[11](#pmid_21395678),[12](#pmid_28701371),[13](#pmid_30409810),[14](#pmid_31704690)\n* Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (\\<200pmol/L or 0.6ng/mL)[15](#pmid_30225972),[16](#pmid_23771925) or urinary C-peptide/creatinine ratio \\<0.2 nmol/mmol[12](#pmid_28701371),[13](#pmid_30409810)",
"label": "PS4",
"ns": "017",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Seven or more unrelated occurrences = Strong.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "4-6 unrelated occurrences = Moderate. ",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903876",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903876",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRgC---"
},
{
"entContent": {
"_uniqueProp": "017_PS2_nuclear_HNF1A",
"additionalComments": "To obtain maximum points (“phenotype highly specific for gene”) patient must meet criteria for PP4 (result of ≥50% chance or higher of testing positive for MODY on the MODY Probability calculator (https://www.diabetesgenes.org/mody-probability-calculator/) AND have negative HNF4A testing). If patient does not meet PP4 but is noted to have diabetes, use points corresponding to “phenotype consistent with gene but not highly specific”. If patient shows evidence of an autoimmune etiology for their diabetes and/or absolute or near-absolute insulin deficiency (see above), do not apply PS2. ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": "Use SVI recommended point-based system with MDEP specifications for “Phenotype Consistency”.\n\nDo not apply PS2 if the proband has an affected parent with any of the following:\n\n* Affected parent meets PP4 specifications\n* Parent is described as having similarly atypical diabetes to the proband\n* Parent was diagnosed with non-autoimmune diabetes before age 30",
"label": "PS2",
"ns": "017",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903874",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903874",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRiq---"
},
{
"entContent": {
"_uniqueProp": "017_BP6_nuclear_HNF1A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "017",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433450",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433450",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRl6---"
},
{
"entContent": {
"_uniqueProp": "017_BP5_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "017",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A variant in other monogenic diabetes gene is P/LP.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903896",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903896",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRfW---"
},
{
"entContent": {
"_uniqueProp": "017_BP3_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "017",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903894",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903894",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRlq---"
},
{
"entContent": {
"_uniqueProp": "017_BP1_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "017",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903892",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903892",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRiW---"
},
{
"entContent": {
"_uniqueProp": "017_BS3_nuclear_HNF1A",
"additionalComments": "To use BS3, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus wild-type allele and other variants in the patient’s genome) it cannot count as BS3. ",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "017",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "BS3 should be applied at the supporting level for the following approved functional studies and cutoffs: \n\n1. Luciferase assays for transactivation: ≥ 75% activity of wildtype \n2. EMSA for DNA binding: ≥ 75% activity of wildtype. \n3. Western blotting and indirect immunoflorescence for protein expression and localization - Determining appropriate thresholds for protein expression is more difficult due to variability in results between different experimental protocols. Altered protein expression can be indirectly captured through the read-out from a transactivation assay and reduced protein expression can provide an explanation for reduced transactivation.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903890",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903890",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YReu---"
},
{
"entContent": {
"_uniqueProp": "017_PP3_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "017",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is above 0.2[8](#pmid_32123317),[9](#pmid_30661751).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903885",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903885",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRc6---"
},
{
"entContent": {
"_uniqueProp": "017_PM3_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "017",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903879",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903879",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRga---"
},
{
"entContent": {
"_uniqueProp": "017_PM2_nuclear_HNF1A",
"additionalComments": "Per guidance from ClinGen/SVI, PM2_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": "Recommend using as supporting level of evidence (PM2\\_Supporting) per ClinGen guidance. Per guidance from ClinGen/SVI, PM2\\_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic. We recommend investigating the genotype metrics in gnomAD for variants that have been flagged for having failed one or more quality parameters, as it is possible that some of these filtered variants are actually real. The number of filtered alleles can be counted to determine whether PM2\\_Supporting would be met even if they were genuine calls. If the filtered calls are sufficient in number to not meet PM2\\_Supporting, then we would not use it. Because it is also possible that these calls are false positives, we would not use filtered variants to support BA1 or BS1.",
"label": "PM2",
"ns": "017",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "gnomAD Grpmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903878",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903878",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRdO---"
},
{
"entContent": {
"_uniqueProp": "017_PP5_nuclear_HNF1A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "017",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433451",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433451",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRi----"
},
{
"entContent": {
"_uniqueProp": "017_BS2_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "017",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Apply to normoglycemic individuals age 70 or older (i.e., genotype positive, phenotype negative)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903889",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903889",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRgy---"
},
{
"entContent": {
"_uniqueProp": "017_BA1_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BA1",
"ns": "017",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "gnomAD Grpmax FAF ≥ 1:10,000 (≥ 0.01% or 0.0001)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903887",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903887",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRhW---"
},
{
"entContent": {
"_uniqueProp": "017_PM6_nuclear_HNF1A",
"additionalComments": "Subsumed by PS2.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "017",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903882",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903882",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRhG---"
},
{
"entContent": {
"_uniqueProp": "017_PM5_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM5",
"ns": "017",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic), or if the previously classified variant is pathogenic but has a greater Grantham distance.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903881",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903881",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRjC---"
},
{
"entContent": {
"_uniqueProp": "017_PS3_nuclear_HNF1A",
"additionalComments": "Studies performed on a cell line generated from a patient sample (which will be heterozygous and also contain other variants in the patient’s genome which could modify function) will not count as PS3 but instead will count toward PP4_Moderate. \nNote that although occurrence in the transactivation domain (codons 281-631, NM_000545.8 has been cited in older publications as evidence for causality, it is known that the transactivation domain is more tolerant to benign missense variation and therefore we will not apply PM1 at any level to variants within this region at this time (PMID: 11272211, 18003757, 23348805).",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": "Applied at the strong level for variants with RNA and in silico evidence of aberrant splicing. Otherwise, applied at the supporting level as described in the Supporting specification, except as noted in the Moderate specification.",
"label": "PS3",
"ns": "017",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Currently applicable for variants with luciferase assay data (evidence of decreased transactivation (≤ 40% of wild type) by the Gloyn/Oxford group[10](#pmid_32910913) ([Althari et al. 2020).](https://pubmed.ncbi.nlm.nih.gov/32910913/) This upgrade from supporting is based on a validation conducted according to the guidelines by Brnich et al. 2019 [1](#pmid_31892348).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "PS3 should be applied at the supporting level for the following approved functional studies and cutoffs except as noted in the PS3\\_Moderate specification: \n\n1. Luciferase assays for transactivation: less than 40% activity of wildtype (WT). Assays should include controls for WT, T2DM-risk, and known MODY variants. \n2. EMSA for DNA binding: less than 40% activity of WT. We recommend that at least two of the following variants be used as positive controls for reduced DNA binding activity: c.335C>T (p.Pro112Leu), c.608G>A (p.Arg203His), c.787C>T (p.Arg263Cys) and c.686G>A (p.Arg229Gln) [4](#pmid_11162430), [5](#pmid_12574234), [6](#pmid_24915262). \n3. Western blotting and indirect immunofluorescence for protein expression and localization - Determining appropriate thresholds for protein expression is more difficult due to variability in results between experimental protocols. Altered protein expression can be indirectly captured through the read-out frame from transactivation assay, and reduced protein expression can provide an explanation for reduced transactivation. When exploring protein mis-localization, we recommend that the c.589\\_615del (p.Lys197\\_Lys205del) variant is included as a positive control for impaired nuclear localization (cytosolic retention).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903875",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903875",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRdu---"
},
{
"entContent": {
"_uniqueProp": "017_PS1_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "017",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applicable for a same amino acid change if the previously established variant is classified as pathogenic by ClinGen MDEP specifications.\n\nPS1 can also be applied for canonical and non-canoncial splicing variants that have a SpliceAI score within 10% of the original variant, or a greater predicted deleterious impact than the comparision (likely) pathogenic variant. See Table 2 from [PMID: 37352859](https://pmc.ncbi.nlm.nih.gov/articles/PMC10357475/table/tbl2/) for determining when PS1 should be applied at the Strong, Moderate, or Supporting level in these instances.[3](#pmid_37352859)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable for a same amino acid change if the previously established variant is classified as likely pathogenic by ClinGen MDEP specifications.\n\nPS1 can also be applied for canonical and non-canoncial splicing variants that have a SpliceAI score within 10% of the original variant, or a greater predicted deleterious impact than the comparision (likely) pathogenic variant. See Table 2 from [PMID: 37352859](https://pmc.ncbi.nlm.nih.gov/articles/PMC10357475/table/tbl2/) for determining when PS1 should be applied at the Strong, Moderate, or Supporting level in these instances.[3](#pmid_37352859)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "PS1 can also be applied for canonical and non-canoncial splicing variants that have a SpliceAI score within 10% of the original variant, or a greater predicted deleterious impact than the comparision (likely) pathogenic variant. See Table 2 from [PMID: 37352859](https://pmc.ncbi.nlm.nih.gov/articles/PMC10357475/table/tbl2/) for determining when PS1 should be applied at the Strong, Moderate, or Supporting level in these instances.[3](#pmid_37352859)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903873",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467903873",
"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRja---"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0015967",
"lbl": "monogenic diabetes",
"meta": {
"basicPropertyValues": [
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"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/254"
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{
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"val": "https://github.com/monarch-initiative/mondo/issues/8319"
},
{
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"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0015967"
},
{
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"val": "https://www.malacards.org/card/rare_genetic_diabetes_mellitus"
},
{
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"val": "http://identifiers.org/medgen/1392102"
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{
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"val": "http://linkedlifedata.com/resource/umls/id/C3888631"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C129739"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_1001511"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_183625"
}
],
"definition": {
"val": "Diabetes mellitus that is caused by mutations in a single gene.",
"xrefs": [
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]
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"xrefs": [
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{
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},
{
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{
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},
{
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},
{
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]
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"type": "CLASS"
},
"MONDOID": "MONDO:0015967",
"name": "monogenic diabetes"
},
"entId": "MONDO:0015967",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0015967",
"entType": "Disease",
"ldhId": "467884025",
"ldhIri": "https://cspec.genome.network/cspec/Disease/id/467884025",
"modified": "2025-10-07T16:14:27.279Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7x3Hu---"
}
],
"Gene": [
{
"entContent": {
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"agr": "HGNC:11621",
"alias_symbol": [
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"LFB1",
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],
"ccds_id": [
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"CCDS76611"
],
"cosmic": "HNF1A",
"date_approved_reserved": "1990-02-12",
"date_modified": "2021-05-26",
"date_name_changed": "2007-08-24",
"date_symbol_changed": "2007-08-24",
"ena": [
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],
"ensembl_gene_id": "ENSG00000135100",
"entrez_id": "6927",
"gene_group": [
"HNF class homeoboxes"
],
"gene_group_id": [
524
],
"hgnc_id": "HGNC:11621",
"homeodb": 8444,
"location": "12q24.31",
"location_sortable": "12q24.31",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/HNF1A",
"LRG_522|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_522.xml"
],
"mane_select": [
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],
"mgd_id": [
"MGI:98504"
],
"name": "HNF1 homeobox A",
"omim_id": [
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],
"orphanet": 158583,
"prev_name": [
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],
"prev_symbol": [
"MODY3",
"TCF1"
],
"pubmed_id": [
1535333,
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],
"refseq_accession": [
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],
"rgd_id": [
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],
"status": "Approved",
"symbol": "HNF1A",
"symbol_report_tag": [
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],
"ucsc_id": "uc001tzg.4",
"uniprot_ids": [
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],
"uuid": "a2a9a790-d0af-471d-889d-7588fb461df1",
"vega_id": "OTTHUMG00000151015"
}
},
"entId": "HNF1A",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11621",
"entType": "Gene",
"ldhId": "467829599",
"ldhIri": "https://cspec.genome.network/cspec/Gene/id/467829599",
"modified": "2021-10-14T11:36:42.130Z",
"modifier": "genbadmin",
"rev": "_inf5BYG--t"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "017_nuclear_HNF1A",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Dominant",
"preferredMondoId": "MONDO:0015967",
"preferredTitle": "monogenic diabetes"
}
],
"gene": "HNF1A",
"preferredTranscript": "NM_000545.8"
}
],
"ns": "017",
"references": [
{
"auths": [
"Brnich SE",
"Abou Tayoun AN",
"et al."
],
"doiStr": "10.1186/s13073-019-0690-2",
"id": "31892348",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 3.",
"source": "Genome Med",
"title": "Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework.",
"vol": "12",
"year": "2019"
},
{
"auths": [
"Popp MW",
"Maquat LE"
],
"doiStr": "10.1146/annurev-genet-111212-133424",
"id": "24274751",
"iss": "",
"namespace": "pmid",
"pages": "p. 139-65.",
"source": "Annu Rev Genet",
"title": "Organizing principles of mammalian nonsense-mediated mRNA decay.",
"vol": "47",
"year": "2013"
},
{
"auths": [
"Walker LC",
"Hoya M",
"et al."
],
"doiStr": "10.1016/j.ajhg.2023.06.002",
"id": "37352859",
"iss": "(7)",
"namespace": "pmid",
"pages": "p. 1046-1067.",
"source": "Am J Hum Genet",
"title": "Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup.",
"vol": "110",
"year": "2023"
},
{
"auths": [
"Bjørkhaug L",
"Ye H",
"et al."
],
"doiStr": "10.1006/bbrc.2000.4024",
"id": "11162430",
"iss": "(3)",
"namespace": "pmid",
"pages": "p. 792-8.",
"source": "Biochem Biophys Res Commun",
"title": "MODY associated with two novel hepatocyte nuclear factor-1alpha loss-of-function mutations (P112L and Q466X).",
"vol": "279",
"year": "2000"
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{
"auths": [
"Bjørkhaug L",
"Sagen JV",
"et al."
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"doiStr": "10.1210/jc.2002-020945",
"id": "12574234",
"iss": "(2)",
"namespace": "pmid",
"pages": "p. 920-31.",
"source": "J Clin Endocrinol Metab",
"title": "Hepatocyte nuclear factor-1 alpha gene mutations and diabetes in Norway.",
"vol": "88",
"year": "2003"
},
{
"auths": [
"SIGMA Type 2 Diabetes Consortium",
"Estrada K",
"et al."
],
"doiStr": "10.1001/jama.2014.6511",
"id": "24915262",
"iss": "(22)",
"namespace": "pmid",
"pages": "p. 2305-14.",
"source": "JAMA",
"title": "Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population.",
"vol": "311",
"year": "2014"
},
{
"auths": [
"Jarvik GP",
"Browning BL"
],
"doiStr": "10.1016/j.ajhg.2016.04.003",
"id": "27236918",
"iss": "(6)",
"namespace": "pmid",
"pages": "p. 1077-1081.",
"source": "Am J Hum Genet",
"title": "Consideration of Cosegregation in the Pathogenicity Classification of Genomic Variants.",
"vol": "98",
"year": "2016"
},
{
"auths": [
"Wai HA",
"Lord J",
"et al."
],
"doiStr": "10.1038/s41436-020-0766-9",
"id": "32123317",
"iss": "(6)",
"namespace": "pmid",
"pages": "p. 1005-1014.",
"source": "Genet Med",
"title": "Blood RNA analysis can increase clinical diagnostic rate and resolve variants of uncertain significance.",
"vol": "22",
"year": "2020"
},
{
"auths": [
"Jaganathan K",
"Kyriazopoulou Panagiotopoulou S",
"et al."
],
"doiStr": "10.1016/j.cell.2018.12.015",
"id": "30661751",
"iss": "(3)",
"namespace": "pmid",
"pages": "p. 535-548.e24.",
"source": "Cell",
"title": "Predicting Splicing from Primary Sequence with Deep Learning.",
"vol": "176",
"year": "2019"
},
{
"auths": [
"Althari S",
"Najmi LA",
"et al."
],
"doiStr": "10.1016/j.ajhg.2020.08.016",
"id": "32910913",
"iss": "(4)",
"namespace": "pmid",
"pages": "p. 670-682.",
"source": "Am J Hum Genet",
"title": "Unsupervised Clustering of Missense Variants in HNF1A Using Multidimensional Functional Data Aids Clinical Interpretation.",
"vol": "107",
"year": "2020"
},
{
"auths": [
"McDonald TJ",
"Colclough K",
"et al."
],
"doiStr": "10.1111/j.1464-5491.2011.03287.x",
"id": "21395678",
"iss": "(9)",
"namespace": "pmid",
"pages": "p. 1028-33.",
"source": "Diabet Med",
"title": "Islet autoantibodies can discriminate maturity-onset diabetes of the young (MODY) from Type 1 diabetes.",
"vol": "28",
"year": "2011"
},
{
"auths": [
"Shields BM",
"Shepherd M",
"et al."
],
"doiStr": "10.2337/dc17-0224",
"id": "28701371",
"iss": "(8)",
"namespace": "pmid",
"pages": "p. 1017-1025.",
"source": "Diabetes Care",
"title": "Population-Based Assessment of a Biomarker-Based Screening Pathway to Aid Diagnosis of Monogenic Diabetes in Young-Onset Patients.",
"vol": "40",
"year": "2017"
},
{
"auths": [
"Patel KA",
"Weedon MN",
"et al."
],
"doiStr": "10.2337/dc18-0373",
"id": "30409810",
"iss": "(2)",
"namespace": "pmid",
"pages": "p. e16-e17.",
"source": "Diabetes Care",
"title": "Zinc Transporter 8 Autoantibodies (ZnT8A) and a Type 1 Diabetes Genetic Risk Score Can Exclude Individuals With Type 1 Diabetes From Inappropriate Genetic Testing for Monogenic Diabetes.",
"vol": "42",
"year": "2019"
},
{
"auths": [
"Carlsson A",
"Shepherd M",
"et al."
],
"doiStr": "10.2337/dc19-0747",
"id": "31704690",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 82-89.",
"source": "Diabetes Care",
"title": "Absence of Islet Autoantibodies and Modestly Raised Glucose Values at Diabetes Diagnosis Should Lead to Testing for MODY: Lessons From a 5-Year Pediatric Swedish National Cohort Study.",
"vol": "43",
"year": "2020"
},
{
"auths": [
"Hattersley AT",
"Greeley SAW",
"et al."
],
"doiStr": "10.1111/pedi.12772",
"id": "30225972",
"iss": "",
"namespace": "pmid",
"pages": "p. 47-63.",
"source": "Pediatr Diabetes",
"title": "ISPAD Clinical Practice Consensus Guidelines 2018: The diagnosis and management of monogenic diabetes in children and adolescents.",
"vol": "19 Suppl 27",
"year": "2018"
},
{
"auths": [
"Pihoker C",
"Gilliam LK",
"et al."
],
"doiStr": "10.1210/jc.2013-1279",
"id": "23771925",
"iss": "(10)",
"namespace": "pmid",
"pages": "p. 4055-62.",
"source": "J Clin Endocrinol Metab",
"title": "Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth.",
"vol": "98",
"year": "2013"
},
{
"auths": [
"Abou Tayoun AN",
"Pesaran T",
"et al."
],
"doiStr": "10.1002/humu.23626",
"id": "30192042",
"iss": "(11)",
"namespace": "pmid",
"pages": "p. 1517-1524.",
"source": "Hum Mutat",
"title": "Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion.",
"vol": "39",
"year": "2018"
}
],
"rules": {
"mainRules": [
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"conditions": [
{
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0016",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": "Disease-specific, Strength",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Award the PS2_Strong point if Criteria 1 AND Criteria 2 are fulfilled. \n\n Criteria 1. The variant is present at a detectable allele fraction but is absent from parental samples with confirmed maternity and paternity.\n\n Criteria 2. The variant is present at a detectable allele fraction in an affected tissue sample but is absent from or detected at a lower allelic fraction in another tissue (e.g. if present in 5% of brain tissue but absent from the blood or skin this point can be awarded).\n\nFor the sake of implementation, these criteria are intended to apply to high-confidence somatic mutations identified by the reporting CLIA laboratory. The expert panel recognizes that in practice there may be significant heterogeneity in the technical methods and thresholds used to identify such variants as 'high confidence', and flags the need to establish consensus statistical frameworks (e.g. Phred-scaled genotype qualities) or experimental approaches (e.g., confirmation of somatic variants by sequencing on orthogonal platforms) by which quality thresholds can be consistently applied.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "004",
"instructionsToUse": "",
"specificationType": "Disease-specific, Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Award the PS2_Moderate point if Criteria 1 is fulfilled, OR if parents are not available but Criteria 2 is fulfilled.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0043",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907163",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467907163",
"modified": "2022-11-11T18:08:11.820Z",
"modifier": "cspecAdministrator",
"rev": "_inf5Apm--U"
},
{
"entContent": {
"_uniqueProp": "018_PP4_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "Not applicable since this criterion is accounted for under PS4.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "018",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0018",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0063",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907175",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467907175",
"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
"rev": "_inf5Api--Q"
},
{
"entContent": {
"_uniqueProp": "018_PP3_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "This criterion is not applicable since these variants are GOF, and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms. Use of this criterion can be revisited if there emerges additional published experience with predictive algorithms specifically designed to detect gain of function mutations.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "018",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0062",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907174",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467907174",
"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--g"
},
{
"entContent": {
"_uniqueProp": "018_PM1_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "018",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0028",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "006",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0054",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Residues affecting critical functional domains provided in Table 4 for each gene.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907166",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467907166",
"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--H"
},
{
"entContent": {
"_uniqueProp": "018_PS4_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS4",
"ns": "018",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0029",
"instructionsToUse": "",
"specificationType": "Disease-specific, Strength",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant meets criteria for (PM2). Strength of evidence is determined by points according to (Table 2B). PS4\\_VeryStrong ≥ 16 points. For PS4, for cases reported in the literature, we recommend assigning each one to the SINGLE category below that is associated with the highest point value (Table 2A). The total score obtained for all reported cases with a particular variant will determine the strength of PS4 assigned according to the scale (Table 2B)*.\n\n_PS4\\_VeryStrong ≥ 16 points._\n\n*Applicable if the variant is absent/rare from controls according to PM2 to ensure the variant is not simply present due to beinging common in the general population.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2). Strength of evidence is determined by points according to (Table 2B). PS4_Strong = 3.5-15.75 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0057",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2). Strength of evidence is determined by points according to (Table 2B). PS4_Moderate = 1.5-3.25 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0032",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2). Strength of evidence is determined by points according to (Table 2B). PS4_Supporting = 0.5 – 1.25 points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907165",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467907165",
"modified": "2022-11-11T18:08:11.820Z",
"modifier": "cspecAdministrator",
"rev": "_inf5Aq---P"
},
{
"entContent": {
"_uniqueProp": "018_PVS1_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "LOF and/or haploinsufficiency have not been clearly identified as disease mechanisms underlying brain malformations related to these genes, so in general this rule is not applicable. The disease mechanism for these genes is gain of function (GOF).",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PVS1",
"ns": "018",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0017",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0020",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0026",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907161",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467907161",
"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6---"
},
{
"entContent": {
"_uniqueProp": "018_PP5_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "018",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433481",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433481",
"modified": "2022-01-19T20:31:34.845Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--c"
},
{
"entContent": {
"_uniqueProp": "018_BP7_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "018",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs, if the nucleotide is non-conserved award this point (PhyloP score <0.1).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907186",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467907186",
"modified": "2021-11-05T21:07:14.143Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--I"
},
{
"entContent": {
"_uniqueProp": "018_BP5_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "018",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0078",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "No change.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907185",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467907185",
"modified": "2022-01-19T20:33:35.979Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--C"
},
{
"entContent": {
"_uniqueProp": "018_BP4_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "018",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Award BP4 for a synonymous, intronic positions (except canonical splice sites) or non-coding variants in the UTRs, if two out of three of the splicing prediction tools predicted no impact on splicing function.\nNot applicable for any variant type except for synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs,. This criterion can be applied when two of three splicing prediction tools predict no splicing change. The splicing prediction tools used are: varSEAK, spliceAI and MaxEntScan.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907184",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467907184",
"modified": "2022-11-11T18:08:11.820Z",
"modifier": "cspecAdministrator",
"rev": "_inf5Aq---R"
},
{
"entContent": {
"_uniqueProp": "018_BP3_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "This is not applicable for the genes specified since the exon regions do not have repetitive regions without a known function.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "018",
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"sepioID": "SEPIO-CG:99045",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907183",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467907183",
"modified": "2022-01-19T20:33:35.979Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--h"
},
{
"entContent": {
"_uniqueProp": "018_BP2_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "018",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0084",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in cis or trans with a known pathogenic variant in the same gene.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907182",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467907182",
"modified": "2022-11-11T18:08:11.820Z",
"modifier": "cspecAdministrator",
"rev": "_inf5Aq---Q"
},
{
"entContent": {
"_uniqueProp": "018_BP1_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "Not applicable as LOF is not the disease mechanism.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "018",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907181",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467907181",
"modified": "2022-01-19T20:33:35.979Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--B"
},
{
"entContent": {
"_uniqueProp": "018_BS3_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "018",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0085",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907179",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467907179",
"modified": "2022-01-19T20:33:35.979Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--A"
},
{
"entContent": {
"_uniqueProp": "018_BA1_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BA1",
"ns": "018",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency (>0.0926%). An allele frequency (>0.0926%) was approved.\n Note: this was adjusted from ACMG Guidelines due to maintaining the 5x threshold for benign (consistent with previously established guidelines)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907176",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467907176",
"modified": "2022-11-11T18:08:11.820Z",
"modifier": "cspecAdministrator",
"rev": "_inf5Ap6--D"
},
{
"entContent": {
"_uniqueProp": "018_PP2_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "018",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0061",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense constraint computed in ExAC/gnomAD was utilized. Award PP2 if the z-score > 3.09. (applicable to MTOR, PIK3CA and AKT3 but not PIK3R2).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907173",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467907173",
"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
"rev": "_inf5Api--P"
},
{
"entContent": {
"_uniqueProp": "018_PP1_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "Not applicable since disease-causing variants are germline mosaic, de novo or mosaic.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP1",
"ns": "018",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0023",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0040",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0060",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907172",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467907172",
"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
"rev": "_inf5Apq--f"
},
{
"entContent": {
"_uniqueProp": "018_PM5_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM5",
"ns": "018",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "008",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "No change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0048",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907170",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467907170",
"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--O"
},
{
"entContent": {
"_uniqueProp": "018_PM4_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "Although there have been reported in-frame deletion/insertions in these genes which cause the overgrowth phenotype, they are exceptionally rare. Most insertion/deletions are associated with a LoF disease mechanism and so this point will still not be used even though we recognize that it is possible that a variant is an in-frame indel that results in a GoF mechanism.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "018",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "009",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907169",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/467907169",
"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
"rev": "_inf5Api--O"
},
{
"entContent": {
"_uniqueProp": "018_PM3_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "Not applicable since disease-causing variants are heterozygous.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "018",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
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{
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"id": "0058",
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"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable for this VCEP",
"id": "007",
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"text": "",
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{
"applicability": "Not Applicable for this VCEP",
"id": "0027",
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"text": "",
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]
},
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"id": "0013",
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"id": "0011",
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{
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"text": "Follow recommendations set forth by the SVI in conjunction with specifications added by the BMVCEP for quality metrics and minimum validation controls required. (Supplemental Document 1) Animal models are considered in a different manner.\n\nAward PS4_Strong if the animal model generated with the variant of interest expressed in neural progenitors shows a complementary brain phenotype.\n\nAward PS3 if the functional assay meets the acceptability criteria delimited in (PMID: 31892348) with specifications added by the BMVCEP. Quality metrics and minimum validation controls required can be found in Supplementary Document 1.\n\nAnimal models are considered in a different manner. Award PS4_Strong if the animal model generated with the variant of interest expressed in neural progenitors show a complementary brain phenotype.\n\nCaveat: Studies of cell lines derived from the affected patient as the only source of functional characterization are by themselves insufficient to provide strong evidence of pathogenicity. This is because cells derived from patient affected tissue are likely to exhibit the desired phenotype since the patient tissue exhibits the phenotype. It is therefore impossible to determine whether the variant of interest was solely responsible for that phenotype. Instead, functional readout of patient-derived cells are now included in PS4.",
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"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
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"id": "0022",
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"label": "PM5",
"ns": "019",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Clarification",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same residue as 2 previously established pathogenic variants or 1 previously established pathogenic and 2 likely pathogenic variants or 4 previously established likely pathogenic variants (all assessed independently of PM5)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Clarification"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Same residue as a previously established pathogenic variant (assessed independently of PM5) or 2 previously established likely pathogenic variants (both assessed independently of PM5)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Clarification",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Same residue as a previously established likely pathogenic variant (assessed independently of PM5)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003692",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003692",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2Mdi---"
},
{
"entContent": {
"_uniqueProp": "019_PM1_nuclear_MYOC",
"additionalComments": "MYOC has no mutational hot spot and benign variants are present though the well-characterised olfactomedin domain in exon 3.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "019",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 4,
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 2,
"id": "006",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003688",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003688",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2MYO---"
},
{
"entContent": {
"_uniqueProp": "019_BP3_nuclear_MYOC",
"additionalComments": "MYOC does not have a repetitive region without a known function.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "019",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003705",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003705",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2MeG---"
},
{
"entContent": {
"_uniqueProp": "019_PM6_nuclear_MYOC",
"additionalComments": "Refer to PS2",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "019",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"defaultPoint": 8,
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 4,
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 2,
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003693",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003693",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2MXy---"
},
{
"entContent": {
"_uniqueProp": "019_PS2_nuclear_MYOC",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": "PS2 and PM6 have been combined under PS2. See Table 3 for point system. The proposed SVI point recommendations for “phenotype consistent with gene but not highly specific” applies to JOAG and “phenotype consistent with the gene but not highly specific and with high genetic heterogeneity” applies to POAG.\n\n* Both maternity and paternity need to be proven for confirmed de novo variants.\n* Parents need to be clinically assessed and not have a diagnosis of glaucoma (If a parent has suspicious signs of glaucoma, the age and the severity of the symptoms should be taken into account before applying criteria).",
"label": "PS2",
"ns": "019",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 8,
"id": "0016",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* ≥2 confirmed de novo in JOAG",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* ≥2 confirmed de novo in POAG\n* Or 1 confirmed de novo in JOAG\n* Or ≥2 assumed _de novo_ in JOAG",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* 1 confirmed de novo in POAG\n* Or ≥2 assumed _de novo_ in POAG\n* Or 1 assumed _de novo_ in JOAG",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003685",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003685",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2MZ----"
},
{
"entContent": {
"_uniqueProp": "019_BP7_nuclear_MYOC",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP7",
"ns": "019",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -4,
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Clarification"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Apply to intronic/noncoding and synonymous (silent) exonic variants if BP4 is met",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003708",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003708",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2MZO---"
},
{
"entContent": {
"_uniqueProp": "019_BP4_nuclear_MYOC",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": "Similar to PP3, The Glaucoma VCEP decided to follow the SVI recommendations to apply the REVEL thresholds calculated for the different levels of evidence.[10](#PMID_36413997)\n\n_MYOC_ which only has 3 exons, one transcript and for which splicing is not known to vary. Based on the disease mechanism and the absence of current evidence supporting pathogenicity of intronic/noncoding variants, the Glaucoma VCEP agreed to apply BP4 to noncoding variants using SpliceAI.",
"label": "BP4",
"ns": "019",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0066",
"instructionsToUse": "",
"specificationType": [
"Clarification",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "REVEL score of ≤ 0.016",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -2,
"id": "0214",
"instructionsToUse": "",
"specificationType": [
"Clarification",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "REVEL score of 0.017-0.183",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Clarification"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants: REVEL score of 0.184-0.290\n* For all other variants located outside of donor/acceptor ±1,2 dinucleotide positions, when splicing assay is not available: SpliceAI ≤ 0.1",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003706",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003706",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2MbC---"
},
{
"entContent": {
"_uniqueProp": "019_BS3_nuclear_MYOC",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": "BS3 at a Moderate or Supporting level applies to variants showing solubility or secretion in functional assays for studies with OddsPath as per the published SVI recommendations.[1](#PMID_31892348)\n\n* Only apply if the assay includes both negative and positive controls and includes technical and/or biological replicates.\n* If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.\n* Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.[1](#PMID_31892348)\n* If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.",
"label": "BS3",
"ns": "019",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -4,
"id": "0072",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -2,
"id": "0100",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "Applies to variants showing solubility or secretion in functional assays for studies with OddsPath \\<0.23 as per the SVI recommendations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Applies to variants showing solubility or secretion in functional assays for studies with OddsPath \\<0.48 as per the SVI recommendations.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003701",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003701",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2Mba---"
},
{
"entContent": {
"_uniqueProp": "019_BS1_nuclear_MYOC",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": "* The highest allele frequency in population databases should be used.\n* Variant must be present in ≥ 5 alleles in any validated general continental population dataset of at least 2,000 observed alleles.\n* Does not apply to p.Gln368Ter.\n\nThe Whiffin/Ware calculator was used to obtain a population allele frequency threshold for BS1 using a more realistic estimate of the penetrance.[13](#PMID_28518168) The prevalence of POAG and the maximum allelic contribution used were the same as for BA1. A penetrance at 56% was used based on the penetrance of p.Gln368Ter in family-based studies using data from the Australian and New Zealand of Advanced Glaucoma and the Glaucoma Inheritance Study in Tasmania.[17](#PMID_30267046) The maximum credible allele frequency calculated was 0.001.\n\nAn exemption was applied to p.Gln368Ter. _MYOC_ p.Gln368Ter is a well-established pathogenic variant but displays incomplete penetrance. Its allele frequency in gnomAD is 0.001588 in European Non-Finnish, 0.003344 in European Finnish, and is 0.0025 in the UKBB. Evidence supports a European founder effect.[18](#PMID_12522550)",
"label": "BS1",
"ns": "019",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency ≥ 0.001 in population databases.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -1,
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
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"modifier": "esouzeau",
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},
{
"entContent": {
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"geneType": "nuclear",
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"modifier": "esouzeau",
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{
"entContent": {
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"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
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"gene": [
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"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "019",
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"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
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"strengthDescriptor": [
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"applicability": "Not applicable",
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"strength": "Stand Alone",
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"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
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"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
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{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
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"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
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"entType": "CriteriaCode",
"ldhId": "638433511",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433511",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2MWW---"
},
{
"entContent": {
"_uniqueProp": "019_BP5_nuclear_MYOC",
"additionalComments": "Multiple molecular diagnoses are possible and variants in different genes could have an additive effect.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
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"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": null,
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"sepioID": "SEPIO-CG:99047",
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"strengthSepioID": "SEPIO:0000328",
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"applicability": "Not applicable",
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"id": "0217",
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"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0078",
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"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
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"entType": "CriteriaCode",
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"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2MdO---"
},
{
"entContent": {
"_uniqueProp": "019_BS2_nuclear_MYOC",
"additionalComments": "MYOC variants have an incomplete penetrance and late age of onset.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "019",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
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"strength": "Very Strong",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0069",
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"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0076",
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"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
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]
},
"entType": "CriteriaCode",
"ldhId": "635003700",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003700",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2Mby---"
},
{
"entContent": {
"_uniqueProp": "019_PP3_nuclear_MYOC",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": "* The combination of PP3 and PM5 should not be higher than 5 points, and the combination of PP3 and PS1 should not be higher than 6 points.\n\nPejaver et al. estimated thresholds for different strength of evidence for computational predictors and recommended using one that reaches a strong level of evidence for pathogenicity and moderate for benignity.[26](#PMID_36413997) The Glaucoma VCEP recommended using only one _in silico_ predictor, in line with a recent study showing a lower rate of concordance when multiple software are used.[25](#PMID_29179779) The Glaucoma VCEP piloted the 4 predictors recommended by Pejaver et al. (REVEL, VEST4, BayesDel2 and MutPred2) on previously established LB/B and LP/P variants by the Glaucoma VCEP. Of the 4 tools, REVEL had the highest sensitivity (PP3 was applied to 95.2% (20/21) of LP/P variants (5x at PP3, 13x at PP3\\_Moderate and 2x at PP3\\_Strong), reclassifying 5x LP variants as P) and the lowest specificity (BP4 was applied to 45.0% (9/20) of LB/B variants (5x at BP4 and 4x at BP4\\_Moderate), reclassifying 2x LB variants as B). MutPred2 had a sensitivity of 47.6% while VEST4 and BayesDel2 had a sensitivity of 81.0%. Of note, two variants classified as LB/B was predicted to have impact with REVEL but this was consistent across the other 3 prediction tools. Therefore the VCEP recommends using REVEL based on its ease of access, high level of accuracy toward variant pathogenicity [27](#PMID_31484976) and more conservative predictions toward benign impact in the context of _MYOC_ variants.\n\nBased on the disease mechanism (GoF), the fact that all pathogenic variants are located in the last exon of the gene and the absence of current evidence supporting splicing as having a deleterious impact, the Glaucoma VCEP does not recommend using SpliceAI for PP3.",
"label": "PP3",
"ns": "019",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0019",
"instructionsToUse": "",
"specificationType": [
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"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "REVEL score of ≥ 0.932",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"Clarification",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "REVEL score of 0.773-0.931",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0062",
"instructionsToUse": "",
"specificationType": [
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],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "REVEL score of 0.644-0.772",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003696",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003696",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2Mcq---"
},
{
"entContent": {
"_uniqueProp": "019_PP2_nuclear_MYOC",
"additionalComments": "Although pathogenic missense variants are common in MYOC, the gene also has a significant amount of benign missense variants as shown by the missense constraint z score in gnomAD (z = 0.52) supporting tolerance to variation.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "019",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
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]
},
"entType": "CriteriaCode",
"ldhId": "635003695",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003695",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2MaC---"
},
{
"entContent": {
"_uniqueProp": "019_PP1_nuclear_MYOC",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": "* BA1 and BS1 must not be met.\n* Multiple families are jointly considered by adding the informative meioses across families according to Kelly et al.[9](#PMID_29300372)\n* Only genotype positive/phenotype positive and obligate carriers/phenotype positive individuals should be counted as segregations.\n* Individuals who are genotype positive/phenotype negative and individuals who are genotype negative/phenotype negative should not be counted\n* Phenotype positive need to be clinically assessed and either have a diagnosis of glaucoma or suspicious signs of glaucoma.\n* Do not apply Strong level of evidence if the variant is present in a single family due to risk of other variant in linkage disequilibrium",
"label": "PP1",
"ns": "019",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Clarification",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥7 meioses in >1 family",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Clarification",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥ 5 meioses regardless of the number of families",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Clarification"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥ 3 meioses regardless of the number of families",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003694",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003694",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2MZu---"
},
{
"entContent": {
"_uniqueProp": "019_PM4_nuclear_MYOC",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": "The disease mechanism for _MYOC_ variants is GoF, not LoF.[2](#PMID_11401512),[3](#PMID_15069026) Therefore, PM4 is used instead of PVS1 for truncating variants in the olfactomedin domain. One stop-loss variant has been reported in _MYOC_.[4](#PMID_34923728)\n\nThere are only four in-frame variants reported in the MYOC database. There is a lack of current data to support a benign/pathogenic classification of in-frame del/ins.[5](#PMID_12215093),[6](#PMID_9639450),[7](#PMID_23566828),[8](#PMID_9535666)",
"label": "PM4",
"ns": "019",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not Applicable for this VCEP",
"id": "0233",
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"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
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},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "In-frame del/ins, stop-loss variants and truncating variants involving >10% of the protein and located within the conserved olfactomedin domain (AA 246-502).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
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"id": "0059",
"instructionsToUse": "",
"specificationType": [
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"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "In-frame del/ins, stop-loss variants and truncating variants involving ≤10% of the protein and located within the conserved olfactomedin domain (AA 246-502).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003691",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003691",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2MYm---"
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"entContent": {
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"additionalComments": "MYOC variants have an autosomal dominant mode of inheritance.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "019",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
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},
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"applicability": "Not applicable",
"id": "0232",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"defaultPoint": 8,
"id": "0038",
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"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
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{
"applicability": "Not applicable",
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"id": "0058",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"defaultPoint": 2,
"id": "007",
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"specificationType": [],
"strength": "Moderate",
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"text": "",
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{
"applicability": "Not applicable",
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"id": "0027",
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"strength": "Supporting",
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},
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"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
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"geneType": "nuclear",
"instructionsToUse": "Case-control data for _MYOC_ variants is limited due to control cohorts often being too small to reflect the true prevalence of variants in a true control population. Instead, the Glaucoma VCEP recommends using PS4 for counting probands from multiple independent studies using a “quasi case-control study” approach.\n\n* Probands need to be clinically assessed and have JOAG or POAG\n* PM2 needs to be met (due to incomplete penetrance, late age of onset of glaucoma and the rate of undiagnosed glaucoma in the general population, pathogenic variants may be present in population databases)\n* Individuals with multiple _MYOC_ VUS/LP/P variants cannot be considered as evidence of either variant",
"label": "PS4",
"ns": "019",
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"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
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}
},
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"strength": "Very Strong",
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"text": "",
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"id": "0053",
"instructionsToUse": "",
"specificationType": [
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],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥ 15 probands from multiple independent studies.",
"type": "EvidenceLineStrength"
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{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0057",
"instructionsToUse": "",
"specificationType": [
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"Strength"
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"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥ 6 probands from multiple independent studies.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥ 2 probands from multiple independent studies.",
"type": "EvidenceLineStrength"
}
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"ldhId": "635003687",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003687",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
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{
"entContent": {
"_uniqueProp": "019_PS1_nuclear_MYOC",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": "* The novel change must not affect splicing (SpliceAI ≤ 0.2)\n* The combination of PP3 and PS1 should not be higher than 6 points",
"label": "PS1",
"ns": "019",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
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"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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"defaultPoint": 4,
"id": "0050",
"instructionsToUse": "",
"specificationType": [
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],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as previously established pathogenic variant",
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"defaultPoint": 2,
"id": "0046",
"instructionsToUse": "",
"specificationType": [
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"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Same amino acid change as a previously established likely pathogenic variant",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
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"text": "",
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"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2McW---"
},
{
"entContent": {
"_uniqueProp": "019_PVS1_nuclear_MYOC",
"additionalComments": "MYOC variants cause JOAG/POAG through a gain of function (GoF) disease mechanism and not loss of function (LoF). Truncating variants in exon 3 are expected to be pathogenic because they escape nonsense-mediated decay.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PVS1",
"ns": "019",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
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"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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"defaultPoint": 8,
"id": "0017",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"defaultPoint": 4,
"id": "0020",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"defaultPoint": 2,
"id": "0026",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003683",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003683",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2Mae---"
},
{
"entContent": {
"_uniqueProp": "019_BP1_nuclear_MYOC",
"additionalComments": "Both truncating and missense MYOC variants are causative.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "019",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
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]
},
"entType": "CriteriaCode",
"ldhId": "635003703",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003703",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2MW6---"
},
{
"entContent": {
"_uniqueProp": "019_BS4_nuclear_MYOC",
"additionalComments": "The presence of phenocopies, the reduced age-related penetrance and the possibility that more than one pathogenic variant can contribute to the phenotype observed in families make non-segregation difficult to assess in the context of MYOC and POAG.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "019",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0071",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003702",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003702",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2MXm---"
},
{
"entContent": {
"_uniqueProp": "019_BA1_nuclear_MYOC",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": "* The highest allele frequency in population databases should be used.\n* Variant must be present in ≥ 5 alleles in any validated general continental population dataset of at least 2,000 observed alleles.\n\nThe Whiffin/Ware calculator[13](#PMID_28518168) was used to obtain a population allele frequency threshold for BA1 using conservative figures. The prevalence of POAG in the African population, which is the highest among all populations, was used (1/24).[14](#PMID_24974815),[15](#PMID_16488940)The maximum allelic contribution for the most common _MYOC_ variant (p.Gln368Ter) was set at 2.6% using data from large disease registries (the Australian and New Zealand of Advanced Glaucoma and the Glaucoma Inheritance Study in Tasmania with data on over 3,236 individuals).[16](#PMID_23453510) A conservative estimate for the penetrance at 7.6% was used based on the penetrance of p.Gln368Ter in a population-based study using data from the UK biobank.[17](#PMID_30267046) The maximum credible allele frequency calculated was 0.007, which was rounded up to 0.01.",
"label": "BA1",
"ns": "019",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"defaultPoint": "Not Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency ≥ 0.01 in population databases.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003698",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003698",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2MZe---"
},
{
"entContent": {
"_uniqueProp": "019_PM2_nuclear_MYOC",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": "* The highest allele frequency in population databases should be used.\n* Only applies to populations of ≥ 10,000 alleles.\n* PM2 should be used at a Supporting level as per the SVI recommendations.\n\nThe filtering allele frequency for PM2 was set one order of magnitude lower than BS1. This is a conservative approach: some pathogenic variants are expected to be present in population databases due to POAG being a complex disease with late onset and age-related penetrance. Moreover, most _MYOC_ pathogenic variants are absent from large population databases.",
"label": "PM2",
"ns": "019",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Allele frequency ≤ 0.0001 in population databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003689",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003689",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2MY----"
},
{
"entContent": {
"_uniqueProp": "019_PS3_nuclear_MYOC",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": "The mechanism by which the variants cause POAG is a GoF mechanism with accumulation of insoluble aggregates inside the endoplasmic reticulum of the trabecular meshwork cells.[31](#PMID_11401512),[32](#PMID_15069026) Follow the SVI recommendations from Brnich et al. when assessing functional assays to apply PS3 toward functional evidence.[33](#PMID_31892348)\n\n* Applies to the following functional studies: stability, solubility or secretion assays OR animal models that replicate the glaucoma phenotype.\n* PS3 should only be applied if the assay includes both negative and positive controls and includes technical and/or biological replicates.\n* If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.\n* Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.[33](#PMID_31892348)\n* If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.\n\nThe characteristics of each study reviewed, the summary of the assays combined, validation controls, OddsPath and recommendations and classification of variants with functional data are detailed in Tables 1 & 2.",
"label": "PS3",
"ns": "019",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 8,
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0052",
"instructionsToUse": "",
"specificationType": [
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"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Assays with OddsPath >18.7 as per the SVI recommendations.[1](#PMID_31892348)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0039",
"instructionsToUse": "",
"specificationType": [
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"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assays with OddsPath >4.3 as per the SVI recommendations.[1](#PMID_31892348)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Assays with OddsPath >2.1 as per the SVI recommendations.[1](#PMID_31892348)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003686",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003686",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
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}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0007665",
"lbl": "obsolete glaucoma 1, open angle, E",
"meta": {
"basicPropertyValues": [
{
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"val": "http://purl.obolibrary.org/obo/OMO_0001000"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/2507"
},
{
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"val": "https://github.com/monarch-initiative/mondo/issues/4936"
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509001",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCnC---"
},
{
"entContent": {
"_uniqueProp": "020_PS4_nuclear_ATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "PS4\\_Moderate: Do not use. Proband counting for genes causing a common disorder need to be calibrated in a population-specific way before use.",
"label": "PS4",
"ns": "020",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639508995",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639508995",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCre---"
},
{
"entContent": {
"_uniqueProp": "020_BP6_nuclear_ATM",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP6",
"ns": "020",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509017",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509017",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCiS---"
},
{
"entContent": {
"_uniqueProp": "020_PM5_nuclear_ATM",
"additionalComments": "No rescue splicing isoforms have been identified in ATM.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "* Based on location of the most C-terminal known pathogenic variant, **p.Arg3047\\*.**\n* Use as **PM5\\_Supporting** (not moderate)\n* Do not use for start-loss variants\n* Do not use for missense changes: Multiple amino acid substitutions at the same residue can be pathogenic or benign and bioinformatic tools cannot yet confidently distinguish them",
"label": "PM5",
"ns": "020",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Apply to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047.\n* Apply to splice variants as with premature termination codons upstream of p.Arg3047 where PVS1\\_VS(RNA) is applied based on high quality observed splicing impact and must be NMD prone.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509000",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509000",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCgK---"
},
{
"entContent": {
"_uniqueProp": "020_PM1_nuclear_ATM",
"additionalComments": "Do not use: Benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined at this time",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "020",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639508996",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639508996",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCl6---"
},
{
"entContent": {
"_uniqueProp": "020_PS2_nuclear_ATM",
"additionalComments": "Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS2",
"ns": "020",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639508993",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639508993",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCkC---"
},
{
"entContent": {
"_uniqueProp": "020_PS1_nuclear_ATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "* Use as ascribed for missense changes as long as a splice defect is ruled out for both variants;\n* Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect. (PMID: 36865205)",
"label": "PS1",
"ns": "020",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* Use for missense changes as long as splicing is ruled-out for both alterations. \n* Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639508992",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639508992",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCqi---"
},
{
"entContent": {
"_uniqueProp": "020_BP5_nuclear_ATM",
"additionalComments": "Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2). In addition, ATM has low penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "020",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509016",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509016",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCfm---"
},
{
"entContent": {
"_uniqueProp": "020_PP3_nuclear_ATM",
"additionalComments": "Check splicing scores for all variant types. Do not combine splice prediction weight with other lines of protein evidence.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "* NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) \n* NOTE: PP3 for splice predictions may not be applied in addition to PVS1 or PVS1\\_Variable(RNA) codes.\n* Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism.\n* The VCEP uses SpliceAI as a sole predictor due to its ability to accurately predict loss of native splice sites and creation of cryptic sites (Jaganathan et al., 2019). This VCEP recommends SpliceAI thresholds set forth by the SVI in applying PP3 and BP4 to non-canonical splice variants: Apply PP3 for SpliceAI scores ≥0.2 and apply BP4 for SpliceAI scores ≤0.1 (Walker et al., 2023).\n* In the event that RNA data are available and they reflect a substantial variant-specific impact, do not use both PVS1(RNA) and PP3 or BP4. However, in the event that RNA data are available and they reflect no variant-specific impacts, PP3 or BP4 may be applied in conjunction with BP7(RNA).",
"label": "PP3",
"ns": "020",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Missense: REVEL **\\>.7333**\n* Splicing: Predicted impact via splicing (SpliceAI **≥0.2**) for silent, missense/in-frame and for intronic variants outside of donor and acceptor 1,2 sites.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509004",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509004",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCfW---"
},
{
"entContent": {
"_uniqueProp": "020_PP2_nuclear_ATM",
"additionalComments": "Do not use: ATM does not have a defined low rate of missense benign variation.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "020",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509003",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509003",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCrq---"
},
{
"entContent": {
"_uniqueProp": "020_PM3_nuclear_ATM",
"additionalComments": "Multiple such cases are additive, Phenotype considerations are detailed in the rules, frequency of >.01% should not use PM3; Observations in cis are not applicable. Source information is considered (laboratory vs database setting).",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "See **ATM PM3/BP2 table** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points.\n\nAtaxia Telangiectasia (A-T) is a rare, severe, early-onset disease with some exceptions denoted ‘variant’ or ‘atypical’ A-T in which cases phenotypes are more mild with slower progression. Phenotypes associated with A-T are very specific and do not generally require differential diagnosis. Therefore, publications that claim a ‘clinical diagnosis of A-T’ are taken at face value and granted a ‘confident diagnosis. Specific phenotype criteria may qualify for ‘confident or ‘consistent’ diagnosis of A-T based on the below criteria. No additional weight modifications are made for ‘atypical’ cases if they meet ‘confident or ‘consistent’ criteria as although the disease progression is different, the clinical features are the same.\n\nVariant may not exceed general population frequency >0.01%. \n\nIf the variant under assessment has co-occurred with at least 2 different P/LP variants, one co-occurrence must be weighed as phase unknown while the remaining can be assumed in _trans_\n\nMultiple unrelated cases are additive. \n\n* For example, one individual with a ‘confident A-T phenotype’ is homozygous for a variant scores 2.0 points. Another individual who has a ‘consistent A-T phenotype’ and has the same variant and another phase-unknown truncating ATM variant scores 1.0 points. The total points towards PM3 are 3.0 points leading to PM3 used as its baseline moderate strength.\n\nCONFIDENT PHENOTYPE (must include Laboratory result)\n\n* Presence of ≥2 Laboratory results 1-4 (see notes) -OR- \n* Presence of Clinical feature 1a or 1b **AND** presence of Laboratory result 1 or 2 -OR-\n* Presence of Clinical feature 2 or 3 **AND** Laboratory result 1 or 2\n\nCONSISTENT PHENOTYPE (does not require laboratory result)\n\n* Presence of two or more Clinical features of ataxia (1a-1e) -OR-\n* Presence of one Clinical feature 1a or 1b **AND** either Clinical feature 2 or 3\n\nClinical features (Neurological and MRI findings):\n\n1. Progressive cerebellar ataxia, manifesting as:\n * a: Progressive truncal/limb ataxia \n * b: Cerebellar degeneration (atrophy of the frontal and posterior vermis and both hemispheres by MRI).\n * c: Oculomotor apraxia (inability to follow an object across visual fields) or abnormal ocular saccades (rapid refixation from one object to another).\n * d: Choreoathetosis or dystonia (involuntary movements; twisting and repetitive movements, abnormal postures).\n * e: Peripheral axonal neuropathy OR Anterior horn cell neuronopathy\n2. Oculocutaneous telangiectasia of the conjunctivae, ears, or face.\n3. Immunodeficiency (often frequent infections) and/or leukemia/lymphoma.\n\nLaboratory Results:\n\n1. ATM protein levels ≤ 15% of controls in patient fibroblast or lymphoblastoid cell lines. If ATM protein levels are slightly greater than 15%, the ATM kinase activity must be shown to be \"negative or low or residual\" (see notes).\n2. Elevated serum alpha-fetoprotein (AFP) levels >65ug/L in a patient ≥ 2 years old.\n3. Increased sensitivity to ionizing radiation in patient fibroblast or lymphoblastoid cell lines.\n4. Presence of a 7;14 chromosomal translocation in patient peripheral blood cells (≥ 5% of cells).\n\nNotes:\n\n1. ATM protein levels ≤15% of control levels show >95% sensitivity and >98% specificity for diagnosing ataxia-telangiectasia (A-T). Protein levels >15% may arise due to a missense variant, a leaky splicing variant, a variant resulting in a kinase-dead protein (where protein levels may not be affected), or a diagnosis other than A-T.\n2. When assigning case report criteria based solely on laboratory results (i.e., presence of TWO or more of laboratory results 1-4), there is a greater likelihood that the most specific laboratory results #1 and #2 will be available, and that there will be some clinical indication that the individual(s) has A-T.",
"label": "PM3",
"ns": "020",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation",
"Gene-specific",
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "PM3\\_VeryStrong **≥ 8** points\n\nSee ATM PM3/BP2 table for approach to assign points per proband.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation",
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "PM3\\_Strong = **4** points\n\nSee ATM PM3/BP2 table for approach to assign points per proband.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation",
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "PM3 = **2** points\n\nSee ATM PM3/BP2 table for approach to assign points per proband.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation",
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "PM3\\_Supporting = **1** point\n\nSee ATM PM3/BP2 table for approach to assign points per proband.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639508998",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639508998",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OChq---"
},
{
"entContent": {
"_uniqueProp": "020_PM2_nuclear_ATM",
"additionalComments": "PM2_Supporting is not considered a conflicting piece of evidence to an otherwise benign body of evidence; Coverage must be >30X at the locus.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "* Is not considered a conflicting piece of evidence for variants that otherwise are likely benign/benign \n* Use as **PM2\\_Supporting** (not moderate)",
"label": "PM2",
"ns": "020",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Frequency **≤.001%** in gnomAD v4 dataset\n\nIf n=1 in a single sub population, that is sufficiently rare and PM2\\_supporting would apply.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639508997",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639508997",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCq6---"
},
{
"entContent": {
"_uniqueProp": "020_PVS1_nuclear_ATM",
"additionalComments": "Used with PM5_Supporting for non-splice, non-start-loss LoF variants with PTCs upsteram of p.R3047. Per points system, PVS1 + 1 Supporting = LP.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "Use ATM PVS1 Decision Tree.\n\n* PVS1: Predicted splice defect \n* PVS1\\_Strength(RNA): Observed splice defect\n* The default RefSeq transcript for nucleotide (c.) annotation is **NM\\_000051.3/ENST00000278616.8.** All exons from this transcript can be considered constitutive exons without major alternate splice isoforms that could potentially rescue presumed LoF events (ENIGMA unpublished data).\n* Of note, ATM is occasionally annotated with multiple non-coding first exons so exon numbering must be carefully reviewed for variant interpretation using literature sources of data.\n* **The FAT/PI3K/FATC (collectively the FATKIN)** domains are considered _critical_ for ATM protein function (PMID 28508083, 31740029, 31320732). PVS1 alterations that are predicted to escape NMD, but that adversely affect these domains can be granted PVS1 (as opposed to PVS1\\_Strong as the recommended base-line (PMID 30192042). \n* **The HEAT repeat domain** is considered _important_ for protein function based on the appearance of many A-T affected individuals harboring a variant resulting in an in-frame, single exon loss in this domain (PMID 10980530, 19535770, 30819809, 15054841, 22927201, 19691550, 10330348, 17124347, 8845835, 16266405, 9463314, 24090759, 22213089). PVS1-eligible alterations that are predicted to escape NMD, but that adversely affect the HEAT repeat domain can be granted PVS1\\_Strong. They are limited to strong due to a lack of known missense pathogenic alterations in this domain.\n* The most 3’/C-Terminal residue considered to be pathogenic is p.R3047 (PMIDs: 8755918, 19691550, 18560558, 10980530, 26628246)\n* NOTE: Many diagrams for ATM show the FAT, PI3-K and FATC domains as separated by spacers, however these are not empirically derived and there is evidence of missense pathogenic alterations in the ‘spacer’ regions. This VCEP considers them a contiguous domain (PMID 28508083).\n* PVS1 can be applied as per the PVS1 decision tree.\n * PVS1\\_Variable(RNA) shall be used for observed splice defects, whether from canonical +/-1,2 positions or other spliceogenic regions (including mid-exonic missense/synonymous variants that cause splice defects) with baseline weight as per the below decision tree. Weight can be further modified based on the quality of the RNA study including consideration of concepts such as:\n * Starting material (where patient material is preferable to in vitro minigene)\n * Use of NMD inhibitors where translation does occur such as cell lines[5](https://cspec.genome.network/cspec/ed/svi/doc/GN077#pmid_9628884)[6](https://cspec.genome.network/cspec/ed/svi/doc/GN077#pmid_7499432)\n * Primer design (to make sure it’s comprehensive to capture possible multicassette events)\n * Method of quantification \n * where e.g. capillary electrophoresis is preferable to estimation by gel band density\n * where SNP analysis is most preferred (where analysis of exonic SNPs and their relative presence in aberrant and WT transcripts is informative)\n * Quantification (where complete effects should have increased weight over incomplete effects)\n * Specific guidance on the use of RNA evidence in variant assessment is not a gene-specific consideration for PALB2 at this time, therefore discretion is left to assessors until further guidance is provided for this general concept from the Sequence Variant Interpretation group.\n* In the event that RNA data are available and they reflect a substantial variant-specific impact, do not use both PVS1(RNA) and PP3 or BP4. However, in the event that RNA data are available and they reflect no variant-specific impacts, PP3 or BP4 may be applied in conjunction with BP7(RNA).",
"label": "PVS1",
"ns": "020",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use ATM PVS1 Decision Tree",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use ATM PVS1 Decision Tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use ATM PVS1 Decision Tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use ATM PVS1 Decision Tree",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639508991",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639508991",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCi----"
},
{
"entContent": {
"_uniqueProp": "020_BP7_nuclear_ATM",
"additionalComments": "BP4 may be used in addition to BP7 for sysnonymous and deep intronic variants to achieve LB; BP7 is not a conflicting piece of evidence against an otherwise pathogenic body of evidence; BP7_O should NOT be used in conjunction with BP4.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "* BP7: Synonymous and deep intronic\n * Can be used for deep intronic variants beyond (but not including) +7 (donor) and -21 (acceptor)\n * May also apply BP4 to achieve Likely Benign\n * Is not considered a conflicting piece of evidence against a body of evidence supporting a pathogenic splice defect\n* BP7\\_Variable(RNA): RNA functional studies\n * Lack of aberrant splice defect: Please see PVS1\\_Variable(RNA) section (above) for guidance on baseline weights and modifications of weight based on quality for RNA assays\n * In the event that RNA data are available and they reflect a substantial variant-specific impact, do not use both PVS1(RNA) and PP3 or BP4. However, in the event that RNA data are available and they reflect no variant-specific impacts, PP3 or BP4 may be applied in conjunction with BP7(RNA).",
"label": "BP7",
"ns": "020",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": "General recommendation",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "BP7\\_Strong(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0220",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "BP7\\_Moderate(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* BP7: Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively.\n* BP7(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509018",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509018",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCg6---"
},
{
"entContent": {
"_uniqueProp": "020_BS1_nuclear_ATM",
"additionalComments": "FAF is a statistical model that accounts for population size and founder populations.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "Follow all [SVI general guidance](https://clinicalgenome.org/working-groups/sequence-variant-interpretation/) on applying population filters.",
"label": "BS1",
"ns": "020",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Grpmax Filtering AF **\\>.05%** in gnomAD v4 dataset",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509008",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509008",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCoa---"
},
{
"entContent": {
"_uniqueProp": "020_PM4_nuclear_ATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "Do not use for in-frame insertions or deletions less than a single exon; Use for stop-loss variants, only.",
"label": "PM4",
"ns": "020",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use for stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639508999",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639508999",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCga---"
},
{
"entContent": {
"_uniqueProp": "020_BP4_nuclear_ATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "* NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) \n* NOTE: BP4 for splice predictions may not be applied in conjunction with BP7\\_Variable(RNA) (a lack of observed RNA defect) \n* Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism.\n* The VCEP uses SpliceAI as a sole predictor due to its ability to accurately predict loss of native splice sites and creation of cryptic sites (Jaganathan et al., 2019). This VCEP recommends SpliceAI thresholds set forth by the SVI in applying PP3 and BP4 to non-canonical splice variants: Apply PP3 for SpliceAI scores ≥0.2 and apply BP4 for SpliceAI scores ≤0.1 (Walker et al., 2023).\n* In the event that RNA data are available and they reflect a substantial variant-specific impact, do not use both PVS1(RNA) and PP3 or BP4. However, in the event that RNA data are available and they reflect no variant-specific impacts, PP3 or BP4 may be applied in conjunction with BP7(RNA).",
"label": "BP4",
"ns": "020",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* Missense: REVEL score **≤.249**\n* Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509015",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509015",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCla---"
},
{
"entContent": {
"_uniqueProp": "020_BP1_nuclear_ATM",
"additionalComments": "Do not use: Missense pathogenic variants are known for ATM",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "020",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509012",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509012",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCf6---"
},
{
"entContent": {
"_uniqueProp": "020_BS4_nuclear_ATM",
"additionalComments": "AD Condition: Co-segregation analysis in low penetrance genes can lead to false positive results (PMID 32773770)\nAR Condition: Informative instances of lack of co-segregation in A-T families are too rare to be considered for weight at this time and can also be considered for BP2 if biallelic unaffected patients are observed in an A-T family.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "020",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509011",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509011",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCnu---"
},
{
"entContent": {
"_uniqueProp": "020_BS3_nuclear_ATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "For protein, see detailed notes on ATM-specific assays; \n\nFor RNA use code BP7\\_RNA and modulate strength based on assay quality and quantity (curator discretion).",
"label": "BS3",
"ns": "020",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "Use when a variant rescues both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509010",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509010",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCoC---"
},
{
"entContent": {
"_uniqueProp": "020_BS2_nuclear_ATM",
"additionalComments": "Do not use: ATM has incomplete penetrance.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "020",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509009",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509009",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OClG---"
},
{
"entContent": {
"_uniqueProp": "020_PP5_nuclear_ATM",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP5",
"ns": "020",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509006",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509006",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCrG---"
},
{
"entContent": {
"_uniqueProp": "020_PP1_nuclear_ATM",
"additionalComments": "Informative pedigrees for segregation in families with AR Ataxia-Telangiectasia are not available. However, this VCEP would consider rules similar to the Glanzman and Hearing Loss VCEP rules if a pedigree becomes available.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "* AR Condition: Affected relatives must have both variants identified in proband.\n* AD Condition – Do not use: Co-segregation analysis in lower-penetrance genes can lead to false positive results (PMID 32773770)",
"label": "PP1",
"ns": "020",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "AR Condition: Segregation in ≥3 affected relatives",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "AR Condition: Segregation in 2 affected relatives",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "AR Condition: Segregation in 1 affected relative",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509002",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509002",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCqK---"
},
{
"entContent": {
"_uniqueProp": "020_PS3_nuclear_ATM",
"additionalComments": "Conflicting functional studies should not be given any weight.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "For protein, see detailed notes on ATM-specific assays; For RNA use code PVS1\\_Strength(RNA) and modulate strength based on assay quality and quantity (curator discretion).\n\nNOTE: Do not use phenotypic evidence (e.g. a lack of ATM activity in cells from an Ataxia-Telangiectasia patient) as functional data. That is a general assay that confirms the patient’s diagnosis and should be considered as part of PM3. However, splice data from patient material can be considered a functional effect because the effect is relatively specific to the variant (an undetected ATM variant is unlikely to cause the same splice defect as the variant under consideration for splice defect). See the accompanying tables for details on three papers using the below methods.",
"label": "PS3",
"ns": "020",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Do not use as strong.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use when a variant fails to rescue both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use when a variant fails to rescue an ATM specifc feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639508994",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639508994",
"modified": "2025-11-07T16:04:40.053Z",
"modifier": "mhoenig",
"rev": "_kj6OCja---"
}
],
"Disease": [
{
"created": "2024-11-20T22:14:03.908Z",
"creator": "cspecAdministrator",
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0700270",
"lbl": "ATM-related cancer predisposition",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6515"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0002-4142-7153"
}
],
"definition": {
"val": "Hereditary cancer predisposition due to variation(s) in the ATM gene. Pathogenic germline variation in ATM confers an autosomal dominant predisposition to tumor formation at multiple primary sites, including breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer.",
"xrefs": [
"https://clinicalgenome.org/affiliation/40023/"
]
},
"subsets": [
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"http://purl.obolibrary.org/obo/mondo#rare"
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0700270",
"name": "ATM-related cancer predisposition"
},
"entId": "MONDO:0700270",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0700270",
"entType": "Disease",
"ldhId": "66816762",
"ldhIri": "https://cspec.genome.network/cspec/Disease/id/66816762",
"modified": "2025-10-07T16:16:51.236Z",
"modifier": "cspecAdministrator",
"rev": "_kZ70Dpa---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0016419",
"lbl": "hereditary breast carcinoma",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0016419"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/hereditary_breast_carcinoma"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/87542"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C562840"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/254843006"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0346153"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C4503"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_227535"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/114480"
}
],
"comments": [
"Editor note: check w clingen before merge https://github.com/monarch-initiative/mondo/issues/84"
],
"definition": {
"val": "Breast carcinoma that has developed in relatives of patients with history of breast carcinoma.",
"xrefs": [
"NCIT:P378"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#omim_susceptibility",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "breast cancer susceptibility, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, early-onset, susceptibility to, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, invasive ductal, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, lobular, somatic"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, male, susceptibility to, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, protection against, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, somatic"
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"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509401",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509401",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmqm---"
},
{
"entContent": {
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"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "021",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509397",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509397",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmw---B"
},
{
"entContent": {
"_uniqueProp": "021_BS1_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS1",
"ns": "021",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "* Variants with a highest population minor allele frequency (MAF) ≥0.0035 (0.35%) in any continental population with >2000 alleles in gnomAD will meet BS1.\n * Calculated using the Prevalence of 1:30,000, Allelic Contribution of 0.5, Genetic Contribution of 1, and Penetrance of 0.75 to allow for mild VLCAD that may develop in adulthood.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509396",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509396",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmtO---"
},
{
"entContent": {
"_uniqueProp": "021_PP4_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "021",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Abnormal tests that are consistent with VLCAD deficiency include deficient VLCAD enzyme activity in patient cells (leukocytes, fibroblasts, liver, heart, or skeletal muscle, or amniocytes), abnormal C14:1 acylcarnitine values from newborn screening (NBS), and abnormal acylcarnitine values from follow-up plasma analysis.\n * 2 points (See PP4 Table)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Abnormal tests that are consistent with VLCAD deficiency include deficient VLCAD enzyme activity in patient cells (leukocytes, fibroblasts, liver, heart, or skeletal muscle, or amniocytes), abnormal C14:1 acylcarnitine values from newborn screening (NBS), and abnormal acylcarnitine values from follow-up plasma analysis.\n * 1 point (See PP4 Table)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509393",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509393",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmqK---"
},
{
"entContent": {
"_uniqueProp": "021_PM6_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "021",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of paternity and maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509389",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509389",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmvO---"
},
{
"entContent": {
"_uniqueProp": "021_PS4_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS4",
"ns": "021",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509383",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509383",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmpq---"
},
{
"entContent": {
"_uniqueProp": "021_PS2_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS2",
"ns": "021",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509381",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509381",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmtm---"
},
{
"entContent": {
"_uniqueProp": "021_BP6_nuclear_ACADVL",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP6",
"ns": "021",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509405",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509405",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmvy---"
},
{
"entContent": {
"_uniqueProp": "021_BP4_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "021",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* Missense changes with a REVEL score \\<0.5 will meet BP4.\n* For in-frame deletions and insertions, use Mutation Taster. \n* For non-canonical splice site variants, use Splice AI. Based on data from Jaganathan et al., 2019 (PMID: 30661751), Houdayer et al., 2012 (PMID: 22505045), Tang et al., 2016 (PMID: 27313609), and Walker et al., (2023) PMID:37352859, BP4 can be applied if there is a Δ Score ≤ 0.1.\n* Do not apply this rule if there is evidence for creation of a cryptic splice site.\n* Can be used with BP7 code.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509403",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509403",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmw2---"
},
{
"entContent": {
"_uniqueProp": "021_BP1_nuclear_ACADVL",
"additionalComments": "This rule does not apply. There are known pathogenic missense variants in ACADVL.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "021",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509400",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509400",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmuS---"
},
{
"entContent": {
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"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "021",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Enzyme activity assays, total protein production, protein stability, dimer formation and transcript production are valid assays to consider for PS3. Apply criteria at the level determined by validation parameters (see PS3 BS3 flowchart).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "Enzyme activity assays, total protein production, protein stability, dimer formation and transcript production are valid assays to consider for PS3. Apply criteria at the level determined by validation parameters (see PS3 BS3 flowchart).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Enzyme activity assays, total protein production, protein stability, dimer formation and transcript production are valid assays to consider for PS3. Apply criteria at the level determined by validation parameters (see PS3 BS3 flowchart).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509398",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509398",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmxu---"
},
{
"entContent": {
"_uniqueProp": "021_BA1_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BA1",
"ns": "021",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "* Variants with a highest population minor allele frequency (MAF) ≥0.007 (0.7%) in any continental population with >2000 alleles in gnomAD will meet BA1.\n * Calculated using the Prevalence of 1:30,000, Allelic Contribution of 1, Genetic Contribution of 1, and Penetrance of 0.75 to allow for mild VLCADD that may develop in adulthood.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509395",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509395",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmvi--A"
},
{
"entContent": {
"_uniqueProp": "021_PP2_nuclear_ACADVL",
"additionalComments": "This rule does not apply as there are benign and pathogenic missense variants in ACADVL.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "021",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509391",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509391",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmxi---"
},
{
"entContent": {
"_uniqueProp": "021_PM1_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "021",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* See table PM1, curators may seek approval from the expert panel for identifying additional hotspots or critical regions as discovered in literature searches for inclusion. \n * Moderate\n * p.1-40,mitochondrial signal peptide, PMIDs: 18227065\\*, 20060901 \n * p.214-223, nucleotide/substrate binding, PMIDs: 18227065\\*, 20060901 \n * p.249-251, nucleotide/substrate binding, PMIDs: 18227065\\*, 20060901 \n * p.R326, CpG dinucleotide, PMID: 9973285 \n * p.381-382, FAD binding and salt-bridge interaction, PMID: 20060901 \n * p.R429, CpG dinucleotide, PMID: 9973285 \n * p.E441, Adjacent to FAD binding, on dimer formation loop, PMIDs: 20060901 \n * p.R459, dimerization, PMID: 14517516 \n * p.481-516, membrane binding, PMIDs: 18227065\\*, 20060901 \n * p.562, nucleotide/substrate binding, PMIDs: 18227065\\*, 20060901 \n * \\*protein is described in mature protein nomenclature without signal peptide; add 40 amino acids to reach HGVS nomenclature",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509384",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509384",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmra---"
},
{
"entContent": {
"_uniqueProp": "021_PVS1_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PVS1",
"ns": "021",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Loss of function is a known mechanism for VLCAD Deficiency. The specifications below are based on published guidance for assigning strength of evidence for PVS1 (Abou Tayoun et al., (2018) PMID: 30192042). There are multiple transcripts for ACADVL. The major isoform, NM\\_000018.4, encodes a 655 amino acid precursor protein that contains a 40 amino acid N-terminal target sequence that is removed during uptake (Aoyama et al., (1995) PMID: 7668252). In a joint project between NCBI and EMBL-EBI (MANE), NM\\_000018.4 was designated as the most relevant transcript. Nonsense or Frameshift:\n\n* Use caution when interpreting LOF variants at the 3’ end of the gene.\n* NMD is not predicted if the variant is in the last exon (exon 20) or in the last 50 nucleotides of the penultimate exon (exon 19). \n* Canonical Splice Site (+1, +2, -1, -2): All donor/acceptor sites follow the GT/AG rule, except for the donor splice site of intron 8, which begins with GC. PVS1 should not be applied for variants in the splice donor site of intron 8 since the impact of GC donor splice sites is not well understood. For +1 or +2 GT donor splice site variants, the exon immediately 5’ of the variant is predicted to be skipped. For -1 or -2 AG acceptor splice site variants, the exon immediately 3’ of the variants is predicted to be skipped.\n* Initiation codon: The next in-frame methionine is at position 6 (on transcript NM\\_000018). However, the first 40 amino acids comprise the leader sequence in the precursor peptide and are important for proper localization of the protein (Aoyama et al., (1995) PMID: 7668252). Therefore, initiator codon variants will meet PVS1\\_Strong.\n* Well-established \\_in vitro\\_ or \\_in vivo\\_ functional studies supportive of a damaging effect \\_as measured by effect on mRNA transcript profile (mRNA assay only).\\_ Apply as PVS1 (RNA) at appropriate strength. \n* See ACADVL PVS1 decision tree; cannot be combined with PM1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Loss of function is a known mechanism for VLCAD Deficiency. The specifications below are based on published guidance for assigning strength of evidence for PVS1 (Abou Tayoun et al., (2018) PMID: 30192042). There are multiple transcripts for ACADVL. The major isoform, NM\\_000018.4, encodes a 655 amino acid precursor protein that contains a 40 amino acid N-terminal target sequence that is removed during uptake (Aoyama et al., (1995) PMID: 7668252). In a joint project between NCBI and EMBL-EBI (MANE), NM\\_000018.4 was designated as the most relevant transcript. Nonsense or Frameshift:\n\n* Use caution when interpreting LOF variants at the 3’ end of the gene.\n* NMD is not predicted if the variant is in the last exon (exon 20) or in the last 50 nucleotides of the penultimate exon (exon 19). \n* Canonical Splice Site (+1, +2, -1, -2): All donor/acceptor sites follow the GT/AG rule, except for the donor splice site of intron 8, which begins with GC. PVS1 should not be applied for variants in the splice donor site of intron 8 since the impact of GC donor splice sites is not well understood. For +1 or +2 GT donor splice site variants, the exon immediately 5’ of the variant is predicted to be skipped. For -1 or -2 AG acceptor splice site variants, the exon immediately 3’ of the variants is predicted to be skipped.\n* Initiation codon: The next in-frame methionine is at position 6 (on transcript NM\\_000018). However, the first 40 amino acids comprise the leader sequence in the precursor peptide and are important for proper localization of the protein (Aoyama et al., (1995) PMID: 7668252). Therefore, initiator codon variants will meet PVS1\\_Strong.\n* Well-established \\_in vitro\\_ or \\_in vivo\\_ functional studies supportive of a damaging effect \\_as measured by effect on mRNA transcript profile (mRNA assay only).\\_ Apply as PVS1 (RNA) at appropriate strength. \n* See ACADVL PVS1 decision tree; cannot be combined with PM1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Loss of function is a known mechanism for VLCAD Deficiency. The specifications below are based on published guidance for assigning strength of evidence for PVS1 (Abou Tayoun et al., (2018) PMID: 30192042). There are multiple transcripts for ACADVL. The major isoform, NM\\_000018.4, encodes a 655 amino acid precursor protein that contains a 40 amino acid N-terminal target sequence that is removed during uptake (Aoyama et al., (1995) PMID: 7668252). In a joint project between NCBI and EMBL-EBI (MANE), NM\\_000018.4 was designated as the most relevant transcript. Nonsense or Frameshift:\n\n* Use caution when interpreting LOF variants at the 3’ end of the gene.\n* NMD is not predicted if the variant is in the last exon (exon 20) or in the last 50 nucleotides of the penultimate exon (exon 19). \n* Canonical Splice Site (+1, +2, -1, -2): All donor/acceptor sites follow the GT/AG rule, except for the donor splice site of intron 8, which begins with GC. PVS1 should not be applied for variants in the splice donor site of intron 8 since the impact of GC donor splice sites is not well understood. For +1 or +2 GT donor splice site variants, the exon immediately 5’ of the variant is predicted to be skipped. For -1 or -2 AG acceptor splice site variants, the exon immediately 3’ of the variants is predicted to be skipped.\n* Initiation codon: The next in-frame methionine is at position 6 (on transcript NM\\_000018). However, the first 40 amino acids comprise the leader sequence in the precursor peptide and are important for proper localization of the protein (Aoyama et al., (1995) PMID: 7668252). Therefore, initiator codon variants will meet PVS1\\_Strong.\n* Well-established \\_in vitro\\_ or \\_in vivo\\_ functional studies supportive of a damaging effect \\_as measured by effect on mRNA transcript profile (mRNA assay only).\\_ Apply as PVS1 (RNA) at appropriate strength. \n* See ACADVL PVS1 decision tree; cannot be combined with PM1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Loss of function is a known mechanism for VLCAD Deficiency. The specifications below are based on published guidance for assigning strength of evidence for PVS1 (Abou Tayoun et al., (2018) PMID: 30192042). There are multiple transcripts for ACADVL. The major isoform, NM\\_000018.4, encodes a 655 amino acid precursor protein that contains a 40 amino acid N-terminal target sequence that is removed during uptake (Aoyama et al., (1995) PMID: 7668252). In a joint project between NCBI and EMBL-EBI (MANE), NM\\_000018.4 was designated as the most relevant transcript. Nonsense or Frameshift:\n\n* Use caution when interpreting LOF variants at the 3’ end of the gene.\n* NMD is not predicted if the variant is in the last exon (exon 20) or in the last 50 nucleotides of the penultimate exon (exon 19). \n* Canonical Splice Site (+1, +2, -1, -2): All donor/acceptor sites follow the GT/AG rule, except for the donor splice site of intron 8, which begins with GC. PVS1 should not be applied for variants in the splice donor site of intron 8 since the impact of GC donor splice sites is not well understood. For +1 or +2 GT donor splice site variants, the exon immediately 5’ of the variant is predicted to be skipped. For -1 or -2 AG acceptor splice site variants, the exon immediately 3’ of the variants is predicted to be skipped.\n* Initiation codon: The next in-frame methionine is at position 6 (on transcript NM\\_000018). However, the first 40 amino acids comprise the leader sequence in the precursor peptide and are important for proper localization of the protein (Aoyama et al., (1995) PMID: 7668252). Therefore, initiator codon variants will meet PVS1\\_Strong.\n* Well-established \\_in vitro\\_ or \\_in vivo\\_ functional studies supportive of a damaging effect \\_as measured by effect on mRNA transcript profile (mRNA assay only).\\_ Apply as PVS1 (RNA) at appropriate strength. \n* See ACADVL PVS1 decision tree; cannot be combined with PM1",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509379",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509379",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmry---"
},
{
"entContent": {
"_uniqueProp": "021_BP7_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "021",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "BP7\\_Strong (RNA) in vitro evidence of no splicing impact for intronic or synonymous variants irrespective of position and predicted impact on splicing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved\n* Can be used for intronic variants that fall outside the minimal splice region (≥+7 or ≤-21)\n* Can be used with BP4 code.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509406",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509406",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmyO---"
},
{
"entContent": {
"_uniqueProp": "021_BP3_nuclear_ACADVL",
"additionalComments": "There are no known repetitive regions without known function in ACADVL.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "021",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509402",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509402",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmyC---"
},
{
"entContent": {
"_uniqueProp": "021_PP1_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP1",
"ns": "021",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* See PP1 table. Probands are NOT counted toward segregation. Likewise, carrier parents DO NOT count as unaffected segregations. Affected segregations = # affected individuals in the family with the variants - 1. Affected segregations are defined as affected family members (typically siblings) who harbor the variant in question and a second variant on the remaining allele. Unaffected segregations are defined as unaffected family members, typically siblings, who are at risk to inherit the two variants identified in the proband. These individuals should be either wild-type for both variants identified in the proband, or a heterozygous carrier for a single variant. There may be scenarios where individuals other than siblings could be counted as segregations, such as in families where one parent is affected with the autosomal recessive disorder, in large families with multiple branches, or in consanguineous families.\n * Strong (32:1 Likelihood)\n * A LOD score ≥ 1.50",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* See PP1 table. Probands are NOT counted toward segregation. Likewise, carrier parents DO NOT count as unaffected segregations. Affected segregations = # affected individuals in the family with the variants - 1. Affected segregations are defined as affected family members (typically siblings) who harbor the variant in question and a second variant on the remaining allele. Unaffected segregations are defined as unaffected family members, typically siblings, who are at risk to inherit the two variants identified in the proband. These individuals should be either wild-type for both variants identified in the proband, or a heterozygous carrier for a single variant. There may be scenarios where individuals other than siblings could be counted as segregations, such as in families where one parent is affected with the autosomal recessive disorder, in large families with multiple branches, or in consanguineous families.\n * Moderate (16:1 Likelihood)\n * A LOD score \\< 1.50 ≥ 1.20",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* See PP1 table. Probands are NOT counted toward segregation. Likewise, carrier parents DO NOT count as unaffected segregations. Affected segregations = # affected individuals in the family with the variants - 1. Affected segregations are defined as affected family members (typically siblings) who harbor the variant in question and a second variant on the remaining allele. Unaffected segregations are defined as unaffected family members, typically siblings, who are at risk to inherit the two variants identified in the proband. These individuals should be either wild-type for both variants identified in the proband, or a heterozygous carrier for a single variant. There may be scenarios where individuals other than siblings could be counted as segregations, such as in families where one parent is affected with the autosomal recessive disorder, in large families with multiple branches, or in consanguineous families.\n * Supporting (4:1 Likelihood)\n * An LOD score \\< 1.20 ≥ 0.60",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509390",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509390",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmv----"
},
{
"entContent": {
"_uniqueProp": "021_PM4_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "021",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509387",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509387",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmpW---"
},
{
"entContent": {
"_uniqueProp": "021_PM3_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "021",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "* Details of the cDNA change must be used to describe any variants used as evidence for PM3. If the variant is described only as an amino acid change, this is not sufficient. Probands must also meet PP4 criteria to be counted.\n* If more than one case has the same genotype and the variants are not confirmed in trans, then only one case should be used for assigning points to avoid overcounting evidence if the variants are actually in cis and hence inherited together in multiple individuals or potentially counting the same case twice. If the variants are confirmed to be in trans, more than one individual with the same genotype can be counted as long as the reports do not represent the same case.\n* These variant interpretation guidelines should be used to determine the classification of the “other variant” in order to determine the appropriate number of points to assign.\n* For a variant to be “confirmed in trans” in a compound heterozygous patient, parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed. Otherwise, the phase of the variants is unknown. Parental testing is not required for homozygous cases.\n* See PM3 table\n * PM3 score ≥ 4.0",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* Details of the cDNA change must be used to describe any variants used as evidence for PM3. If the variant is described only as an amino acid change, this is not sufficient. Probands must also meet PP4 criteria to be counted.\n* If more than one case has the same genotype and the variants are not confirmed in trans, then only one case should be used for assigning points to avoid overcounting evidence if the variants are actually in cis and hence inherited together in multiple individuals or potentially counting the same case twice. If the variants are confirmed to be in trans, more than one individual with the same genotype can be counted as long as the reports do not represent the same case.\n* These variant interpretation guidelines should be used to determine the classification of the “other variant” in order to determine the appropriate number of points to assign.\n* For a variant to be “confirmed in trans” in a compound heterozygous patient, parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed. Otherwise, the phase of the variants is unknown. Parental testing is not required for homozygous cases.\n* See PM3 table\n * PM3 score ≥ 2.0 \\< 4.0",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Details of the cDNA change must be used to describe any variants used as evidence for PM3. If the variant is described only as an amino acid change, this is not sufficient. Probands must also meet PP4 criteria to be counted.\n* If more than one case has the same genotype and the variants are not confirmed in trans, then only one case should be used for assigning points to avoid overcounting evidence if the variants are actually in cis and hence inherited together in multiple individuals or potentially counting the same case twice. If the variants are confirmed to be in trans, more than one individual with the same genotype can be counted as long as the reports do not represent the same case.\n* These variant interpretation guidelines should be used to determine the classification of the “other variant” in order to determine the appropriate number of points to assign.\n* For a variant to be “confirmed in trans” in a compound heterozygous patient, parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed. Otherwise, the phase of the variants is unknown. Parental testing is not required for homozygous cases.\n* See PM3 table \n * PM3 score ≥ 1.0 \\< 2.0",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Details of the cDNA change must be used to describe any variants used as evidence for PM3. If the variant is described only as an amino acid change, this is not sufficient. Probands must also meet PP4 criteria to be counted.\n* If more than one case has the same genotype and the variants are not confirmed in trans, then only one case should be used for assigning points to avoid overcounting evidence if the variants are actually in cis and hence inherited together in multiple individuals or potentially counting the same case twice. If the variants are confirmed to be in trans, more than one individual with the same genotype can be counted as long as the reports do not represent the same case.\n* These variant interpretation guidelines should be used to determine the classification of the “other variant” in order to determine the appropriate number of points to assign.\n* For a variant to be “confirmed in trans” in a compound heterozygous patient, parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed. Otherwise, the phase of the variants is unknown. Parental testing is not required for homozygous cases.\n* See PM3 table \n * PM3 score ≥ 0.5 \\< 1.0",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509386",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509386",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmsi---"
},
{
"entContent": {
"_uniqueProp": "021_PP5_nuclear_ACADVL",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP5",
"ns": "021",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509394",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509394",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmxK---"
},
{
"entContent": {
"_uniqueProp": "021_PP3_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "021",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Missense changes with a REVEL scores >0.75 will meet PP3\n* For in-frame deletions and insertions, use Mutation Taster.\n* For non-canonical splice site variants, use Splice AI. Based on data from Jaganathan et al., (2019) PMID: 30661751, Houdayer et al., (2012) PMID: 22505045 and Tang et al., (2016) PMID: 27313609 and Walker et al., (2023) PMID:37352859, PP3 can be applied if there is, a SpliceAI “high score” (Δ Score ≥ 0.5 “confidently predicted splice variants”) (exclude any results with Δ Score ≤ 0.2 from consideration of pathogenicity, \\<0.2 are not “predicted to alter splicing”).\n* For SpliceAI’s cryptic splice-site rules, the creation of a new splice-site with Δ Score ≥ 0.5 may be enough to produce a large proportion of aberrant transcripts.\n* If a new splice site is predicted to be generated, this rule can be applied if the newly generated splice site is significantly stronger than the wild type site (Δ Score ≥ 0.5 using SpliceAI).\n* Do not apply this rule for canonical splice site changes meeting PVS1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509392",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509392",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmrC---"
},
{
"entContent": {
"_uniqueProp": "021_PM5_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM5",
"ns": "021",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* See PM5 table. Note: Cannot be applied with PM1, apply criteria with the highest strength. If both are applicable at the same strength, apply PM5 as it is amino acid specific.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* See PM5 table. Note: Cannot be applied with PM1, apply criteria with the highest strength. If both are applicable at the same strength, apply PM5 as it is amino acid specific. \n * Two likely pathogenic variants at the same codon\n * One pathogenic variant at the same codon",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* See PM5 table. Note: Cannot be applied with PM1, apply criteria with the highest strength. If both are applicable at the same strength, apply PM5 as it is amino acid specific. \n * One likely pathogenic variant at the same codon",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509388",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509388",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmsS---"
},
{
"entContent": {
"_uniqueProp": "021_PM2_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM2",
"ns": "021",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Variants with a highest population minor allele frequency (MAF) \\<0.001 (0.1%) in any continental population with >2000 alleles in gnomAD will meet PM2\\_supporting.\n\n* Calculated using the Prevalence of 1:100,000, Allelic Contribution of 0.2, Genetic Contribution of 1, and Penetrance of 0.75 to allow for mild VLCADD that may develop in adulthood. This was multiplied by 1.5 to account for mildly pathogenic variants being present in carriers within the population databases.\n* It is acceptable for an ACADVL variant to be present in controls because VLCAD deficiency is a recessive condition. It is also possible for homozygous ACADVL variants to be present in population databases due to later onset of the condition. If homozygous variants are present, the number should be noted and discussed with an expert.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509385",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/639509385",
"modified": "2025-09-04T13:01:47.025Z",
"modifier": "mweaver",
"rev": "_kPRPmtC---"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0008723",
"lbl": "very long chain acyl-CoA dehydrogenase deficiency",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0008723"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/acyl_coa_dehydrogenase_very_long_chain_deficiency_of"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/907810567"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/854382"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/237997005"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C3887523"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/E71.310"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0080155"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C98647"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_26793"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/201475"
}
],
"definition": {
"val": "An inherited disorder of mitochondrial long-chain fatty acid oxidation with a variable presentation including: cardiomyopathy, hypoketotic hypoglycemia, liver disease, exercise intolerance and rhabdomyolysis.",
"xrefs": [
"Orphanet:26793"
]
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"instructionsToUse": null,
"label": "PP5",
"ns": "022",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243121",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243121",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--C"
},
{
"entContent": {
"_uniqueProp": "022_PP4_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "022",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0018",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Use if patient fulfils revised Ghent criteria.\n* Can be used if any of the family members have a highly specific phenotype.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243120",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243120",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--R"
},
{
"entContent": {
"_uniqueProp": "022_PM6_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": "\n* Use the SVI WG point-based system https://clinicalgenome.org/working-groups/sequence-variant-interpretation/\n* The expert panel provided definitions for:\n ‘highly specific phenotype’: TAAD + ectopia lentis (mainly caused by variants in FBN1).\n ‘consistent phenotype:’ TAAD + systemic score ≥7 (can be caused by variants in few other HTAD genes).\n ‘consistent but genetic heterogeneity’:(isolated) TAAD, isolated ectopia lentis and in case of a child (age <20yrs) systemic score≥ 7 in whom TAAD is progressive and can be developed later in life.\nThe EP recommends that the parents had a full clinical work-up and an echocardiogram to exclude MFS/HTAAD.",
"label": "PM6",
"ns": "022",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0014",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0037",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2-3 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0022",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243116",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243116",
"modified": "2022-08-30T14:08:37.772Z",
"modifier": "cspecAdministrator",
"rev": "_inf5Apm--J"
},
{
"entContent": {
"_uniqueProp": "022_BP4_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "022",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* Recommended prediction program for missense variants: REVEL. Use 0.326 as a discriminatory cut-off value.\n* Recommended prediction programs for splice variants: GeneSplicer, MaxEntscan, and NNSPLICE. The outcome of all 3 prediction programs need to be in concordance.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243130",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243130",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--E"
},
{
"entContent": {
"_uniqueProp": "022_BS3_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "022",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Use the ‘Funtional Assay SVI Documentation’ (https://clinicalgenome.org/working-groups/sequence-variant-interpretation/).\nFor step 2 assessment.\n* Functional studies deemed appropriate:\n * cDNA analyses showing altered FBN1 sequence.\n * Functional studies showing altered FBN1 protein or RNA expression, proteolysis, folding, assembly, trafficking, secretion, Ca2+ binding, matrix deposition (cfr Dave Hollister assay), microfibril fragmentation/catabolism in an in vitro engineered system.\n* Functional studies NOT deemed appropriate: non-specific altered TGF-beta signaling or histological hallmarks of medial degeneration, which are associated with many other types of variants in genes that are associated with MFS or HTAAD in general.\nFor step 3 assessment: Studies should be performed in the presence of NMD inhibitor.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0085",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243125",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243125",
"modified": "2022-08-30T14:08:37.772Z",
"modifier": "cspecAdministrator",
"rev": "_inf5Ap2--l"
},
{
"entContent": {
"_uniqueProp": "022_BS2_nuclear_FBN1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "022",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0069",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243124",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243124",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--T"
},
{
"entContent": {
"_uniqueProp": "022_BA1_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BA1",
"ns": "022",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency above 0.1% in ExAc and gnomAD\n* Use the ethnic population with the highest allele frequency.\n* Caveat: Do not use Finnish, Ashkenazi Jewish, or “Other” populations in gnomAD.\n* Minimum amount of studied alleles should be 2000.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243122",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243122",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--D"
},
{
"entContent": {
"_uniqueProp": "022_PP2_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "022",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0061",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Add caveat: if this argument is used pro-pathogenicity, there must be other arguments supporting pathogenicity, and no arguments supporting a benign assertion.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243118",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243118",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--L"
},
{
"entContent": {
"_uniqueProp": "022_PM1_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "022",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0028",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* Cys residues in cbEGF-like domains\n* Add caveat: PM5/PS1 should not be used when this argument applies.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Cys in EGF-like domain, Cys in TB domain, Cys in hybrid domain, (D/N)-X-(D/N)-(E/Q)-Xm-(D/N)-Xn-(Y/F) substitution in cbEGF-like domain, invariant calcium-binding or hydroxylation residue in cbEGF-like domain, critical Gly between Cys2-Cys3 in cbEGF-like domain, Gly between Cys3-Cys4 if there is an upstream cbEGF domain, Cys-creating variants.\n* Add caveat: N to S substitution in the second N of de consensus sequence and G to A might be tolerated, PM1 should not be used in these cases.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243111",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243111",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--J"
},
{
"entContent": {
"_uniqueProp": "022_PS3_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": "Use the ‘Funtional Assay SVI Documentation’ (https://clinicalgenome.org/working-groups/sequence-variant-interpretation/).\nFor step 2 assessment\n* Functional studies deemed appropriate:\n cDNA analyses showing altered FBN1 sequence.\n Functional studies showing altered FBN1 protein or RNA expression, proteolysis, folding, assembly, trafficking, secretion, Ca2+ binding, matrix deposition (cfr Dave Hollister assay), microfibril fragmentation/catabolism in an in vitro engineered system.\n* Functional studies NOT deemed appropriate: non-specific altered TGF-beta signaling or histological hallmarks of medial degeneration, which are associated with many other types of variants in genes that are associated with MFS or HTAAD in general.\nFor step 3 assessment: Studies should be performed in the presence of NMD inhibitor.",
"label": "PS3",
"ns": "022",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Follow the ‘Funtional Assay SVI Documentation’",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0039",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Follow the ‘Funtional Assay SVI Documentation’",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0045",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use the ‘Funtional Assay SVI Documentation’. ",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243109",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243109",
"modified": "2022-08-30T14:08:37.772Z",
"modifier": "cspecAdministrator",
"rev": "_inf5Aq---D"
},
{
"entContent": {
"_uniqueProp": "022_PS2_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": "\n* Use the SVI WG point-based system https://clinicalgenome.org/working-groups/sequence-variant-interpretation/\n* The expert panel provided definitions for:\n ‘highly specific phenotype’: TAAD + ectopia lentis (mainly caused by variants in FBN1).\n ‘consistent phenotype:’ TAAD + systemic score ≥7 (can be caused by variants in few other HTAD genes).\n ‘consistent but genetic heterogeneity’:(isolated) TAAD, isolated ectopia lentis and in case of a child (age <20yrs) systemic score≥ 7 in whom TAAD is progressive and can be developed later in life.\nThe EP recommends that the parents had a full clinical work-up and an echocardiogram to exclude MFS/HTAAD.",
"label": "PS2",
"ns": "022",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0016",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Four points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Two-three points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "004",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "One point",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0043",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243108",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243108",
"modified": "2022-08-30T14:08:37.772Z",
"modifier": "cspecAdministrator",
"rev": "_inf5Aq----"
},
{
"entContent": {
"_uniqueProp": "022_PVS1_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": "\n* Follow the adapted flowchart.\n* There is only 1 relevant transcript for FBN1 (NM_000138).\n* The C-terminal region is proven to be critical to protein function (multiple LP/P variants identified in this region).\n* PP3 cannot be applied if using the PVS1criterion for splice site variants in position +/- ½.",
"label": "PVS1",
"ns": "022",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": " * Nonsense/frameshift variants predicted to undergo NMD (not affecting last exon or 55 last nt of penultimate exon).\n * 1,2 splice site variants leading to exon skipping or use of a cryptic splice site disrupting the reading frame and predicted to undergo NMD.\n * Full gene deletion.\n * Single to multi-exon deletion disrupting the reading frame and predicted to undergo NMD.\n * Duplication (>=1 exon in size and completely contained within gene) proven in tandem and disrupting the reading frame and predicted to undergo NMD.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0020",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": " * Nonsense/frameshift variants predicted to escape NMD (affecting last exon, last 55nt of the penultimate exon).\n * 1,2 splice site variants leading to exon skipping or use of a cryptic splice site disrupting the reading frame and predicted to escape NMD.\n * 1,2 splice site variants leading to exon skipping or use of a cryptic splice site but preserving the reading frame.\n * Single to multi-exon deletion disrupting the reading frame and predicted to escape NMD.\n * Single to multi-exon deletion preserving the reading frame.\n * Duplication (>=1 exon in size and completely contained within gene) presumed in tandem and presumably disrupting the reading frame and predicted to escape NMD.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0026",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": " * Initiation codon variant with 1 or more pathogenic variant(s) upstream of closest potential in-frame start codon.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243106",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243106",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--Q"
},
{
"entContent": {
"_uniqueProp": "022_BP3_nuclear_FBN1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "022",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243129",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243129",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--U"
},
{
"entContent": {
"_uniqueProp": "022_BS4_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "022",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "* Caution is warranted when the phenotype is not highly specific. Lack of segregation should then be clear in >1 affected family member.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243126",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243126",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--b"
},
{
"entContent": {
"_uniqueProp": "022_BS1_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS1",
"ns": "022",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease (>0.005%).\n* Use the ethnic population with the highest allele frequency.\n* Caveat: Do not use Finnish, Ashkenazi Jewish, or “Other” populations in gnomAD.\n* Minimum amount of studied alleles should be 2000.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243123",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243123",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--S"
},
{
"entContent": {
"_uniqueProp": "022_PP3_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "022",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Recommended prediction program for missense variants: REVEL. Use 0.75 as a discriminatory cut-off value.\n* Recommended prediction programs for splice variants: GeneSplicer, MaxEntscan, and NNSPLICE. The outcome of all 3 prediction programs need to be in concordance.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243119",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243119",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_inf5Api--f"
},
{
"entContent": {
"_uniqueProp": "022_PP1_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": "\n* Only count affected individuals from the same family (minus proband) that carry the variant or obligate carriers known with the disease.\n* The EP will not specifically define “affected”, “clinical examination” or cut-offs for aortic Z-scores. These are left to the discretion of the referring physicians.",
"label": "PP1",
"ns": "022",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0023",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥5 affected individuals.\n",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0040",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "4 affected individuals.\n",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "2-3 affected individuals.\n",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243117",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243117",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_inf5Api--e"
},
{
"entContent": {
"_uniqueProp": "022_PM2_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM2",
"ns": "022",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0030",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Threshold: <5.0E-6 (<0.0005%).\n* Use the highest ethnic population allele frequency.\n* Caveat: PVS1 + PM2_Supportive may reach Likely Pathogenic.\n* Caveat: Do not use Finnish, Ashkenazi Jewish, or “Other” populations in gnomAD.\n* Minimum amount of studied alleles should be 2000.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243112",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243112",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--K"
},
{
"entContent": {
"_uniqueProp": "022_PS1_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "022",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* Beware of changes that impact splicing rather than the amino acid. Splicing predictions should remain the same for WT and mutant alleles.\n* Original variant should be pathogenic according to the (modified) ACMG guidelines for variant classification.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0046",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243107",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243107",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--I"
},
{
"entContent": {
"_uniqueProp": "022_BP7_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "022",
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"text": "",
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"geneType": "nuclear",
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"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
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"text": "",
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"id": "008",
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"id": "0048",
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"text": "",
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"text": "",
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"specificationType": "Strength",
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},
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"id": "0087",
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{
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"id": "0201",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"specificationType": [],
"strength": "Strong",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243150",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
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{
"entContent": {
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"geneType": "nuclear",
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"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
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"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0023",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Segregation in three affected relatives for recessive.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0040",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Segregation in two affected relatives for recessive.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Segregation in one affected relative for recessive.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243145",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243145",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
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},
{
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"geneType": "nuclear",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"specificationType": [],
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"text": "",
"type": "EvidenceLineStrength"
},
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"id": "0056",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at same codon as two different pathogenic missense variants.\nLocated at an amino acid residue with known pathogenic variation (at least 2 other variants at the same site meet pathogenic criteria for based on independent data).\n* Caveat: Assess whether the variants in question could have an impact at the DNA level, such as through splicing impacts.",
"type": "EvidenceLineStrength"
},
{
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"id": "008",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at same codon as another pathogenic missense variant.\nNo changes. Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0048",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243143",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
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},
{
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],
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"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0012",
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"specificationType": [],
"strength": "Very Strong",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0035",
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"text": "",
"type": "EvidenceLineStrength"
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"id": "009",
"instructionsToUse": "",
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"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length change due to an in-frame deletion or insertion that are not located in repetitive regions.\nNo changes. Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group.",
"type": "EvidenceLineStrength"
},
{
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"id": "0059",
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"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
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},
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"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
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},
{
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"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS4",
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"id": "0243",
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"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
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"specificationType": "Disease-specific",
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"type": "EvidenceLineStrength"
},
{
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"id": "0053",
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"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0057",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0032",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243138",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243138",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_inf5Api--j"
},
{
"entContent": {
"_uniqueProp": "023_BP2_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "023",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a dominant variant/observed in cis with a pathogenic variant (use with caution).\n* Use with caution. For genes that are associated with both dominant and recessive hearing loss, consider whether an earlier onset/more severe phenotype could be present if variant is identified in trans with a dominant variant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243156",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243156",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--K"
},
{
"entContent": {
"_uniqueProp": "023_PP4_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "023",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0018",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Patient's phenotype highly specific for gene or fully sequenced gene set (see specifications in Table 7).\n* The HL-EP applied this rule to HL syndromes if all causative genes have been sequenced and the detection rate at least doubles when the added clinical feature is present.\n* See table below for applicable gene-disease phenotypes.\n* Advise against using PP4 for patients with nonsyndromic or apparently nonsyndromic hearing loss, given genetic heterogeneity.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243148",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243148",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_inf5Api--m"
},
{
"entContent": {
"_uniqueProp": "023_PP2_nuclear_OTOF_MYO15A",
"additionalComments": "Advise against using this rule because there are few such genes that this would apply to, particularly genes associated to autosomal recessive hearing loss.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "023",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243146",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243146",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--e"
},
{
"entContent": {
"_uniqueProp": "023_BP6_nuclear_OTOF_MYO15A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP6",
"ns": "023",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243160",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243160",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_inf5Api--q"
},
{
"entContent": {
"_uniqueProp": "023_BP3_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "023",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0081",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame indels in repeat region without known function.\n* No changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243157",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243157",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--h"
},
{
"entContent": {
"_uniqueProp": "023_BS3_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "023",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0072",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0085",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Functional study shows no deleterious effect (none are defined for OTOF and MYO15A).\n* Recommend that functional evidence is not used as strong evidence, due to the absence of well-established functional studies for hearing loss genes.\n\n* No specific assays are listed for OTOF or MYO15A. However, BS3_Supporting can be used for functional analyses if\n * The assay has been validated by a known pathogenic and benign variant AND\n * There is plausible reason that the function the assay is testing relates to the phenotype AND\n * The assay conditions are likely to mimic the physiological environment.\n",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243153",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243153",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--J"
},
{
"entContent": {
"_uniqueProp": "023_PP3_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "023",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "REVEL score ≥0.7, or predicted impact to splicing using MaxEntScan.\n* Use REVEL and MAXENTSCAN\n * For missense variants, award PP3 if REVEL score is ≥0.7\n * If splicing is predicted to be impacted, either creation of a cryptic splice site, or disruption of a native splice site, award PP3\n* For splice variants (except for canonical -/+1 or 2), use MAXENTSCAN.\n * For -/+ 1 or 2 splice variants, do not use PP3 if you are using PVS1",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243147",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243147",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--H"
},
{
"entContent": {
"_uniqueProp": "023_PM6_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "023",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See PS2 above.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243144",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243144",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--U"
},
{
"entContent": {
"_uniqueProp": "023_PS1_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "023",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as an established pathogenic variant; OR splice variants at same nucleotide and with similar impact prediction as previously reported pathogenic variant.\n* Established variant must meet criteria for pathogenicity by the HL specifications.\n* Can also use PS1 for splice variants located in the splice consensus sequence, at the same nucleotide position as a previously reported pathogenic variant.\n * Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T.\n* No additional hearing loss specifications for missense variants. Follow recommendations as outlined in Richard 2015 and/or the Sequence Variant Interpretation working group within ClinGen.\n* Caveat (from ACMG/AMP guidelines): Assess the possibility that the variant may act directly through the DNA change (e.g. through splicing disruption as assessed by at least computational analysis) instead of through the amino acid change).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0046",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243135",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243135",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--R"
},
{
"entContent": {
"_uniqueProp": "023_BP7_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "023",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Silent variant with no predicted impact to splicing.\n* No changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243161",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243161",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--X"
},
{
"entContent": {
"_uniqueProp": "023_BP5_nuclear_OTOF_MYO15A",
"additionalComments": "Autosomal recessive: Do not use. An individual could be carrier of pathogenic variant and have an alternate cause. Therefore, BP5 shouldn’t be used as evidence for benign in this case.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "023",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243159",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243159",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--L"
},
{
"entContent": {
"_uniqueProp": "023_BP1_nuclear_OTOF_MYO15A",
"additionalComments": null,
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "023",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243155",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243155",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_inf5Api--p"
},
{
"entContent": {
"_uniqueProp": "023_BS4_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "023",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Non-segregation with disease.\n* Phenotype+/genotype-\n * Strong evidence for benign.\n * Be cautious when using this as the possibility for phenocopy is high. The hearing loss phenotype should be consistent within the family to consider it a non-segregation, though intra-familial variability has been reported. Factors to consider are:\n * Age of onset (ie. congenital/early childhood vs. adult onset)\n * Hearing loss prevalence increases significantly with age. A congenital hearing loss in a child and a late onset hearing loss in a grandparent would not be a consistent phenotype.\n * Severity (ie - mild vs. profound)\n * Minor differences may exist among family members.\n * Keep in mind that progression in older individuals may account for a discrepancy between individuals.\n * Audiogram shape\n * May not be completely consistent among family members even with same etiology.\n- Genotype+/phenotype-\n* Confounding variables to applying this rule: Age-related penetrance, variable expressivity, etc.\n* If the gene is associated with later onset and individual with the non-segregation is beyond the expected age that the hearing loss would occur, consider applying BS4_Supporting\n.\n* Recommend only using for fully penetrant genes (typically genes associated with AR hearing loss)\no Must be confident that patient is truly unaffected and a hearing loss is not missed or subclinical. Be cautious if only phenotyping was newborn hearing screening. Diagnostic audiometric testing (auditory brainstem response (ABR) or audiogram should be required).\n\n* Any evidence for reduced penetrance, do not use BS4.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243154",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243154",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_inf5Api--o"
},
{
"entContent": {
"_uniqueProp": "023_PM3_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "023",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0038",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 points awarded from tables 7a and 7b.\nExample: Detected in trans in ≥4 probands with a pathogenic variant (recessive).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0058",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 points awarded from tables 7a and 7b.\nExample: Detected in trans in 2 probands with a pathogenic variant (recessive).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "007",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 point awarded from tables 7a and 7b\nExample: Detected in trans with a pathogenic variant (recessive).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0027",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 points awarded from tables 7a and 7b\nExamples: \nTwo variants that meet PM2_Supporting detected in trans; OR\na homozygous variant meeting PM2_Supporting.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243141",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243141",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_inf5Api--l"
},
{
"entContent": {
"_uniqueProp": "023_PM2_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM2",
"ns": "023",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0030",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/Rare in population databases (absent or ≤0.00007 (0.007%) for autosomal recessive).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243140",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243140",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--S"
},
{
"entContent": {
"_uniqueProp": "023_PS2_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS2",
"ns": "023",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0016",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 points per tables 5a and 5b:\nExamples: 2 proven de novo occurrences; OR\n1 proven + 2 assumed de novo occurrences; OR\n4 assumed de novo occurrences.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 points per tables 5a and 5b:\nExamples: 1 proven de novo occurrence; OR 2 assumed de novo occurrences.\n\n* OTOF and MYO15A are associated with autosomal recessive conditions. Therefore, de novo variants are expected to be an unlikely occurrence. It is recommended that de novo evidence is only awarded when phase with another variant (VUS, Likely Pathogenic, or Pathogenic) can be confirmed in trans. This is to avoid inappropriately awarding de novo evidence, which would lead to potentially incorrect classification.\n\n* Follow recommendations as specified by the Sequence Variant Interpretation working group within ClinGen, as outlined below\n \n* Determine number of points per proband using table 1 below. Sum the total number of points for all probands, and determine the strength of the evidence by using table 2.\n\n * Please note, the phenotype for de novo occurrences for MYO15A and OTOF are not considered “highly specific”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "004",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 point per tables 5a and 5b:\nExamples: 1 proven de novo occurrence (phenotype consistent but not specific to gene); OR\n1 assumed de novo occurrence; OR 2 assumed de novo occurrences (phenotype/gene not specific).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0043",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 points per tables 5a and 5b:\nExample: 1 assumed de novo occurrence (phenotype/gene not specific).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243136",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243136",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_inf5Api--i"
},
{
"entContent": {
"_uniqueProp": "023_PVS1_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PVS1",
"ns": "023",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene with established LOF as a disease mechanism; see PVS1_Strong, PVS1_Moderate, PVS1_Supporting for reduced evidence applications.\nPVS1 should also be considered for both of the genes OTOF and MYO15A with variants falling in two exons being exceptions to this rule: OTOF: NM_194248.2 Exon 46 (c.5841 to c.5994; PMID: 19250381) and MYO15A: NM_016239.3 Exon 8 (c.4033 to c. 4038; PMID: 10552926) and Exon 26 (c.5911 to c.5964; PMID: 30096381 and high frequency LOF variant https://gnomad.broadinstitute.org/variant/17-18046894-G-A?dataset=gnomad_r2_1)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0020",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "See PVS1 flow chart for PVS1_Strong variants in gene where LOF is a known mechanism of disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0026",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See PVS1 flowchart for PVS1_Moderate variants in gene where LOF is a known mechanism of disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "001",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "See PVS1 flowchart for PVS1_Supporting variants in gene where LOF is a known mechanism of disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243134",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243134",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--d"
},
{
"entContent": {
"_uniqueProp": "023_BS2_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "023",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observation of variant (biallelic with known pathogenic variant for recessive) in controls inconsistent with disease penetrance.\n* Advise caution when using this rule, since most of hearing loss is autosomal recessive, and autosomal dominant hearing loss could display reduced penetrance or variable expression.\n* However, if biallelic observations in controls are inconsistent with disease penetrance, this may be applicable. Ensure age of the unaffected individual is appropriate. MYO15A and OTOF are expected to cause congenital or childhood onset hearing loss. Therefore, an adult (ie >18 years) may be an appropriate individual to consider application of this criteria. Please see additional considerations listed under BS4 “Genotype+/phenotype-”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243152",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243152",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_inf5Api--n"
},
{
"entContent": {
"_uniqueProp": "023_BS1_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS1",
"ns": "023",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0222",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "MAF of ≥0.003 (0.3%) for autosomal recessive. Likely benign, provided there is no conflicting evidence.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0070",
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"type": "EvidenceLineStrength"
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{
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"text": "",
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"id": "0086",
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"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
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"type": "EvidenceLineStrength"
}
]
},
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{
"entContent": {
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"applicability": "Not Applicable for this VCEP",
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"entContent": {
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"text": "",
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{
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"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable for this VCEP",
"id": "0028",
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},
{
"applicability": "Applicable with VCEP specification",
"id": "0045",
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"specificationType": "None",
"strength": "Supporting",
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}
]
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"title": "ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.4.0",
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"text": "An in vitro cleavage assay must demonstrate the variant produces both 5p and 3p microRNAs from a pre-miRNA (positive and negative controls also performed). An example of an appropriate assay to which criteria could be applied is Wu et al. 2018[7](#pmid_28862265).",
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"applicability": "Applicable",
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"geneType": "nuclear",
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"sepioID": "SEPIO-CG:99025",
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"id": "0052",
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"specificationType": [
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"strength": "Strong",
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"text": "RNA assay shows splicing impact that is out-of-frame, in-frame ≥193 residues, or in-frame with RNase IIIb disruption. (PS3\\_Moderate if PVS1\\_Strong is applied).",
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"strength": "Moderate",
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"strength": "Supporting",
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"text": "In vitro cleavage assay shows failure or severely reduced capacity to produce either 5p or 3p microRNAs from a premiRNA (positive and negative controls also performed).",
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"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
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"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
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"gene": [
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"geneType": "nuclear",
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"ns": "024",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
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"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
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"strength": "Stand Alone",
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"text": "",
"type": "EvidenceLineStrength"
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"instructionsToUse": "",
"specificationType": [
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"General recommendation"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Follow SVI guidance, using DICER1-specific information. Per the PVS1 workflow guidance provided in Tayoun et al. 2018[1](#pmid_30192042), the following will apply:\n\n* Nonsense or frameshift variants:\n* PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD); the predicted NMD cutoff for DICER1 occurs at p.Pro1850.\n* PVS1\\_Moderate applies to variants resulting in protein truncation 3’ of this cutoff\n* Canonical splice variants (+/- 1,2 intronic positions): PVS1 applies with the following exceptions:\n* Exon 10 SDS/SAS: PVS1\\_Strong (in-frame but exon includes >10% protein)\n* Exons 5, 15, 18, 22 SDS/SAS: PVS1\\_Moderate (in-frame and each \\<10% of protein)\n* Exon 27 SAS: PVS1\\_Moderate (final exon)\n* Exon 1: no criteria (non-coding)\n* Variants that disrupt the translation start site (p.M1?): no criteria applied given p.M1 is not highly conserved, there are three in-frame possible alternate start codons (p.Met11, p.Met17, p.Met24), and multiple lab cases of p.Met1? without DICER1 phenotype. SDS = splice donor site; SAS = splice acceptor site. Refer to PS3 weight guidelines when a variant meets criterion for application of both PVS1 and PS3. A disease-specific PVS1 decision tree incorporating the above bullets is also included at the end of this document as an additional curation tool.",
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"text": "",
"type": "EvidenceLineStrength"
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"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0026",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
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"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
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"applicability": "Not applicable",
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"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "024",
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"sepioID": "SEPIO-CG:99043",
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"text": "",
"type": "EvidenceLineStrength"
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"text": "",
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"text": "",
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"text": "",
"type": "EvidenceLineStrength"
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"id": "0082",
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"strength": "Supporting",
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"text": "",
"type": "EvidenceLineStrength"
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"modified": "2025-07-08T17:29:48.992Z",
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"additionalComments": null,
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"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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"geneType": "nuclear",
"instructionsToUse": "All variants should be assessed by MaxEntScan (MES) and SpliceAI for predicting de novo and cryptic splice sites. However, for predicting impact to consensus splice sites, SpliceAI scores alone should be considered for variants outside the MES validation threshold, as MES is not capable of predicting native splice site impact for such variants. (MES validation threshold = last 3 nucleotides of exon through intronic position +6 (donor sites); intronic position -20 through first 3 nucleotides of exon (acceptor sites))",
"label": "PP3",
"ns": "024",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
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"Pilot Rules In Prep": {
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"strengthDescriptor": [
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"applicability": "Not Applicable for this VCEP",
"id": "0238",
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"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0024",
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"specificationType": [],
"strength": "Very Strong",
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"text": "",
"type": "EvidenceLineStrength"
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"defaultPoint": 4,
"id": "0019",
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"specificationType": [],
"strength": "Strong",
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"text": "",
"type": "EvidenceLineStrength"
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"defaultPoint": 2,
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
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{
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"defaultPoint": 1,
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For missense variants, REVEL score ≥ 0.750 OR agreement in splicing predictors predict splicing effects. For splicing variants, concordance of MaxEntScan and SpliceAI.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243175",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243175",
"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
"rev": "_j8qUJ0y---"
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{
"entContent": {
"_uniqueProp": "024_PP2_nuclear_DICER1",
"additionalComments": "While DICER1 does meet recommended cutoff for missense constraint z score of ≥3.09 established by the SVI (4.23 on gnomAD) the VCEP recommends this rule not be used for DICER1 due to the presence of various missense variants throughout the gene that are clinically interpreted as benign (9) or likely benign (30) in ClinVar.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
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"geneType": "nuclear",
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"label": "PP2",
"ns": "024",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
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"strengthDescriptor": [
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"applicability": "Not applicable",
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"instructionsToUse": "",
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"strength": "Stand Alone",
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243174",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243174",
"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
"rev": "_j8qUJxm---"
},
{
"entContent": {
"_uniqueProp": "024_PM6_nuclear_DICER1",
"additionalComments": "Combined with PS2. Use PS2 instead of PM6.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "024",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 8,
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 4,
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 2,
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243172",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243172",
"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
"rev": "_j8qUJte---"
},
{
"entContent": {
"_uniqueProp": "024_BP6_nuclear_DICER1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP6",
"ns": "024",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243188",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243188",
"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
"rev": "_j8qUJty---"
},
{
"entContent": {
"_uniqueProp": "024_BP4_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": "All variants should be assessed by MaxEntScan (MES) and SpliceAI for predicting de novo and cryptic splice sites. However, for predicting impact to consensus splice sites, SpliceAI scores alone should be considered for variants outside the MES validation threshold, as MES is not capable of predicting native splice site impact for such variants. (MES validation threshold = last 3 nucleotides of exon through intronic position +6 (donor sites); intronic position -20 through first 3 nucleotides of exon (acceptor sites))",
"label": "BP4",
"ns": "024",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -4,
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "For missense variants, REVEL score \\< 0.500 and agreement in splicing predictors that no splicing effects are predicted. For synonymous/intronic/non-coding variants concordance of MaxEntScan and SpliceAI.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243186",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243186",
"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
"rev": "_j8qUJsW---"
},
{
"entContent": {
"_uniqueProp": "024_PP5_nuclear_DICER1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP5",
"ns": "024",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243177",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243177",
"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
"rev": "_j8qUJvu---"
},
{
"entContent": {
"_uniqueProp": "024_PM3_nuclear_DICER1",
"additionalComments": "Autosomal dominant.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "024",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 8,
"id": "0038",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 4,
"id": "0058",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 2,
"id": "007",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0027",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243169",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243169",
"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
"rev": "_j8qUJsm---"
},
{
"entContent": {
"_uniqueProp": "024_PM2_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": "In general, the most recent/most comprehensive gnomAD version should be used.",
"label": "PM2",
"ns": "024",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Allele frequency \\<0.000005 across gnomAD with no more than one allele in any subpopulation and at least 20x coverage.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243168",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243168",
"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
"rev": "_j8qUJwK---"
},
{
"entContent": {
"_uniqueProp": "024_PS2_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": "De novo points should be tallied using the simplified table for tallying proband points and used to determine the applied strength of PS2, consistent with SVI guidance. To avoid redundancy and increase consistency, the EP has opted to drop PM6 and exclusively use PS2 for de novo evidence.",
"label": "PS2",
"ns": "024",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 8,
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥4 de novo points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥2 but less than 4 de novo points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "004",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥1 but less than 2 de novo points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥0.5 but less than 1 de novo points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243164",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243164",
"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
"rev": "_j8qUJyO---"
},
{
"entContent": {
"_uniqueProp": "024_BP5_nuclear_DICER1",
"additionalComments": "Given the broad spectrum of DICER1-related neoplasms and the General recommendation lack of evidence of other high-penetrance germline variants that could account for such neoplasms (except perhaps for some already low-specificity phenotypes such as Wilms tumor), this rule should not be used at this time.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "024",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243187",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243187",
"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
"rev": "_j8qUJxK---"
},
{
"entContent": {
"_uniqueProp": "024_BP3_nuclear_DICER1",
"additionalComments": "Not applicable at this time.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "024",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243185",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243185",
"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
"rev": "_j8qUJzu---"
},
{
"entContent": {
"_uniqueProp": "024_BS4_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "024",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Family members should be phenotype-positive (must be high- or moderatespecificity phenotype; see phenotype table), genotype-negative 1st, 2nd, or 3rd degree relatives of the proband.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -1,
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243182",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243182",
"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
"rev": "_j8qUJvW---"
},
{
"entContent": {
"_uniqueProp": "024_PP1_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": "Phenotype-positive individuals should have high, moderate, or low-specificity phenotypes (see phenotype table). (Caveat: segregation with a single low-specificity phenotype across multiple individuals (e.g. familial Wilms tumor) does not fulfill PP1.) Do not apply PP1 if variant meets BA1/BS1 criteria.",
"label": "PP1",
"ns": "024",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥7 meioses across ≥2 families",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "5 – 6 meioses across ≥1 family",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "3 – 4 meioses across ≥1 family",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243173",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243173",
"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
"rev": "_j8qUJwe---"
},
{
"entContent": {
"_uniqueProp": "024_PS4_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": "Unrelated probands may contribute up to 1 point each based on phenotype (see Tables 2 & 3 in ruleset) Caveats:\n\n* Do not apply PS4 if variant meets BA1/BS1 criteria.\n* Do not apply points for a phenotype in an individual with a likely pathogenic germline variant in a second gene that could have reasonably contributed to the phenotype (e.g. Wilms tumor in an individual with a P/LP WT1 variant).\n* Do not apply points for a proband whose tumor sequencing is consistent with a likely sporadic event (i.e. sequencing reveals a somatic, VCEPcurated, non-hotspot, likely pathogenic DICER1 variant in addition to a somatic hotspot variant and the germline variant under assessment). Of note, DICER1 tumors that consistently or occasionally follow a classical 2- hit hypothesis (i.e. LOF of both alleles) are exempt from this caveat. For example, identification of a somatic pathogenic non-hotspot DICER1 variant in pineoblastoma[2](#pmid_25022261), pituitary blastoma[3](#pmid_24839956), and lung cysts or cystic nephroma lacking mesenchymal cells[4](#pmid_25500911),[5](#pmid_25978641) should not exclude the proband from PS4.",
"label": "PS4",
"ns": "024",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 8,
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥4 phenotype points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "2 – 3.5 phenotype points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1 – 1.5 phenotype points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243166",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243166",
"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
"rev": "_j8qUJ0a---"
},
{
"entContent": {
"_uniqueProp": "024_BP2_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "024",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -4,
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥1 observation in trans with P/LP DICER1 variant or ≥3\nobservations in cis or phase unknown with 2+ different\nP/LP DICER1 variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243184",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243184",
"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
"rev": "_j8qUJ1----"
},
{
"entContent": {
"_uniqueProp": "024_BS2_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "024",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "40+ unrelated females from a single source are tumor-free through age 50 (caveat: ratio of BS2-eligible females to PS4-eligible probands must be ≥ 40:1) \nOR 2+ observations of homozygosity in healthy individuals\nOR 1+ observation(s) of homozygosity in a healthy individual with status confirmed by parental testing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "10+ unrelated females from a single source are tumor-free through age 50 (caveat: ratio of BS2-eligible females to PS4-eligible probands must be ≥ 10:1) \nOR 2+ observations of homozygosity in individuals lacking clinical information",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243180",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243180",
"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
"rev": "_j8qUJu2---"
},
{
"entContent": {
"_uniqueProp": "024_BS1_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": "In general, the most recent/most comprehensive gnomAD version should be used.",
"label": "BS1",
"ns": "024",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Frequency >0.0003 (0.03%) in gnomAD subpopulations. Subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -1,
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243179",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243179",
"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
"rev": "_j8qUJ0----"
},
{
"entContent": {
"_uniqueProp": "024_BA1_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": "In general, the most recent/most comprehensive gnomAD version should be used.",
"label": "BA1",
"ns": "024",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"defaultPoint": "Not Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Frequency >0.003 (0.3%) in gnomAD subpopulations. Subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243178",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243178",
"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
"rev": "_j8qUJs2---"
},
{
"entContent": {
"_uniqueProp": "024_PP4_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "024",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0018",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Somatic tumor testing identifies somatic hotspot second hit and no additional somatic LOF variants. Tumor testing[6](#pmid_30311369) of a neoplasm with known DICER1 association in a proband who carries the germline variant under evaluation reveals the following:\n\n* A previously reported somatic second hit of DICER1 in an RNase IIIb-disrupting “hotspot” codon (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, or p.E1813) AND\n* Retention of the germline DICER1 variant under evaluation. PP4 is NOT applicable if:\n* The germline variant is a missense variant in one of the seven RNase IIIb “hotspot” codons (see PM1), OR\n* Somatic sequencing reveals additional DICER1 non-hotspot variants (could be consistent with sporadic tumorigenesis).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243176",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243176",
"modified": "2025-07-08T17:29:48.992Z",
"modifier": "dagherjn",
"rev": "_j8qUJx6---"
},
{
"entContent": {
"_uniqueProp": "024_PM5_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": "All variants should be assessed by MaxEntScan (MES) and SpliceAI for predicting de novo and cryptic splice sites. However, for predicting impact to consensus splice sites, SpliceAI scores alone should be considered for variants outside the MES validation threshold, as MES is not capable of predicting native splice site impact for such variants. (MES validation threshold = last 3 nucleotides of exon through intronic position +6 (donor sites); intronic position -20 through first 3 nucleotides of exon (acceptor sites))",
"label": "PM5",
"ns": "024",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "008",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense variant under evaluation should have equal or worse Grantham score. Splicing should be ruled out with either RNA data or agreement in splicing predictors (MaxEntScan and SpliceAI) that show no splicing effects. The other variant must be interpreted as pathogenic by the ClinGen DICER1 VCEP. Likely pathogenic changes do not apply. This rule cannot be applied in combination with PM1 or PS1.",
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"strength": "Strong",
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"title": "Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion.",
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{
"auths": [
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"title": "Integrating somatic variant data and biomarkers for germline variant classification in cancer predisposition genes.",
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"auths": [
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"notes": "A final point value of -1 may be overriden to Likely Benign in cases where at least 2 benign evidence codes are applied AND PM2_Supporting is the only pathogenic code applied."
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"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243195",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243195",
"modified": "2024-12-03T14:46:45.842Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_i2x65Ay---"
},
{
"entContent": {
"_uniqueProp": "025_PVS1_nuclear_GATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": "For all Splice site variants (+1, +2, -1, -2), follow the guidance from the ClinGen SVI Splicing Subgroup capturing evidence related to predicted and observed impact on splicing (Walker et al, 2023, PMID: 37352859). Follow the decision tree outlined in Figure 5. As shown, if PVS1 is applied at any strength, PP3 should not be applied. Experimental evidence, such as RT-PCR, is used to determine the weight of PVS1; this may be denoted as “PVS1\\_Strength (RNA)”. PS1 may also be applied for splice variants (see Table 3 in PMID: 37352859). Regarding assays to assess splicing, in patients who are compound heterozygotes for a splicing variant and another variant type that does not disrupt splicing (such as a missense variant), evidence of normal splicing is expected. Therefore, the presence of normal splice products could complicate the assessment of the impact of the splice variant.",
"label": "PVS1",
"ns": "025",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "**Nonsense-mediated decay predicted.**\n\nCCDS VCEP notes: \nLoss of function (LOF) of GATM is a known mechanism of disease for arginine:glycine amidinotransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D ([https://databases.lovd.nl/shared/variants/GATM/unique](https://databases.lovd.nl/shared/variants/GATM/unique)). The specifications below are based on the PVS1 decision tree (see Appendix 1) (based on Figure 1, Abou Tayoun et al, 2018, PMID 30192042).\n\nGATM specifications: \n**Nonsense and frameshift variants** \n\\* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, please refer to the PVS1 flowchart for guidance on PVS1 weight (Appendix 1).\n\n**Splice site variants (+1, +2, -1, -2)** \n\\* All canonical splice site pairs in GATM are GT-AG. \n\\* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. However, to apply PVS1 at the very strong level, splice site variants must have no detectable nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing, as predicted by SpliceAI. Otherwise, the PVS1 strength should be reduced accordingly. \n\\* For the predicted in frame/out of frame consequences of exon skipping and considerations for strength of PVS1, see Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss). \n\\* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \n\\* Non-canonical splice variants, such as +3 or -3, may also meet PVS1 - refer to Walker et al, PMID: 37352859.\n\n**Deletions (single or multi exon)** \n\\* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 at the very strong level unless not predicted to undergo NMD. If not predicted to undergo NMD, please refer to Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss). \n\\* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. For weight of PVS1, see Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss) . \n\\* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.\n\n**Duplications** \n\\* To assess the impact of duplications, see Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**In frame loss of >10% of the protein.** \nCCDS VCEP notes: \nLoss of function (LOF) of GATM is a known mechanism of disease for arginine:glycine amidinotransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D ([https://databases.lovd.nl/shared/variants/GATM/unique](https://databases.lovd.nl/shared/variants/GATM/unique)). The specifications below are based on the PVS1 decision tree (see Appendix 1) (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).\n\nGATM specifications: \n**Nonsense and frameshift variants** \n\\* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, please refer to the PVS1 flowchart for guidance on PVS1 weight (Appendix 1).\n\n**Splice site variants (+1, +2, -1, -2)** \n\\* All canonical splice site pairs in GATM are GT-AG. \n\\* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. However, it is recommended to use SpliceAI to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. \n\\* For considerations for strength at which PVS1 may be applied see Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss) . \n\\* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \n\\* Non-canonical splice variants, such as +3 or -3, may also meet PVS1 - refer to Walker et al, PMID: 37352859.\n\n**Deletions (single or multi exon)** \n\\* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 at the very strong level unless not predicted to undergo NMD. If not predicted to undergo NMD, please refer to Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss). \n\\* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. For weight of PVS1, see Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss) . \n\\* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.\n\n**Duplications** \n\\* To assess the impact of duplications, see Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**Single exon or larger deletion resulting in loss of \\<10% of the protein, and initiator codon variants.**\n\nCCDS VCEP notes: \nLoss of function (LOF) of GATM is a known mechanism of disease for arginine:glycine amidinotransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D ([https://databases.lovd.nl/shared/variants/GATM/unique](https://databases.lovd.nl/shared/variants/GATM/unique)). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042). \n\nGATM specifications:\n\n**Nonsense and frameshift variants** \n\\* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, please refer to the PVS1 flowchart for guidance on PVS1 weight (Appendix 1).\n\n**Splice site variants (+1, +2, -1, -2)** \n\\* All canonical splice site pairs in GATM are GT-AG. \n\\* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. However, it is recommended to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. \n\\* For considerations for strength at which PVS1 may be applied see Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss). \n\\* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \n\\* Non-canonical splice variants, such as +3 or -3, may also meet PVS1 (refer to Walker et al, PMID: 37352859).\n\n**Initiator codon variants** \n\\* All initiator codon variants will meet PVS1\\_Moderate. The next in-frame methionine is at amino acid position 130 (based on NP\\_001473). \n\n**Deletions (single or multi exon)** \n\\* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 at the very strong level unless not predicted to undergo NMD. If not predicted to undergo NMD, please refer to Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss). \n\\* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. For weight of PVS1, see Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss) . \n\\* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.\n\n**Duplications** \n\\* To assess the impact of duplications, see Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243190",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243190",
"modified": "2024-12-03T14:46:45.842Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_i2x65Gy---"
},
{
"entContent": {
"_uniqueProp": "025_BP5_nuclear_GATM",
"additionalComments": "Variant found in a case with an alternate molecular basis for disease.\nCCDS VCEP notes for BP5: An individual could be a carrier of a pathogenic variant in GATM and have another disorder",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "025",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243215",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243215",
"modified": "2024-12-03T14:46:45.842Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_i2x65Ou---"
},
{
"entContent": {
"_uniqueProp": "025_BP2_nuclear_GATM",
"additionalComments": "CCDS VCEP notes for BP1: Does not apply. All types of variants cause AGAT-D",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "025",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in cis with a pathogenic variant (to take AR inheritance for AGAT deficiency into account).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243212",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243212",
"modified": "2024-12-03T14:46:45.842Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_i2x648m---"
},
{
"entContent": {
"_uniqueProp": "025_BS2_nuclear_GATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "025",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the homozygous state in a healthy adult.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243208",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243208",
"modified": "2024-12-03T14:46:45.842Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_i2x65P2---"
},
{
"entContent": {
"_uniqueProp": "025_PM6_nuclear_GATM",
"additionalComments": "CCDS VCEP notes for PS2 and PM6: De novo variants have not been reported in patients with AGAT deficiency, to our knowledge. Furthermore, the observation that a variant in GATM has arisen de novo does not support its causality because AGAT deficiency is an autosomal recessive disorder. The occurrence of de novo variants is more supportive in autosomal dominant and X-linked disorders. Any de novo variants in GATM, should they be observed, will be assessed based on the variant type, functional evidence, and in trans data as described.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "025",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243200",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243200",
"modified": "2024-12-03T14:46:45.842Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_i2x65M2---"
},
{
"entContent": {
"_uniqueProp": "025_PS4_nuclear_GATM",
"additionalComments": "CCDS VCEP notes for PS4:\nThis rule is typically used for autosomal dominant disorders, with PM3 used as a case-counting mechanism for autosomal recessive conditions.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS4",
"ns": "025",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243194",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243194",
"modified": "2024-12-03T14:46:45.842Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_i2x646----"
},
{
"entContent": {
"_uniqueProp": "025_PS2_nuclear_GATM",
"additionalComments": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to non-maternity.\nCCDS VCEP notes for PS2 and PM6: De novo variants have not been reported in patients with AGAT deficiency, to our knowledge. Furthermore, the observation that a variant in GATM has arisen de novo does not support its causality because AGAT deficiency is an autosomal recessive disorder. The occurrence of de novo variants is more supportive in autosomal dominant and X-linked disorders. Any de novo variants in GATM, should they be observed, will be assessed based on the variant type, functional evidence, and in trans data as described.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS2",
"ns": "025",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
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{
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"geneType": "nuclear",
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"text": "",
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"id": "0227",
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"strength": "Very Strong",
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"text": "",
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"id": "0071",
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"text": "",
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"text": "",
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"id": "0077",
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"strength": "Supporting",
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"modified": "2024-12-03T14:46:45.842Z",
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"rev": "_i2x65L6---"
},
{
"entContent": {
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"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
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"geneType": "nuclear",
"instructionsToUse": null,
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"ns": "025",
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"references": [
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"rev": "_i2x65Ny---"
},
{
"entContent": {
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"evidenceCategory": "Functional Data",
"gene": [
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"geneType": "nuclear",
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"ns": "025",
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"sepioID": "SEPIO-CG:99034",
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},
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{
"applicability": "Not applicable",
"id": "0049",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0033",
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"strength": "Strong",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0034",
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"strength": "Moderate",
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"text": "",
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{
"applicability": "Not applicable",
"id": "0061",
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"text": "",
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"rev": "_i2x65IK---"
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{
"entContent": {
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"evidenceCategory": "Computational And Predictive Data",
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"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "025",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
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},
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
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"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [
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"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Experimental evidence, such as RT-PCR, shows no impact on splicing. Follow the decision tree outlined in Figure 5, Walker et al, 2023, PMID: 37352859. Note that splicing may appear normal in compound heterozygous patients with one allele that is degraded by nonsense-mediated decay as the results of a frameshift and premature termination codon due to splicing defect. Therefore. caution must be used in asessing the data prior to applying this code.",
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"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0079",
"instructionsToUse": "",
"specificationType": [
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],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant OR an intronic variant at or beyond positions +7 and -21, for which SpliceAI, [https://spliceailookup.broadinstitute.org/](https://spliceailookup.broadinstitute.org/), predicts no impact on splicing (score \\<0.1) (see Walker et al, 2023, PMID: 37352859).",
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"entType": "CriteriaCode",
"ldhId": "643243217",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243217",
"modified": "2024-12-03T14:46:45.842Z",
"modifier": "jennifer.goldstein@unc.edu",
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},
{
"entContent": {
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"additionalComments": null,
"applicability": "Applicable",
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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"geneType": "nuclear",
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"label": "PP3",
"ns": "025",
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"text": "",
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{
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"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0019",
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"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense variant with a REVEL score >0.773 (based on guidance from Pejaver et al, 2022, PMID: 36413997).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
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],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Missense variant with a REVEL score 0.644-0.773 (based on guidance from Pejaver et al, 2022, PMID: 36413997).\n* In frame deletion or insertion predicted deleterious by PROVEAN and MutationTaster. Results must be consistent to count.\n* For non-canonical splice site variants (e.g., +3, -3), predict the impact on splicing by using SpliceAI, [https://spliceailookup.broadinstitute.org/](https://spliceailookup.broadinstitute.org/) , and apply PP3 for a score equal to or >0.2 (as indicated in PMID: 37352859, Table 1 and Figure 4). Assess the possibility of activation of cryptic splice sites.",
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}
]
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"ldhId": "643243203",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243203",
"modified": "2024-12-03T14:46:45.842Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_i2x65Iu---"
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{
"entContent": {
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"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "025",
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"sepioID": "SEPIO-CG:99030",
"status": {
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"strength": "Very Strong",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0035",
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"specificationType": [],
"strength": "Strong",
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"text": "",
"type": "EvidenceLineStrength"
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"strength": "Moderate",
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"text": "CCDS VCEP notes: Stop loss variants in GATM have not been reported, as far as we are aware. \n\nGATM specifications: Use this rule “as is” for in frame deletions and insertions of 2 or more amino acids, but downgrade to PM4\\_Supporting for single amino acid deletions and insertions.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Downgrade to PM4\\_Supporting for in frame deletion/insertion of a single amino acid.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243198",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243198",
"modified": "2024-12-03T14:46:45.842Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_i2x65Se---"
},
{
"entContent": {
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"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM2",
"ns": "025",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
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"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
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"specificationType": [],
"strength": "Moderate",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Applicable",
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"instructionsToUse": "",
"specificationType": [
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"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**Allele frequency \\<0.000055 (\\<0.0055%) in all populations in gnomAD.**\n\nCCDS VCEP notes: It is acceptable for a GATM variant to be present in controls, if heterozygous, because AGAT-D is a recessive disorder. Homozygotes should not be seen in a population database, such as gnomAD, because the penetrance of this condition in individuals with biallelic pathogenic variants is expected to be 100%. \n\nGATM specifications:\n\n* All subpopulations in gnomAD must have a maximum allele frequency less than 0.000055 (based on the prevalence of the most common suspected pathogenic variants, c.484+1G>T and p.Arg169Ter) (see Appendix 4). Use the current version recommended by SVI; version number will be stated in classification summary.\n* Note – PM2 will NOT be used at moderate strength; PM2 will only be applied as a Supporting criterion.\n* If homozygotes are observed, the variant will meet BS2 (assuming 100% penetrance for an individual with 2 pathogenic variants in trans).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243196",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243196",
"modified": "2024-12-03T14:46:45.842Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_i2x65Rm---"
},
{
"entContent": {
"_uniqueProp": "025_PS3_nuclear_GATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS3",
"ns": "025",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
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"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
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"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
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"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
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],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "AGAT activity data from an in vitro assay in which GATM variants were overexpressed in HeLa cells has been published (DesRoches et al, 2016; PMID 27233232). Any variant with AGAT activity at or below 15% of normal in this paper meets PS3\\_Supporting (see Appendix 3 for further details on AGAT functional assays).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243193",
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"modified": "2024-12-03T14:46:45.842Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_i2x65Fu---"
},
{
"entContent": {
"_uniqueProp": "025_BS1_nuclear_GATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS1",
"ns": "025",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "**GrpMax >0.0001 (0.01%) in gnomAD**\n\n* Any variant with a GrpMax (lower bound 95%ile) >0.0001 in gnomAD. Use the current version recommended by SVI; version number will be stated in classification summary.\n* Threshold based on max allelic contribution = 25% and max genetic contribution = 100% based on estimated prevalence of 1 in 3,450,000, (PMID 27233232), and penetrance of 100%) (PMID 30311383) (see Appendix 3).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243207",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243207",
"modified": "2024-12-03T14:46:45.842Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_i2x649K---"
},
{
"entContent": {
"_uniqueProp": "025_BA1_nuclear_GATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BA1",
"ns": "025",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
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}
},
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"applicability": "Applicable",
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"instructionsToUse": "",
"specificationType": [
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],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "**GrpMax >0.0005 (0.05%) in gnomAD**\n\n* Any variant with a GrpMax (lower bound 95%ile) >0.0005 in gnomAD. Use the current version recommended by SVI; version number will be stated in classification summary. \n* Threshold based on (max allelic contribution = 100% and max genetic contribution = 100% based on estimated prevalence of 1 in 3,450,000 (PMID 27233232), and penetrance of 100%) (PMID 30311383) (see Appendix 3)",
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{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
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"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243206",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243206",
"modified": "2024-12-03T14:46:45.842Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_i2x647e---"
},
{
"entContent": {
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"additionalComments": "CCDS VCEP notes for PP1: Sibships large enough to use meet this criterion are extremely rare. In addition, because GATM is the only gene involved in AGAT-D, ALL patients are expected to be bi-allelic, regardless of whether the pathogenic variants can be, or have been, detected. A variant under assessment may not be the true pathogenic variant but instead in linkage disequilibrium with an unidentified pathogenic variant. For this reason, this criterion does not facilitate assessment of pathogenicity.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
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],
"geneType": "nuclear",
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"ns": "025",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
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}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243201",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243201",
"modified": "2024-12-03T14:46:45.842Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_i2x643a---"
},
{
"entContent": {
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"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
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"evidenceCategory": "Allelic Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "025",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
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},
"strengthDescriptor": [
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"applicability": "Not Applicable for this VCEP",
"id": "0232",
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"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
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],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",
"type": "EvidenceLineStrength"
},
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"id": "0058",
"instructionsToUse": "",
"specificationType": [
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],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243197",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243197",
"modified": "2024-12-03T14:46:45.842Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_i2x65-i---"
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],
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"_uniqueProp": "026_BS1_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": "See Appendix 3 for details on allele frequency thresholds for GAMT.",
"label": "BS1",
"ns": "026",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "* Allele frequency >0.001 (0.1%) in gnomAD v4.0 in any continental population with >2000 alleles (based on the estimated prevalence 1 in 114,000 (PMID: 24071436) in gnomAD v4.0 (max allelic contribution = 40%; max genetic contribution = 100%).\n* Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243235",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243235",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Ati--g"
},
{
"entContent": {
"_uniqueProp": "026_PM2_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": "See Appendix 3 for details on allele frequency thresholds for GAMT.\n\nNote – PM2 will NOT be used at moderate strength; PM2 will only be applied as a Supporting criterion based on ClinGen SVI recommendations ([https://www.clinicalgenome.org/site/assets/files/5182/pm2_-_svi\\_recommendation_\\-\\_approved\\_sept2020.pdf](https://www.clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf) ).",
"label": "PM2",
"ns": "026",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**Allele frequency \\<0.0004 (\\<0.04%) in all populations in gnomAD.**\n\nIt is acceptable for a GAMT variant to be present in controls, if heterozygous, because GAMT-D is a recessive disorder. Homozygotes should not be seen in a population database, such as gnomAD, because the penetrance of this condition in individuals with biallelic pathogenic variants is expected to be 100% and the condition is expected to present with severe symptoms early in life.\n\nGAMT specifications:\n\n* All subpopulations in gnomAD v4.0 must have a maximum allele frequency less than 0.0004 (the highest population minor allele frequency of the most common pathogenic GAMT variant, c.327G>A, in gnomAD). Any variant with a frequency below this cutoff will meet PM2\\_Supporting.\n* If homozygotes are observed, or variant is confirmed in trans with a known pathogenic variant, the variant will meet BS2 (assuming 100% penetrance for an individual with 2 pathogenic variants in trans).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243224",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243224",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Ata--l"
},
{
"entContent": {
"_uniqueProp": "026_PS1_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": "As noted, any additional variants used to support the classification of the variant under assessment MUST have been previously classified by the CCDS VCEP, using these criteria, and the classification MUST be approved.",
"label": "PS1",
"ns": "026",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* This criterion is applicable for any variant resulting in the same amino acid change as a variant that has been previously established as pathogenic by the CCDS VCEP, by assessment using these criteria, regardless of nucleotide change.\n* If the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing.\n* PS1 may also be applied for splicing variants under specific circumstances (see Table 3 in PMID: 37352859).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* This criterion is applicable for any variant resulting in the same amino acid change as a variant that has been previously established as likely pathogenic by the CCDS VCEP, by assessment using these criteria, regardless of nucleotide change.\n* If the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing.\n* PS1\\_Moderate may also be applied for splicing variants under specific circumstances (see Table 3 in PMID: 37352859).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "PS1\\_Supporting may be applied for splicing variants under specific circumstances (see Table 3 in PMID: 37352859).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243219",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243219",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Atm--H"
},
{
"entContent": {
"_uniqueProp": "026_PM6_nuclear_GAMT",
"additionalComments": "Assumed de novo but without confirmation of paternity and maternity.\nCCDS VCEP notes for PS2 and PM6: De novo variants have not been reported in patients with GAMT deficiency, to our knowledge. Furthermore, the observation that a variant in GAMT has arisen de novo does not support its causality because GAMT deficiency is an autosomal recessive disorder. The occurrence of de novo variants is more supportive in autosomal dominant and X-linked disorders. Any de novo variants in GAMT, should they be observed, will be assessed based on the variant type, functional evidence, and in trans data as described.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "026",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243228",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243228",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Atq--O"
},
{
"entContent": {
"_uniqueProp": "026_PM5_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": "As noted, any additional variants used to support the classification of the variant under assessment MUST have been previously classified by the CCDS VCEP, using these criteria, and the classification MUST be approved.",
"label": "PM5",
"ns": "026",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* This criterion is applicable for any variant resulting in a different amino acid change, at the same amino acid position, as a variant that has been previously established as pathogenic by the CCDS VCEP, by assessment using these criteria, regardless of nucleotide change.\n* If the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing. \n* If the variant is likely pathogenic, use PM5\\_Supporting.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* This criterion is applicable for any variant resulting in a different amino acid change, at the same amino acid position, as a variant that has been previously established as likely pathogenic by the CCDS VCEP, by assessment using these criteria, regardless of nucleotide change.\n* If the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing. \n* If the variant is likely pathogenic, use PM5.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243227",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243227",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Atq--P"
},
{
"entContent": {
"_uniqueProp": "026_PS4_nuclear_GAMT",
"additionalComments": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\nCCDS VCEP notes for PS4:\nThis rule is typically used for autosomal dominant disorders, with PM3 used as a case-counting mechanism for autosomal recessive conditions.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS4",
"ns": "026",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243222",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243222",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Ata--j"
},
{
"entContent": {
"_uniqueProp": "026_PS3_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": "See Appendix 2 for further details on GAMT functional assays.",
"label": "PS3",
"ns": "026",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "PS3\\_Supporting can be assigned if a variant is expressed in GAMT-deficient fibroblasts, HeLa cells and has \\<15% of the control value, for values published in Mercimek-Mahmutoglu et al, 2014, PMID 24415674; Mercimek-Mahmutoglu et al, 2016, PMID 26319512; or DesRoches et al, 2016, PMID 26003046.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243221",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243221",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Atm--I"
},
{
"entContent": {
"_uniqueProp": "026_PS2_nuclear_GAMT",
"additionalComments": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to non-maternity.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS2",
"ns": "026",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243220",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243220",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Ate--1"
},
{
"entContent": {
"_uniqueProp": "026_BP6_nuclear_GAMT",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP6",
"ns": "026",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243244",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243244",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Atq--L"
},
{
"entContent": {
"_uniqueProp": "026_BP5_nuclear_GAMT",
"additionalComments": "An individual could be a carrier of a pathogenic variant in GAMT and have another disorder.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "026",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243243",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243243",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Ati--d"
},
{
"entContent": {
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"additionalComments": "There are no known repetitive regions without known function in GAMT.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "026",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243241",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243241",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Ata--q"
},
{
"entContent": {
"_uniqueProp": "026_BP2_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "026",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in cis with a pathogenic variant (to take AR inheritance into account).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243240",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243240",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Ati--e"
},
{
"entContent": {
"_uniqueProp": "026_PM4_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "026",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "GAMT specifications: Use this rule “as is” for stop loss variant, and in frame deletions and insertions of 2 or more amino acids, but downgrade to PM4\\_Supporting for single amino acid deletions and insertions.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Downgrade to PM4\\_Supporting for single amino acid deletions and insertions.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243226",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243226",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Ate--z"
},
{
"entContent": {
"_uniqueProp": "026_BP7_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "026",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Experimental evidence, such as RT-PCR, shows no impact on splicing. Follow the decision tree outlined in Figure 5, Walker et al, 2023, PMID: 37352859. Note that splicing may appear normal in compound heterozygous patients if the splicing defect generates a transcript that is degraded by nonsense-mediated decay. Therefore, caution must be used when assessing the data prior to applying this code.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant OR an intronic variant at or beyond positions +7 and -21, for which SpliceAI, [https://spliceailookup.broadinstitute.org/](https://spliceailookup.broadinstitute.org/), predicts no impact on splicing (score \\<0.1).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243245",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243245",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Ata--n"
},
{
"entContent": {
"_uniqueProp": "026_BS4_nuclear_GAMT",
"additionalComments": "Lack of segregation in a family. Caveat: The presence of phenocopies for common phenotypes.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "026",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243238",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243238",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Ate--4"
},
{
"entContent": {
"_uniqueProp": "026_BA1_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": "See Appendix 3 for details on allele frequency thresholds for GAMT.",
"label": "BA1",
"ns": "026",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "* Allele frequency >0.003 (0.3%) in gnomAD v4.0 in any continental population with >2000 alleles (based on the estimated prevalence 1 in 114,000, PMID 24071436) in gnomAD v4.0 (max allelic contribution = 100%; max genetic contribution = 100%).\n* Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243234",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243234",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Atq--M"
},
{
"entContent": {
"_uniqueProp": "026_PP4_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "026",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "4 points based on any combination of the following. Two or more data types are required to apply PP4\\_Strong:\n\n* Elevated urine guanidinoacetate with or without low or low normal creatine (1 point).\n* Elevated plasma guanidinoacetate with or without low or low normal creatine (2 points).\n* Significantly decreased creatine peak in brain magnetic resonance spectroscopy with or without visible guanidinoacetate peak (3 points).\n* GAMT enzyme activity \\<5% of normal (3 points).\n* Variant must meet PM2\\_Supporting for PP4 to apply at any strength.\n* For PP4 to be applied at strong, full GAMT gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "3 points based on any combination of the following. Two or more data types are recommended to apply PP4\\_Moderate:\n\n* Elevated urine guanidinoacetate with or without low or low normal creatine (1 point).\n* Elevated plasma guanidinoacetate with or without low or low normal creatine (2 points).\n* Significantly decreased creatine peak in brain magnetic resonance spectroscopy with or without visible guanidinoacetate peak (3 points).\n* GAMT enzyme activity \\<5% of normal (3 points).\n* Variant must meet PM2\\_Supporting for PP4 to apply at any strength.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1-2 points based on: \n\n* Elevated urine guanidinoacetate with or without low or low normal creatine (1 point).\n* Elevated plasma guanidinoacetate with or without low or low normal creatine (2 points).\n* Variant must meet PM2\\_Supporting for PP4 to apply at any strength.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243232",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243232",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Atq--N"
},
{
"entContent": {
"_uniqueProp": "026_PP3_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": "See Appendix 3 for justification of PP3 strength using REVEL score.\n\nDo not apply PP3 if PVS1 has been applied at any strength.",
"label": "PP3",
"ns": "026",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense variant with a REVEL score equal to or >0.932 (based on guidance from Pejaver et al, 2022, PMID: 36413997).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense variant with a REVEL score 0.773-0.932 (based on guidance from Pejaver et al, 2022, PMID: 36413997).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"None"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Missense variant with a REVEL score 0.644-0.773 (based on guidance from Pejaver et al, 2022, PMID: 36413997).\n* In frame deletion or insertion predicted deleterious by PROVEAN and MutationTaster. Results must be consistent to count.\n* For non-canonical splice site variants (e.g., +3, -3), predict the impact on splicing by using SpliceAI, [https://spliceailookup.broadinstitute.org/](https://spliceailookup.broadinstitute.org/) , and apply PP3 for a score equal to or >0.2 (as indicated in PMID: 37352859, Table 1 and Figure 4). Assess the possibility of activation of cryptic splice sites.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243231",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243231",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Ati--i"
},
{
"entContent": {
"_uniqueProp": "026_PP2_nuclear_GAMT",
"additionalComments": "Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease.\nCCDS VCEP notes for PP2: Does not apply; there are benign and pathogenic missense variants in GAMT",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "026",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243230",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243230",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Ate--3"
},
{
"entContent": {
"_uniqueProp": "026_PP1_nuclear_GAMT",
"additionalComments": "Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nCCDS VCEP notes for PP1: Sibships large enough to use meet this criterion are extremely rare. In addition, because GAMT is the only gene involved in GAMT-D, ALL patients are expected to be bi-allelic, regardless of whether the pathogenic variants can be, or have been, detected. A variant under assessment may not be the true pathogenic variant but instead in linkage disequilibrium with an unidentified pathogenic variant. For this reason, this criterion does not facilitate assessment of pathogenicity.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP1",
"ns": "026",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243229",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243229",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Atm--G"
},
{
"entContent": {
"_uniqueProp": "026_PM3_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": "Any additional variants used to support the classification of the variant under assessment MUST have been previously classified by the CCDS VCEP, using these criteria, and the classification MUST be approved. In other words, when awarding points for PM3 for a compound heterozygote, the second variant MUST have been assessed by the VCEP and an appropriate classification approved.\n\nAs noted in the SVI guidance, circularity must be avoided. Variant A can support the classification of Variant B, or vice versa but NOT both.",
"label": "PM3",
"ns": "026",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243225",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243225",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Ata--o"
},
{
"entContent": {
"_uniqueProp": "026_BP4_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "026",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"None"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* REVEL score \\<0.29 for missense variants (based on guidance from Pejaver et al, 2022, PMID: 36413997).\n* In frame deletion or insertion predicted benign by PROVEAN and MutationTaster.\n* No predicted impact on splicing by SpliceAI, [https://spliceailookup.broadinstitute.org/](https://spliceailookup.broadinstitute.org/) , based on a score \\<0.1 (as indicated in PMID: 37352859, Table 1 and Figure 4).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243242",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243242",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Ate--t"
},
{
"entContent": {
"_uniqueProp": "026_BS3_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "026",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In vitro assays in which a variant is expressed in GAMT-deficient cultured cells (e.g. GAMT-deficient fibroblasts) or in-fusion High-Fidelity cloning of GAMT transcript and site directed mutagenesis to generate missense variant overexpressed in HeLa cells and measurement of GAMT activity in cells for wild-type and missense variant. Any variant with enzyme activity at or above 30% of normal in the following publications meets BS3\\_Supporting (Mercimek-Mahmutoglu et al, 2014; PMID 24415674; Mercimek-Mahmutoglu et al, 2016, PMID 26319512; DesRoches et al, 2016, PMID 26003046).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243237",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243237",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Ati--v"
},
{
"entContent": {
"_uniqueProp": "026_PP5_nuclear_GAMT",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP5",
"ns": "026",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243233",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243233",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Ate--x"
},
{
"entContent": {
"_uniqueProp": "026_PM1_nuclear_GAMT",
"additionalComments": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "026",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243223",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243223",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Ati--n"
},
{
"entContent": {
"_uniqueProp": "026_PVS1_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": "Loss of function (LOF) of GAMT is a known mechanism of disease for guanidinoacetate methyltransferase deficiency (GAMT-D). There are examples of various LOF variants, including nonsense and frameshift, in GAMT in individuals with GAMT-D ([https://databases.lovd.nl/shared/variants/GAMT/unique](https://databases.lovd.nl/shared/variants/GAMT/unique)). The specifications are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042). See “GAMT PVS1 flowchart”.\n\nFor all Splice site variants (+1, +2, -1, -2), **f**ollow the guidance from the ClinGen SVI Splicing Subgroup capturing evidence related to predicted and observed impact on splicing (Walker et al, 2023, PMID: 37352859). Follow the decision tree outlined in Figure 5. As shown, if PVS1 is applied at any strength, PP3 should not be applied. Experimental evidence, such as RT-PCR, is used to determine the weight of PVS1; PS3 is not applied if PVS1 is applied; instead PVS1\\_Strength (RNA) is used. PS1 may also be applied for splice variants (see Table 3 in PMID: 37352859). Regarding assays to assess splicing in patients who are compound heterozygotes for a splicing variant and another variant type that does not disrupt splicing (such as a missense variant), evidence of normal splicing is expected. Therefore, the presence of normal splice products could complicate the assessment of the impact of the splice variant.",
"label": "PVS1",
"ns": "026",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "**Nonsense-mediated decay predicted**\n\n**Nonsense and frameshift variants**\n\n* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1\\_Strong or PVS1\\_Moderate will be applied, depending on whether >10% or \\<10% of the protein is lost.\n\n**Splice site variants (+1, +2, -1, -2)**\n\n* All canonical splice site pairs in GAMT are GT-AG.\n* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants.\n* For the predicted in frame/out of frame consequences of exon skipping and assigned strength of PVS1, see Appendix 1.\n* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.\n* Use SpliceAI to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. Otherwise, the PVS1 strength should be reduced accordingly.\n* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.\n\n**Deletions (single or multi exon)**\n\n* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. \n* If not predicted to undergo NMD, use PVS1\\_Strong if >10% of the protein is predicted to be removed, and use PVS1\\_Moderate if \\<10% of the protein is predicted to be removed.\n* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\\_Strong if more than 10% of the protein is removed and PVS1\\_Moderate if \\<10% of the protein is removed.\n* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \n Appendix 1 can be used to predict the consequences of single exon deletions.\n\n**Duplications**\n\n* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**Single exon or larger deletion resulting in loss of >10% of the protein.** \n\n**Nonsense and frameshift variants**\n\n* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1\\_Strong will be applied if >10% of the protein is lost.\n\n**Splice site variants (+1, +2, -1, -2)**\n\n* All canonical splice site pairs in GAMT are GT-AG.\n* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants.\n* Use SpliceAI to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. \n* For considerations for strength at which PVS1 may be applied see Appendix 1.\n* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.\n* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.\n\n**Deletions (single or multi exon)**\n\n* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD.\n* If not predicted to undergo NMD, use PVS1\\_Strong if >10% of the protein is predicted to be removed, and use PVS1\\_Moderate if \\<10% of the protein is predicted to be removed.\n* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\\_Strong if more than 10% of the protein is removed and PVS1\\_Moderate if \\<10% of the protein is removed.\n* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \n Appendix 1 can be used to predict the consequences of single exon deletions.\n\n**Duplications**\n\n* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**Single exon or larger deletion resulting in loss of \\<10% of the protein.** \n\n**Nonsense and frameshift variants**\n\n* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1\\_Moderate will be applied if \\<10% of the protein is lost.\n\n**Splice site variants (+1, +2, -1, -2)**\n\n* All canonical splice site pairs in GAMT are GT-AG.\n* Use SpliceAI to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. \n* For any canonical splice site variant (+1, +2, -1, -2), if RT-PCR data predicts in-frame loss of \\<10% of the protein, apply PVS1\\_Moderate.\n* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.\n* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.\n\n**Initiator codon variants**\n\n* All initiator codon variants will meet PVS1\\_Moderate. The next in-frame methionine is at amino acid position 42 (based on NP\\_000147.1).\n\n**Deletions (single or multi exon)**\n\n* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. \n* If not predicted to undergo NMD, use PVS1\\_Strong if >10% of the protein is predicted to be removed, and use PVS1\\_Moderate if \\<10% of the protein is predicted to be removed.\n* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\\_Strong if more than 10% of the protein is removed and PVS1\\_Moderate if \\<10% of the protein is removed.\n* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \n Appendix 1 can be used to predict the consequences of single exon deletions.\n\n**Duplications**\n\n* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243218",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243218",
"modified": "2024-05-23T13:46:42.596Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_inf5Ati--p"
}
],
"Disease": [
{
"entContent": {
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"meta": {
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"val": "https://www.malacards.org/card/cerebral_creatine_deficiency_syndrome_2"
},
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"val": "https://rarediseases.info.nih.gov/diseases/2578/guanidinoacetate-methyltransferase-deficiency"
},
{
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"val": "http://id.who.int/icd/entity/1811642217"
},
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"val": "http://identifiers.org/medgen/154356"
},
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},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/612736"
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],
"definition": {
"val": "A creatine deficiency syndrome characterized by global developmental delay/intellectual disability (DD/ID), prominent speech delay, autistic/hyperactive behavioral disorders, seizures, and various types of pyramidal and/or extra-pyramidal manifestations.",
"xrefs": [
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},
"subsets": [
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"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
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"synonyms": [
{
"pred": "hasExactSynonym",
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"xrefs": [
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},
{
"pred": "hasExactSynonym",
"val": "cerebral creatine deficiency syndrome 2",
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},
{
"pred": "hasExactSynonym",
"val": "cerebral creatine deficiency syndrome type 2",
"xrefs": [
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},
{
"pred": "hasExactSynonym",
"val": "disorder of guanidinoacetate N-methyltransferase activity",
"xrefs": [
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},
{
"pred": "hasExactSynonym",
"val": "guanidinoacetate N-methyltransferase activity disease",
"xrefs": [
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},
{
"pred": "hasExactSynonym",
"val": "guanidinoacetate methyltransferase deficiency",
"xrefs": [
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},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "CCDS2",
"xrefs": [
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},
{
"pred": "hasRelatedSynonym",
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}
],
"xrefs": [
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{
"val": "GARD:2578"
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{
"val": "ICD9:277.6"
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{
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},
{
"val": "MESH:C537622"
},
{
"val": "NANDO:1201034"
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{
"val": "NANDO:2201300"
},
{
"val": "NORD:1967"
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{
"val": "OMIM:612736"
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{
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{
"val": "SCTID:124239003"
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{
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},
"type": "CLASS"
},
"MONDOID": "MONDO:0012999",
"name": "guanidinoacetate methyltransferase deficiency"
},
"entId": "MONDO:0012999",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0012999",
"entType": "Disease",
"ldhId": "467873663",
"ldhIri": "https://cspec.genome.network/cspec/Disease/id/467873663",
"modified": "2025-10-07T16:13:46.189Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7xPEu---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056948186415000,
"agr": "HGNC:4136",
"alias_symbol": [
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"TP53I2"
],
"ccds_id": [
"CCDS12064",
"CCDS45897"
],
"date_approved_reserved": "1996-07-19",
"date_modified": "2021-05-26",
"ena": [
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],
"ensembl_gene_id": "ENSG00000130005",
"entrez_id": "2593",
"gene_group": [
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],
"gene_group_id": [
2063
],
"hgnc_id": "HGNC:4136",
"location": "19p13.3",
"location_sortable": "19p13.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/GAMT"
],
"mane_select": [
"ENST00000252288.8",
"NM_000156.6"
],
"mgd_id": [
"MGI:1098221"
],
"name": "guanidinoacetate N-methyltransferase",
"omim_id": [
"601240"
],
"orphanet": 122011,
"pubmed_id": [
9570966,
8547310
],
"refseq_accession": [
"NM_138924"
],
"rgd_id": [
"RGD:2659"
],
"status": "Approved",
"symbol": "GAMT",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc002lsj.5",
"uniprot_ids": [
"Q14353"
],
"uuid": "bd41090a-ab7b-4ce8-9e9c-94bd915309e5",
"vega_id": "OTTHUMG00000180095"
}
},
"entId": "GAMT",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:4136",
"entType": "Gene",
"ldhId": "467827323",
"ldhIri": "https://cspec.genome.network/cspec/Gene/id/467827323",
"modified": "2021-10-14T11:36:39.860Z",
"modifier": "genbadmin",
"rev": "_inf5BN---v"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "026_nuclear_GAMT",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0012999",
"preferredTitle": "guanidinoacetate methyltransferase deficiency"
}
],
"gene": "GAMT",
"preferredTranscript": "NM_000156.6"
}
],
"ns": "026",
"references": [],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PM3_Strong",
"PP4_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PM3",
"PM4",
"PM5",
"PP3_Moderate",
"PP4_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PM3",
"PM4",
"PM5",
"PP3_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP3",
"PP4"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PM3_Strong",
"PP4_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PM3_Strong",
"PP4_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PM3",
"PM4",
"PM5",
"PP3_Moderate",
"PP4_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PM3_Strong",
"PP4_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PM3",
"PM4",
"PM5",
"PP3_Moderate",
"PP4_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PM3_Strong",
"PP4_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PM3",
"PM4",
"PM5",
"PP3_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP3",
"PP4"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule9, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PM3",
"PM4",
"PM5",
"PP3_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule9, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule9"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2"
],
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS3_Supporting",
"BP2",
"BP4",
"BP7"
],
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS3_Supporting",
"BP2",
"BP4",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PM3_Strong",
"PP3_Strong",
"PP4_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule14, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PM4",
"PM5",
"PP3_Moderate",
"PP4_Moderate"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule14, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PM3_Strong",
"PP3_Strong",
"PP4_Strong"
],
"condition": "==1",
"getpartitionPath": "",
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"rev": "_jg-xuTa---"
},
{
"entContent": {
"_uniqueProp": "027_PP2_nuclear_SLC6A8",
"additionalComments": "Not applicable, gnomAD (01/2019) expected missense 243.5, observed missense 117, for Z=2.94 (o/e =0.48). No constraint against missense variation.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "027",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243258",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243258",
"modified": "2025-04-10T14:56:24.779Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_jg-xuWK--A"
},
{
"entContent": {
"_uniqueProp": "027_PP1_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP1",
"ns": "027",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* 3 affected segregations + 0 unaffected segregations OR\n* 2 affected segregations + 3 unaffected segregations",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* 2 affected segregations + 0 unaffected segregations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* 1 affected family member + 3 unaffected segregations.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243257",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243257",
"modified": "2025-04-10T14:56:24.779Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_jg-xuP2--A"
},
{
"entContent": {
"_uniqueProp": "027_BP5_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "027",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\nBP5 applicable as described; the case must have specific features of creatine transporter deficiency, such as low creatine on brain magnetic resonance spectroscopy, or elevated urine creatine in order to apply this criterion. Presence of developmental delay and seizures is not sufficient.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243271",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243271",
"modified": "2025-04-10T14:56:24.779Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_jg-xuS---A"
},
{
"entContent": {
"_uniqueProp": "027_BP3_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "027",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243269",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243269",
"modified": "2025-04-10T14:56:24.779Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_jg-xuT2--B"
},
{
"entContent": {
"_uniqueProp": "027_BS1_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS1",
"ns": "027",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency > 0.0002 (0.02%) OR ≥ 5 hemizygotes in gnomAD",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243263",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243263",
"modified": "2025-04-10T14:56:24.779Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_jg-xuP---A"
},
{
"entContent": {
"_uniqueProp": "027_PP3_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "027",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* REVEL score >0.75 for missense variants\n* In frame deletion or insertion predicted deleterious by PROVEAN, MutPred indel, and MutationTaster.\n* Predicted impact on splicing by SpliceAI and varSEAK.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243259",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243259",
"modified": "2025-04-10T14:56:24.779Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_jg-xuNK---"
},
{
"entContent": {
"_uniqueProp": "027_PM1_nuclear_SLC6A8",
"additionalComments": "Not applicable",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "027",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243251",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243251",
"modified": "2025-04-10T14:56:24.779Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_jg-xuUi--B"
},
{
"entContent": {
"_uniqueProp": "027_PS3_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS3",
"ns": "027",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**RT-PCR evidence of mis-splicing for non-canonical intronic variants.**\n\nFor non-canonical splicing variants, RT-PCR evidence demonstrating transcripts of alternative length or specific intron or exon inclusion/exclusion. These studies can be performed in patient derived cells, by placing the mutant genomic DNA into plasmid vectors, or by over-expressing mutant transcript. Assays should demonstrate defective splicing with RT-PCR analysis or RNA sequencing to confirm alternative transcripts.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Creatine transport activity \\<10% wild type with less than or equal to 125uM creatine used in SLC6A8 deficient fibroblasts\n* RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products. For non-canonical splicing variants, RT-PCR evidence demonstrating transcripts of alternative length or specific intron or exon inclusion/exclusion. These studies can be performed in patient derived cells, by placing the mutant genomic DNA into plasmid vectors, or by over-expressing mutant transcript. Assays should demonstrate defective splicing with RT-PCR analysis or RNA sequencing to confirm alternative transcripts.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243249",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243249",
"modified": "2025-04-10T14:56:24.779Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_jg-xuPO--B"
},
{
"entContent": {
"_uniqueProp": "027_PS2_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PS2",
"ns": "027",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"None"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Note: Confirmation of paternity in females only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.\n\nX-linked disorder. Only maternity needs to be confirmed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Newly hemizygous male with the variant identified de novo in the mother with no family history of other affected males.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243248",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243248",
"modified": "2025-04-10T14:56:24.779Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_jg-xuR---A"
},
{
"entContent": {
"_uniqueProp": "027_PS1_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "027",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"None"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "PS1 is applicable as described.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
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{
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],
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"strengthSepioID": "SEPIO:0000329",
"text": "",
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"modifier": "jennifer.goldstein@unc.edu",
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},
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{
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"id": "0075",
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"text": "",
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"text": "",
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"modified": "2025-04-10T14:56:24.779Z",
"modifier": "jennifer.goldstein@unc.edu",
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{
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"status": {
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},
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"id": "0091",
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{
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"id": "0224",
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"text": "",
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"id": "0069",
"instructionsToUse": "",
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"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "The variant is observed in ≥2 hemizygotes in gnomAD, or one or more hemizygous male(s) or homozygous female(s) who have documented normal urine creatine/creatine ratio.",
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},
{
"applicability": "Not Applicable",
"id": "0098",
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"specificationType": [],
"strength": "Moderate",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
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},
"entType": "CriteriaCode",
"ldhId": "643243264",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243264",
"modified": "2025-04-10T14:56:24.779Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_jg-xuWi--B"
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{
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"sepioID": "SEPIO-CG:99038",
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"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
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"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0202",
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"strengthSepioID": "SEPIO:0000328",
"text": "",
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{
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"id": "0203",
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{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
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"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
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"entType": "CriteriaCode",
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{
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],
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"ns": "027",
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"sepioID": "SEPIO-CG:99032",
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"completed": true
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},
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"applicability": "Not applicable",
"id": "0235",
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{
"applicability": "Not applicable",
"id": "0014",
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"strengthSepioID": "SEPIO:0000220",
"text": "",
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{
"applicability": "Not Applicable",
"id": "0037",
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"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0010",
"instructionsToUse": "",
"specificationType": [
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],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant identified as de novo in an affected male with the mother negative for the variant but maternity not confirmed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
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"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
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},
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"modified": "2025-04-10T14:56:24.779Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_jg-xuV6--A"
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{
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"text": "",
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{
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"id": "0047",
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"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "008",
"instructionsToUse": "",
"specificationType": [
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],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
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],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense change at an amino acid residue where a different missense change determined to be likely pathogenic has been seen before.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243255",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243255",
"modified": "2025-04-10T14:56:24.779Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_jg-xuPm--A"
},
{
"entContent": {
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"applicability": "Not Applicable for this VCEP",
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"defaultStrength": "Benign Supporting",
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"instructionsToUse": null,
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"references": [
{
"id": "29543229",
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],
"sepioID": "SEPIO-CG:99048",
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"strength": "Stand Alone",
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
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{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
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"modified": "2025-04-10T14:56:24.779Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_jg-xuQO--A"
},
{
"entContent": {
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "027",
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"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
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"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
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],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* REVEL score \\<0.2 for missense variants\n* In frame deletion or insertion predicted benign by PROVEAN, MutPred indel, and MutationTaster.\n* No predicted impact on splicing by SpliceAI and varSEAK.",
"type": "EvidenceLineStrength"
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"modified": "2025-04-10T14:56:24.779Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_jg-xuOu--A"
},
{
"entContent": {
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"evidenceCategory": "Segregation Data",
"gene": [
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"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "027",
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"sepioID": "SEPIO-CG:99042",
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},
"strengthDescriptor": [
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"id": "0229",
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"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
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],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243266",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243266",
"modified": "2025-04-10T14:56:24.779Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_jg-xuQm--A"
},
{
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "027",
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"sepioID": "SEPIO-CG:99041",
"status": {
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"completed": true
}
},
"strengthDescriptor": [
{
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"id": "0226",
"instructionsToUse": "",
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"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
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"instructionsToUse": "",
"specificationType": [
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"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* Creatine transport assay demonstrating ≥50% normal transport activity using physiological creatine concentrations (≤125μM creatine).\n* RT-PCR evidence demonstrating no observable effect of splicing.\n* Expression assay demonstrating wild type transcript levels",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243265",
"modified": "2025-04-10T14:56:24.779Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_jg-xuRq--A"
},
{
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "027",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [
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],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "4 or more points based on combinations of the following. \n\n* Elevated urine creatine/creatinine ratio on one occasion (1 point)\n* Elevated urine creatine/creatinine ratio on more than one occasion (2 points)\n* Significantly decreased creatine peak, with absent guanidinoacetate peak, if reported (3 points)\n* Deficient creatine uptake in cultured fibroblasts (\\<10% of normal with \\<125uM creatine) (3 points)\n\nAdditional specifications:\n\n* Two or more data types are required for PP4\\_Strong.\n* An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.\n* Variant must meet PM2\\_Supporting for PP4 to apply at any strength.\n* For PP4 to be applied at strong, full SLC6A8 gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "3 or more points based on: \n\n* Elevated urine creatine/creatinine ratio on one occasion (1 point)\n* Elevated urine creatine/creatinine ratio on more than one occasion (2 points)\n* Significantly decreased creatine peak, with absent guanidinoacetate peak, if reported (3 points)\n* Deficient creatine uptake in cultured fibroblasts (\\<10% of normal with \\<125uM creatine) (3 points)\n\nAdditional specifications:\n\n* Two or more data types are recommended for PP4\\_Moderate.\n* An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.\n* Variant must meet PM2\\_Supporting for PP4 to apply at any strength.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1-2 or more points based on: \n\n* Elevated urine creatine/creatinine ratio on one occasion (1 point)\n* Elevated urine creatine/creatinine ratio on more than one occasion (2 points)\n\nAdditional specifications:\n\n* An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.\n* Variant must meet PM2\\_Supporting for PP4 to apply at any strength.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243260",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243260",
"modified": "2025-04-10T14:56:24.779Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_jg-xuNi--B"
},
{
"entContent": {
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"additionalComments": "",
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"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": null,
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"ns": "027",
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}
},
"strengthDescriptor": [
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"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
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],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243254",
"modified": "2025-04-10T14:56:24.779Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_jg-xuOe--A"
},
{
"entContent": {
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"additionalComments": "",
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"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM2",
"ns": "027",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
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],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample. Threshold: \\<0.00002 (0.002%) AND 0 hemizygotes in gnomAD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243252",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/643243252",
"modified": "2025-04-10T14:56:24.779Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_jg-xuVq--A"
}
],
"Disease": [
{
"entContent": {
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"modified": "2025-10-07T16:13:10.537Z",
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],
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},
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"modified": "2021-10-14T11:37:07.969Z",
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],
"RuleSet": [
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"genes": [
{
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}
],
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],
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],
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"conditions": [
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],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
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],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
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"rule": "Rule1"
},
{
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}
],
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},
{
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],
"condition": "==1",
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"partitionPath": "Pathogenic.Supporting"
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],
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"rule": "Rule3"
},
{
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},
{
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],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
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],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
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},
{
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"PP1_Moderate",
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],
"condition": ">=3",
"label": "Rule6, Condition2",
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}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
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"PS3",
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],
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"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
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"condition": "==2",
"label": "Rule7, Condition2",
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},
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],
"condition": ">=2",
"label": "Rule7, Condition3",
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}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
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],
"condition": "==1",
"label": "Rule8, Condition1",
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},
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],
"condition": "==1",
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},
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"PP4"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
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"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176864",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572176864",
"modified": "2025-07-30T16:35:55.384Z",
"modifier": "gmillikin",
"rev": "_kDuuu_W---"
},
{
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"label": "BS4",
"ns": "032",
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"sepioID": "SEPIO-CG:99042",
"specificationType": [
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],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member, when seen in two or more families\n* Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176853",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572176853",
"modified": "2025-07-30T16:35:55.384Z",
"modifier": "gmillikin",
"rev": "_kDuut9i---"
},
{
"entContent": {
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"additionalComments": "Not applicable for TCF4.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "032",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176852",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572176852",
"modified": "2025-07-30T16:35:55.384Z",
"modifier": "gmillikin",
"rev": "_kDuuu_2---"
},
{
"entContent": {
"_uniqueProp": "032_PM1_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "032",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n\n* Basic Helix-Loop-Helix domain (bHLH): aa 564-617[3](#PMID_17436254),[2](#PMID_22045651)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176843",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572176843",
"modified": "2025-07-30T16:35:55.384Z",
"modifier": "gmillikin",
"rev": "_kDuut6S---"
},
{
"entContent": {
"_uniqueProp": "032_BS3_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "032",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for other functional studies.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176841",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572176841",
"modified": "2025-07-30T16:35:55.384Z",
"modifier": "gmillikin",
"rev": "_kDuuu-W---"
},
{
"entContent": {
"_uniqueProp": "032_BS2_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "* Should be applied in cases where the healthy adult is devoid of neurodevelopmental phenotypes.\n* Best to use with internal curated data that includes clinical information or published patients that have been phenotyped.",
"label": "BS2",
"ns": "032",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 2 unaffected (related or unrelated) heterozygotes",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 1 unaffected (related or unrelated) heterozygote",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176840",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572176840",
"modified": "2025-07-30T16:35:55.384Z",
"modifier": "gmillikin",
"rev": "_kDuut7----"
},
{
"entContent": {
"_uniqueProp": "032_PM2_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "032",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176838",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572176838",
"modified": "2025-07-30T16:35:55.384Z",
"modifier": "gmillikin",
"rev": "_kDuuuB----"
},
{
"entContent": {
"_uniqueProp": "032_BP6_nuclear_TCF4",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "032",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176863",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572176863",
"modified": "2025-07-30T16:35:55.384Z",
"modifier": "gmillikin",
"rev": "_kDuut4----"
},
{
"entContent": {
"_uniqueProp": "032_PP1_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"label": "PP1",
"ns": "032",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n\n* ≥5 informative meiosis",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 3-4 informative meiosis",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 2 informative meiosis",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176860",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572176860",
"modified": "2025-07-30T16:35:55.384Z",
"modifier": "gmillikin",
"rev": "_kDuut4W---"
},
{
"entContent": {
"_uniqueProp": "032_BP4_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "032",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)\n\n* For missense variants use REVEL with a score ≤ 0.290.\n* For splice site variants use SpliceAI with a score ≤ 0.1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176859",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572176859",
"modified": "2025-07-30T16:35:55.384Z",
"modifier": "gmillikin",
"rev": "_kDuuu-2---"
},
{
"entContent": {
"_uniqueProp": "032_BA1_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoffs are based on MECP2 expected disease allele frequency (1 in 10,000 for the disease prevalence / (1.5 alleles \\[assumes 50/50 male/female ratio\\] \\* 0.8 for 80% penetrance)). MECP2 is the most prevalent of the genes covered in the Rett/Angelman-like working group and was chosen as most conservative number.",
"label": "BA1",
"ns": "032",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency above 0.05%.\n\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.000083 (0.0083%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176848",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572176848",
"modified": "2025-07-30T16:35:55.384Z",
"modifier": "gmillikin",
"rev": "_kDuuu-C---"
},
{
"entContent": {
"_uniqueProp": "032_PS4_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "* Detailed phenotype not needed. Need to confirm patient is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.\n* Patient can be published OR an internal case OR observed at an outside lab (i.e. via ClinVar). However, the independent case has to be confirmed to be a different patient than yours (compare gender/age).\n* Do not use this criterion for variants where BS1 is applied or where PM2 does not apply.",
"label": "PS4",
"ns": "032",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176846",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572176846",
"modified": "2025-07-30T16:35:55.384Z",
"modifier": "gmillikin",
"rev": "_kDuut5y---"
},
{
"entContent": {
"_uniqueProp": "032_BP5_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "* For example if a variant in _TCF4_ is identified in a patient with lissencephaly in whom a pathogenic variant is identified in the _PAFAH1B1_ gene.\n* Do not apply if variant is de novo.",
"label": "BP5",
"ns": "032",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Variant found in a case with an alternate molecular basis for disease.\n\n* 2 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\n\n* 1 case with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176862",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572176862",
"modified": "2025-07-30T16:35:55.384Z",
"modifier": "gmillikin",
"rev": "_kDuut7y---"
},
{
"entContent": {
"_uniqueProp": "032_PVS1_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "Refer to PVS1 flow chart for additional guidance.\n\nFor intragenic deletions/duplications that are predicted to result in a product that preserves the reading frame:\n\n* For single exon in-frame deletions assign the same strength (PVS1) as for splice site variants that preserve reading frame indicated above.\n* For multiple exon in-frame deletions PVS1 can be assigned to deletions that include single in-frame exons in the PVS1 category listed in the splice site section above OR if the exon contains a functionally important domain as specified in PM1.\n* Given the extensive data available for TCF4, classifications for single or multi-exon in-frame deletions are assigned as PVS1 or PVS1\\_strong. Refer to PVS1 flow chart for additional guidance.",
"label": "PVS1",
"ns": "032",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 can be applied for:\n * Null variants up to p.E643, which corresponds to the distal most de novo truncating variant in an affected patient reported to date.[4](#PMID_29695756)\n * Any frameshift variant that results in a read-through of the stop codon\n * Canonical splice site variants predicted to result in an out-of-frame product\n * Canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 15)\n * In-frame deletions including the PM1 functional domains (p.E564\\_V617 (bHLH))\n * Deletions and duplications ≥1 exon in size (that are completely contained within the _TCF4_ gene) where the reading frame is disrupted and NMD is predicted to occur\n * Exon skipping or single exon deletion of exon 19 predicted to disrupt the reading frame but is not predicted to undergo NMD\n * A full gene deletion",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Strong is applicable for single to multi exon deletions that preserve the reading frame and the variant removes \\<10% of the protein.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Moderate is applicable for any truncating variant distal of p.E643 and for single exon deletions that involve just non-coding exon 20.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Supporting is applicable for initiation codon variants in _TCF4._",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176861",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572176861",
"modified": "2025-07-30T16:35:55.384Z",
"modifier": "gmillikin",
"rev": "_kDuuu_m---"
},
{
"entContent": {
"_uniqueProp": "032_BP3_nuclear_TCF4",
"additionalComments": "Not applicable for TCF4.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "032",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function.\n\n* BP3 is applicable if there are in-frame deletions/duplications in a repetitive region where other in-frame deletions/duplications have been observed with an overall frequency commensurate with the BA1 threshold for this gene.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176857",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572176857",
"modified": "2025-07-30T16:35:55.384Z",
"modifier": "gmillikin",
"rev": "_kDuut8m--B"
},
{
"entContent": {
"_uniqueProp": "032_PS1_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "032",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176855",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572176855",
"modified": "2025-07-30T16:35:55.384Z",
"modifier": "gmillikin",
"rev": "_kDuut5m---"
},
{
"entContent": {
"_uniqueProp": "032_BS1_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoffs are based on MECP2 expected disease allele frequency divided by 10-fold. MECP2 is the most prevalent of the genes covered in the Rett/Angelman-like working group and was chosen as most conservative number.",
"label": "BS1",
"ns": "032",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease.\n\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0000083 (0.00083%) and \\<0.000083 (0.0083%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176850",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572176850",
"modified": "2025-07-30T16:35:55.384Z",
"modifier": "gmillikin",
"rev": "_kDuuuAS---"
},
{
"entContent": {
"_uniqueProp": "032_PM5_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "032",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176842",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572176842",
"modified": "2025-07-30T16:35:55.384Z",
"modifier": "gmillikin",
"rev": "_kDuut6m---"
},
{
"entContent": {
"_uniqueProp": "032_PP4_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
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],
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"auths": [
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"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* 1 occurrence of PM6",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178233",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178233",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjE6---"
},
{
"entContent": {
"_uniqueProp": "033_BA1_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoffs are based on MECP2 expected disease allele frequency (1 in 10,000 for the disease prevalence / (1.5 alleles \\[assumes 50/50 male/female ratio\\] \\* 0.8 for 80% penetrance)). MECP2 is the most prevalent of the genes covered in the Rett/Angelman-like working group and was chosen as most conservative number.",
"label": "BA1",
"ns": "033",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.000083 (0.0083%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178227",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178227",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjJK---"
},
{
"entContent": {
"_uniqueProp": "033_PP3_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "033",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.\n\n* For missense variants use REVEL with a score ≥ 0.664.\n* For splice site variants use SpliceAI with a score ≥ 0.2.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178224",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178224",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjJ2---"
},
{
"entContent": {
"_uniqueProp": "033_BS2_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "* Should be applied in cases where the healthy adult is devoid of neurodevelopmental phenotypes.\n* Best to use with internal curated data that includes clinical information or published patients that have been phenotyped.",
"label": "BS2",
"ns": "033",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 2 unaffected (related or unrelated) hemizygotes",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 1 unaffected (related or unrelated) hemizygote",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178219",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178219",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjLq---"
},
{
"entContent": {
"_uniqueProp": "033_BP5_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "* For example if a variant in _SLC9A6_ is identified in a patient with lissencephaly in whom a pathogenic variant is identified in the _PAFAH1B1_ gene.\n* The variant should be in the hemizygous state in the case with an alternate molecular basis for disease for this criteria to be used.\n* Do not apply if variant is de novo.",
"label": "BP5",
"ns": "033",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Variant found in a case with an alternate molecular basis for disease.\n\n* 2 cases with alternate molecular basis for disease",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\n\n* 1 case with alternate molecular basis for disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178241",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178241",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjKa---"
},
{
"entContent": {
"_uniqueProp": "033_BS4_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"label": "BS4",
"ns": "033",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member, when seen in two or more families",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178232",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178232",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjKy---"
},
{
"entContent": {
"_uniqueProp": "033_BP1_nuclear_SLC9A6",
"additionalComments": "Not applicable for SLC9A6.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "033",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178231",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178231",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjIu---"
},
{
"entContent": {
"_uniqueProp": "033_PM5_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "033",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178221",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178221",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjMu---"
},
{
"entContent": {
"_uniqueProp": "033_BS3_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "033",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for other functional studies.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178220",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178220",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjG----"
},
{
"entContent": {
"_uniqueProp": "033_PS3_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "033",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an out-of-frame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178237",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178237",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjMK---"
},
{
"entContent": {
"_uniqueProp": "033_PM3_nuclear_SLC9A6",
"additionalComments": "Not applicable for SLC9A6.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "033",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178228",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178228",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjI6---"
},
{
"entContent": {
"_uniqueProp": "033_PS2_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable to all genes in affected individuals identified as mosaic for the variant (as the presence of a variant in the mosaic state is confirmatory of the variant being de novo). \n\nBecause of the very high de novo rate of pathogenic variants in _SLC9A6_, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene.",
"label": "PS2",
"ns": "033",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* 1 occurrence of PS2",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178226",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178226",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjJe---"
},
{
"entContent": {
"_uniqueProp": "033_PS4_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "* Detailed phenotype not needed. Need to confirm patient is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.\n* Patient can be published OR an internal case OR observed at an outside lab (i.e. via ClinVar) OR described in the reputable databases. However independent case has to be confirmed to be a different patient than yours (compare gender/age).\n* Do not use this criterion for variants where BS1 is applied or where PM2 does not apply.",
"label": "PS4",
"ns": "033",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178225",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178225",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjL----"
},
{
"entContent": {
"_uniqueProp": "033_PP2_nuclear_SLC9A6",
"additionalComments": "Not applicable for SLC9A6.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "033",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178223",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178223",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjLW---"
},
{
"entContent": {
"_uniqueProp": "033_PM1_nuclear_SLC9A6",
"additionalComments": "Not applicable for SLC9A6.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "033",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178222",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178222",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjFm---"
},
{
"entContent": {
"_uniqueProp": "033_PP4_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "033",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178218",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178218",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjNC---"
},
{
"entContent": {
"_uniqueProp": "033_PVS1_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "Refer to PVS1 flow chart for additional guidance.\n\nFor intragenic deletions/duplications that are predicted to result in a product that preserves reading frame:\n\n* For single exon in-frame deletions assign the same strength (PVS1, PVS1\\_strong, or PVS1\\_moderate) as for splice site variants that preserve reading frame indicated above.\n* For multiple exon in-frame deletions, PVS1 can be assigned to deletions that include single in-frame exons in the PVS1 category above (exon 3 or exon 10).",
"label": "PVS1",
"ns": "033",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable for:\n * Null variants up to p.A563\n * Canonical splice site variants predicted to result in an out-of-frame product\n * Canonical splice site variants predicted to preserve the reading frame (exon 10)\n * Multiple in-frame exon deletions that include exon 10.\n * Single exon 3 or 10 in-frame deletion that preserves the reading frame (Note: This gene has no PM1 functional domains)\n * Deletions and duplications ≥1 exon in size (that are completely contained within the _SLC9A6_ gene) where the reading frame is disrupted and NMD is predicted to occur\n * A full gene deletion",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Strong is applicable for: \n * Any truncating variant from p.C564 to p.T601\n * Canonical splice site variants that flank exon 3 (in-frame exon).[3](#PMID_27256868),[2](#PMID_19377476),[4](#PMID_18342287)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Moderate is applicable for\n * Any truncating variant between p.Y602 to p.A669\n * Any frameshift variant that results in a read-through of the stop codon",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Supporting is applicable for initiation codon variants in _SLC9A6_",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178240",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178240",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjGe---"
},
{
"entContent": {
"_uniqueProp": "033_BP4_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "033",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc).\n\n* For missense variants use REVEL with a score ≤ 0.290.\n* For splice site variants use SpliceAI with a score ≤ 0.1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178238",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178238",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjIS---"
},
{
"entContent": {
"_uniqueProp": "033_BP3_nuclear_SLC9A6",
"additionalComments": "Not applicable for SLC9A6.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "033",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
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"text": "",
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},
{
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"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0074",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function\n\n* BP3 is applicable if there are in-frame deletions/duplications in a repetitive region where other in-frame deletions/duplications have been observed with an overall frequency commensurate with the BA1 threshold for this gene.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
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"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjGy---"
},
{
"entContent": {
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"additionalComments": "",
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"gene": [
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],
"geneType": "nuclear",
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"sepioID": "SEPIO-CG:99023",
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"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0240",
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"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
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"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
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"text": "",
"type": "EvidenceLineStrength"
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"id": "0036",
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"strength": "Supporting",
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"text": "",
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"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjHK---"
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{
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"instructionsToUse": "The frequency cutoffs are based on MECP2 expected disease allele frequency divided by 10 fold. MECP2 is the most prevalent of the genes covered in the Rett/Angelman-like working group and was chosen as most conservative number.",
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"completed": true
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"text": "",
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{
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"id": "0222",
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"strength": "Very Strong",
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"text": "",
"type": "EvidenceLineStrength"
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{
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],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
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"type": "EvidenceLineStrength"
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"id": "0223",
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"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
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},
"entType": "CriteriaCode",
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"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
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{
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"text": "",
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{
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"strength": "Very Strong",
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"text": "",
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{
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"id": "0013",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0011",
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"status": "not approved",
"strength": "Moderate",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0030",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178217",
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"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjM----"
},
{
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "For silent variants BP4 and BP7 can be added.",
"label": "BP7",
"ns": "033",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
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},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"id": "0065",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0079",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score \\<1 and/or PhyloP score \\<0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.\n* For splice site variants use SpliceAI with a score ≤ 0.1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178244",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178244",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjH2---"
},
{
"entContent": {
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"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
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"evidenceCategory": "Other Database",
"gene": [
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"instructionsToUse": "",
"label": "PP5",
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"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
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"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
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],
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"strengthDescriptor": [
{
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"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
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{
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"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178243",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178243",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjKK---"
},
{
"entContent": {
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"id": "0236",
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"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0042",
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"status": "not approved",
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"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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],
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"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n\n* ≥5 informative meiosis",
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"id": "0040",
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],
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"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 3-4 informative meiosis",
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},
{
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"id": "0060",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 2 informative meiosis",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178239",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178239",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjEa---"
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{
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
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"evidenceCategory": "Computational And Predictive Data",
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"geneType": "nuclear",
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"ns": "033",
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"sepioID": "SEPIO-CG:99030",
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"status": {
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"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"id": "0035",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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"id": "009",
"instructionsToUse": "",
"specificationType": [
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"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
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{
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"id": "0059",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n\n* Smaller in-frame events (\\< 3 amino acid residues).",
"type": "EvidenceLineStrength"
}
]
},
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572178230",
"modified": "2025-07-30T16:36:49.864Z",
"modifier": "gmillikin",
"rev": "_kDuvjHi---"
}
],
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{
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},
{
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"rev": "_lbVbPsq---"
},
{
"entContent": {
"approvedOn": "2025-07-30T16:37:32.677Z",
"description": "Updated BA1 and BS1 population frequency cutoffs.\n \n \n ",
"hideFlag": false,
"legacyFullySuperseded": true,
"namespace": "GN034",
"releaseNotes": "Modification to the population frequency cutoffs for BA1 and BS1.",
"releasedUnderRevision": true,
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:25.125Z"
},
"name": "Pilot Rules In Prep"
},
{
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{
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{
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"event": {
"name": "pilot-rules-approved",
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},
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},
{
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"event": {
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"timeStamp": "2025-07-30T16:37:32.677Z"
},
"name": "Released"
},
{
"current": false,
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"timeStamp": "2025-11-11T20:32:34.600Z"
},
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},
{
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}
],
"tagNameSpaces": [
"034"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDKL5 Version 5.0.0",
"type": "Richards et.al., 2015 - Combining rules",
"version": "5.0.0",
"versioned": true
},
"entId": "GN034",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "034_PVS1_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "Refer to PVS1 flow chart for additional guidance.\n\nAdditional notes:\n\n* Do not use PVS1 for truncating variants in _CDKL5_ C-terminus (exons 19-21, or after p.P904) **when using the historically used transcript (NM\\_003159.2).**\n* _CDKL5_ has non-coding exons. There is evidence that loss of just non-coding _CDKL5_ exon 1 is pathogenic given previous de novo finding in patients affected with CDKL5-disease (GeneDx internal data), therefore, for losses involving just _CDKL5_ exon 1, PVS1 can be applied.\n\nFor intragenic deletions/duplications that are predicted to result in a product that preserves reading frame:\n\n* For single exon in-frame deletions assign the same strength (PVS1, PVS1\\_strong, or PVS1\\_moderate) as for splice site variants that preserve reading frame indicated above\n* For multiple exon in-frame deletions, PVS1 can be assigned to deletions that include single in-frame exons in the PVS1 category (listed above) **OR** if the exon contains a functionally important domain as specified in PM1\n* Given the extensive data available for _CDKL5_, classifications for single or multi-exon in-frame deletions are assigned as PVS1 or PVS1\\_strong. Exceptions are _CDKL5_ exon 17 (as described above) due to a limited number of pathogenic variants reported to date.",
"label": "PVS1",
"ns": "034",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable for:\n * Null variants up to p.R948 **when using the major brain isoform which has an alternative C-terminus (NM\\_001323289.2)**\n * Frameshift variants that result in a read-through of the stop codon\n * Canonical splice site variants predicted to result in an out-of-frame product\n * Canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exons 7, 10, 13) and for the non-coding CDKL5 exon (exon 1) **(NM\\_001323289.2).**\n * In-frame deletions including the PM1 functional domains (p.V19\\_K43 ATP binding domain or p.T169\\_Y171 TEY phosphorylation domain)\n * Deletions and duplications ≥1 exon in size (that are completely contained within the CDKL5 gene) where the reading frame is disrupted and NMD is predicted to occur\n * A full gene deletion",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Strong is applicable for:\n * Cannonical splice site variants that flank exon 18 **(the final exon of NM\\_001323289.2)**\n * Single to multi exon deletions that disrupt the reading frame such that exon 18 **(the final exon of NM\\_001323289.2)** is truncated/altered\n * Duplications ≥1 exon in size (that are completely contained within the CDKL5 gene) where the reading frame is presumed to be disrupted and NMD is predicted to occur",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Moderate is applicable for:\n * Any truncating variant distal of p.R948 (**when using the major brain isoform, NM\\_001323289.2**)\n * Canonical splice site variants that flank exon 17 (in-frame exon) (**NM\\_001323289.2**)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Supporting is applicable for initiation codon variants in _CDKL5._",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179062",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179062",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNhW---"
},
{
"entContent": {
"_uniqueProp": "034_PS3_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "034",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an out-offrame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See included table for acceptable functional studies.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179059",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179059",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNbq---"
},
{
"entContent": {
"_uniqueProp": "034_PM6_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "Because of the very high de novo rate of pathogenic variants in _CDKL5_, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene.",
"label": "PM6",
"ns": "034",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* 1 occurrence of PM6.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179055",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179055",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNcW---"
},
{
"entContent": {
"_uniqueProp": "034_BP1_nuclear_CDKL5",
"additionalComments": "Not applicable for CDKL5.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "034",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179053",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179053",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNju---"
},
{
"entContent": {
"_uniqueProp": "034_PM4_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "034",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n\n* Do not use for in-frame deletions/insertions in CDKL5 C-terminus (exons 19-21, or after p.P904) **(when using the NM\\_003159.2 transcript)**.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179052",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179052",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNhu---"
},
{
"entContent": {
"_uniqueProp": "034_BS1_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoffs are based on MECP2 expected disease allele frequency divided by 10-fold. MECP2 is the most prevalent of the genes covered in the Rett/Angelman-like working group and was chosen as most conservative number.",
"label": "BS1",
"ns": "034",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease (0.025%).\n\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0000083 (0.00083%) and \\<0.000083 (0.0083%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179051",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179051",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNee---"
},
{
"entContent": {
"_uniqueProp": "034_PS2_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable to all genes in affected individuals identified as mosaic for the variant (as the presence of a variant in the mosaic state is confirmatory of the variant being de novo). Because of the very high de novo rate of pathogenic variants in _CDKL5_, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene.",
"label": "PS2",
"ns": "034",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* 1 occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179048",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179048",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNe2---"
},
{
"entContent": {
"_uniqueProp": "034_PS4_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "* Detailed phenotype not needed. Need to confirm patient is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.\n* Patient can be published OR an internal case OR observed at an outside lab (i.e. via ClinVar) OR described in the reputable databases (RettBASE). However independent case has to be confirmed to be a different patient than yours (compare gender/age).\n* Do not use this criterion for variants where BS1 is applied or where PM2 does not apply.",
"label": "PS4",
"ns": "034",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179047",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179047",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNie---"
},
{
"entContent": {
"_uniqueProp": "034_PM5_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "034",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* Applicable to all genes as written.\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179043",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179043",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNf6---"
},
{
"entContent": {
"_uniqueProp": "034_BP6_nuclear_CDKL5",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "034",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179064",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179064",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNdi---"
},
{
"entContent": {
"_uniqueProp": "034_BP4_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "034",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score ≤ 0.290.\n* For splice site variants use SpliceAI with a score ≤ 0.1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179060",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179060",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNdy--_"
},
{
"entContent": {
"_uniqueProp": "034_BP2_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "Knock out of _CDKL5_ results in disease but viable phenotype.[5](#PMID_23236174)",
"label": "BP2",
"ns": "034",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n\n* BP2 is not applicable for _in trans_ state.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179057",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179057",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNeG---"
},
{
"entContent": {
"_uniqueProp": "034_BS3_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "034",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for other functional studies.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179042",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179042",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNgO---"
},
{
"entContent": {
"_uniqueProp": "034_PM2_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PM2",
"ns": "034",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179039",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179039",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNga---"
},
{
"entContent": {
"_uniqueProp": "034_BP7_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "For silent variants BP4 and BP7 can be added.",
"label": "BP7",
"ns": "034",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score \\<1 and/or PhyloP score \\<0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.\n* For splice site variants use SpliceAI with a score ≤ 0.1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179066",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179066",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNfm---"
},
{
"entContent": {
"_uniqueProp": "034_PP5_nuclear_CDKL5",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "034",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179065",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179065",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNgy---"
},
{
"entContent": {
"_uniqueProp": "034_BP5_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "* For example if a variant in _CKDL5_ is identified in a patient with lissencephaly in whom a pathogenic variant is identified in the _PAFAH1B1_ gene.\n* Do not apply if variant is de novo.",
"label": "BP5",
"ns": "034",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Variant found in a case with an alternate molecular basis for disease.\n\n* 2 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\n\n* 1 case with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179063",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179063",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNhK---"
},
{
"entContent": {
"_uniqueProp": "034_PS1_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "034",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179056",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179056",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNjS---"
},
{
"entContent": {
"_uniqueProp": "034_BS4_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"label": "BS4",
"ns": "034",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member, when seen in two or more families",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179054",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179054",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNcu---"
},
{
"entContent": {
"_uniqueProp": "034_BA1_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoffs are based on MECP2 expected disease allele frequency (1 in 10,000 for the disease prevalence / (1.5 alleles \\[assumes 50/50 male/female ratio\\] \\* 0.8 for 80% penetrance)). MECP2 is the most prevalent of the genes covered in the Rett/Angelman-like working group and was chosen as most conservative number.",
"label": "BA1",
"ns": "034",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency above 0.05%.\n\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.000083 (0.0083%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179049",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179049",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNiO---"
},
{
"entContent": {
"_uniqueProp": "034_PP2_nuclear_CDKL5",
"additionalComments": "Not applicable for CDKL5.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "034",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179045",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179045",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNfO---"
},
{
"entContent": {
"_uniqueProp": "034_PP1_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"label": "PP1",
"ns": "034",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n\n* ≥5 informative meiosis",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 3-4 informative meiosis",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 2 informative meiosis",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179061",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179061",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNjG---"
},
{
"entContent": {
"_uniqueProp": "034_BP3_nuclear_CDKL5",
"additionalComments": "Not applicable for CDKL5.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "034",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function. \n\n* BP3 is applicable if there are in-frame deletions/duplications in a repetitive region where other in-frame deletions/duplications have been observed with an overall frequency commensurate with the BA1 threshold for this gene.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179058",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179058",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNcC---"
},
{
"entContent": {
"_uniqueProp": "034_PM3_nuclear_CDKL5",
"additionalComments": "Not applicable for CDKL5.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "034",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179050",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179050",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNiC---"
},
{
"entContent": {
"_uniqueProp": "034_PP3_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "034",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\n\n* For missense variants use REVEL with a score ≥ 0.644.\n* For splice site variants use SpliceAI with a score ≥ 0.2.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179046",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179046",
"modified": "2025-07-30T16:37:33.239Z",
"modifier": "gmillikin",
"rev": "_kDuwNd----"
},
{
"entContent": {
"_uniqueProp": "034_PM1_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "034",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
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"source": "Am J Hum Genet",
"title": "Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3/BP4 criteria.",
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"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n\n* Do not use PM4 for in-frame deletions/insertions in the Histidine-rich region (p.37-p.57), Proline- and Glutamine-rich region (p.58-p.86) and Proline-rich region (p.105-p.112).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179846",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179846",
"modified": "2025-07-30T16:38:21.690Z",
"modifier": "gmillikin",
"rev": "_kDuw8xK---"
},
{
"entContent": {
"_uniqueProp": "035_PM3_nuclear_FOXG1",
"additionalComments": "Not applicable for FOXG1.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "035",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179844",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179844",
"modified": "2025-07-30T16:38:21.690Z",
"modifier": "gmillikin",
"rev": "_kDuw822---"
},
{
"entContent": {
"_uniqueProp": "035_BA1_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoffs are based on MECP2 expected disease allele frequency (1 in 10,000 for the disease prevalence / (1.5 alleles \\[assumes 50/50 male/female ratio\\] \\* 0.8 for 80% penetrance)). MECP2 is the most prevalent of the genes covered in the Rett/Angelman-like working group and was chosen as most conservative number.",
"label": "BA1",
"ns": "035",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.000083 (0.0083%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179843",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179843",
"modified": "2025-07-30T16:38:21.690Z",
"modifier": "gmillikin",
"rev": "_kDuw83C---"
},
{
"entContent": {
"_uniqueProp": "035_PP2_nuclear_FOXG1",
"additionalComments": "Not applicable for FOXG1.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "035",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179839",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179839",
"modified": "2025-07-30T16:38:21.690Z",
"modifier": "gmillikin",
"rev": "_kDuw8yC---"
},
{
"entContent": {
"_uniqueProp": "035_PM1_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PM1",
"ns": "035",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n\n* Forkhead: aa 181-275[3](#PMID_18571142),[4](#PMID_28661489)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179838",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179838",
"modified": "2025-07-30T16:38:21.690Z",
"modifier": "gmillikin",
"rev": "_kDuw80----"
},
{
"entContent": {
"_uniqueProp": "035_BS3_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "035",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for other functional studies.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179836",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179836",
"modified": "2025-07-30T16:38:21.690Z",
"modifier": "gmillikin",
"rev": "_kDuw84G---"
},
{
"entContent": {
"_uniqueProp": "035_PM2_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "If PVS1 is also applicable, variant can be classified as likely pathogenic",
"label": "PM2",
"ns": "035",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179833",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179833",
"modified": "2025-07-30T16:38:21.690Z",
"modifier": "gmillikin",
"rev": "_kDuw80e---"
},
{
"entContent": {
"_uniqueProp": "035_BP5_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "* For example if a variant in _FOXG1_ is identified in a patient with lissencephaly in whom a pathogenic variant is identified in the _PAFAH1B1_ gene.\n* Do not apply if variant is de novo.",
"label": "BP5",
"ns": "035",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Variant found in a case with an alternate molecular basis for disease.\n\n* 2 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\n\n* 1 case with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179857",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179857",
"modified": "2025-07-30T16:38:21.690Z",
"modifier": "gmillikin",
"rev": "_kDuw8z----"
},
{
"entContent": {
"_uniqueProp": "035_BP3_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "035",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function\n\n* Inframe expansions or deletions in _FOXG1_ repetitive regions: poly His (p.His47-p.His57), poly Gln (p.Gln70-p.Gln73) and poly Pro (p.Pro58-p.Pro61; p.Pro65-p.Pro69; p.Pro74-p.Pro80)\n* BP3 is applicable if there are in-frame deletions/duplications in a repetitive region where other in-frame deletions/duplications have been observed with an overall frequency commensurate with the BA1 threshold for this gene.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179852",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179852",
"modified": "2025-07-30T16:38:21.690Z",
"modifier": "gmillikin",
"rev": "_kDuw83W---"
},
{
"entContent": {
"_uniqueProp": "035_PS1_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "035",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179850",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179850",
"modified": "2025-07-30T16:38:21.690Z",
"modifier": "gmillikin",
"rev": "_kDuw82C---"
},
{
"entContent": {
"_uniqueProp": "035_PM6_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PM6",
"ns": "035",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* 1 occurrence of PM6.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179849",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179849",
"modified": "2025-07-30T16:38:21.690Z",
"modifier": "gmillikin",
"rev": "_kDuw82e---"
},
{
"entContent": {
"_uniqueProp": "035_PS2_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable to all genes in affected individuals identified as mosaic for the variant (as the presence of a variant in the mosaic state is confirmatory of the variant being de novo). \n\nBecause of the very high de novo rate of pathogenic variants in FOXG1, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene.",
"label": "PS2",
"ns": "035",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* 1 occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179842",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179842",
"modified": "2025-07-30T16:38:21.690Z",
"modifier": "gmillikin",
"rev": "_kDuw8xa---"
},
{
"entContent": {
"_uniqueProp": "035_PS4_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "* Detailed phenotype not needed. Need to confirm patient is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.\n* Patient can be published OR an internal case OR observed at an outside lab (i.e. via ClinVar) OR described in the reputable databases (RettBASE). However independent case has to be confirmed to be a different patient than yours (compare gender/age).\n* Do not use this criterion for variants where BS1 is applied or where PM2 does not apply.",
"label": "PS4",
"ns": "035",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179841",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179841",
"modified": "2025-07-30T16:38:21.690Z",
"modifier": "gmillikin",
"rev": "_kDuw8xq---"
},
{
"entContent": {
"_uniqueProp": "035_PP3_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "035",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.\n\n* For missense variants use REVEL with a score ≥ 0.644.\n* For splice site variants use SpliceAI with a score ≥ 0.2.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179840",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179840",
"modified": "2025-07-30T16:38:21.690Z",
"modifier": "gmillikin",
"rev": "_kDuw8zu---"
},
{
"entContent": {
"_uniqueProp": "035_BP4_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "035",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score ≤ 0.290.\n* For splice site variants use SpliceAI with a score ≤ 0.1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179854",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179854",
"modified": "2025-07-30T16:38:21.690Z",
"modifier": "gmillikin",
"rev": "_kDuw806--_"
},
{
"entContent": {
"_uniqueProp": "035_BS4_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"label": "BS4",
"ns": "035",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member, when seen in two or more families",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179848",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179848",
"modified": "2025-07-30T16:38:21.690Z",
"modifier": "gmillikin",
"rev": "_kDuw8wu---"
},
{
"entContent": {
"_uniqueProp": "035_BS1_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoffs are based on MECP2 expected disease allele frequency divided by 10-fold. MECP2 is the most prevalent of the genes covered in the Rett/Angelman-like working group and was chosen as most conservative number.",
"label": "BS1",
"ns": "035",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0000083 (0.00083%) and \\<0.000083 (0.0083%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179845",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179845",
"modified": "2025-07-30T16:38:21.690Z",
"modifier": "gmillikin",
"rev": "_kDuw8ze---"
},
{
"entContent": {
"_uniqueProp": "035_PVS1_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "Refer to PVS1 flow chart for additional guidance.",
"label": "PVS1",
"ns": "035",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable for\n * Null variants up to p.S468 [1](#PMID_30525188)\n * A full gene deletion",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Strong is applicable for any truncating variant from p.G469 to p.Q480 [2](#PMID_29655203).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Moderate is applicable for any truncating variant distal of p.Q480.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Supporting is applicable for initiation codon variants in _FOXG1._",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179856",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572179856",
"modified": "2025-07-30T16:38:21.690Z",
"modifier": "gmillikin",
"rev": "_kDuw8vu---"
},
{
"entContent": {
"_uniqueProp": "035_PS3_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PS3",
"ns": "035",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
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],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
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"type": "EvidenceLineStrength"
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"type": "EvidenceLineStrength"
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"instructionsToUse": "",
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],
"status": "approved",
"strength": "Supporting",
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"type": "EvidenceLineStrength"
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],
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}
},
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"text": "",
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"type": "EvidenceLineStrength"
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{
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"text": "",
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"text": "",
"type": "EvidenceLineStrength"
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"text": "",
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"text": "",
"type": "EvidenceLineStrength"
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{
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{
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"specificationType": [
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],
"status": "approved",
"strength": "Strong",
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"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
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{
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{
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"applicability": "Applicable",
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"evidenceCategory": "Other Data",
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],
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"strength": "Supporting",
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"ldhId": "1572179834",
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],
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},
{
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"type": "CLASS"
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],
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],
"orphanet": 167854,
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"ldhIri": "https://cspec.genome.network/cspec/Gene/id/135641939",
"modified": "2021-10-14T11:36:27.781Z",
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}
],
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{
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}
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{
"auths": [
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"van Ool JS",
"et al."
],
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"id": "30525188",
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"source": "Epilepsia",
"title": "Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability.",
"vol": "60",
"year": "2019"
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{
"auths": [
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"et al."
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"source": "Epilepsia",
"title": "Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders.",
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{
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"title": "FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants.",
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{
"auths": [
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"Li SC",
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"id": "14704420",
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"title": "Foxg1 suppresses early cortical cell fate.",
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"year": "2004"
},
{
"auths": [
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"Byrne AB",
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"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n\n* ≥5 informative meiosis",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 3-4 informative meiosis",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 2 informative meiosis",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180612",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180612",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxlkq---"
},
{
"entContent": {
"_uniqueProp": "036_BP1_nuclear_MECP2",
"additionalComments": "Not applicable for MECP2.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "036",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180604",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180604",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxlh6---"
},
{
"entContent": {
"_uniqueProp": "036_BA1_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoffs are based on MECP2 expected disease allele frequency (1 in 10,000 for the disease prevalence / (1.5 alleles \\[assumes 50/50 male/female ratio\\] \\* 0.8 for 80% penetrance)). MECP2 is the most prevalent of the genes covered in the Rett/Angelman-like working group and was chosen as most conservative number.",
"label": "BA1",
"ns": "036",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.000083 (0.0083%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180600",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180600",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxlqG---"
},
{
"entContent": {
"_uniqueProp": "036_PS2_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable to all genes in affected individuals identified as mosaic for the variant (as the presence of a variant in the mosaic state is confirmatory of the variant being de novo). Because of the very high de novo rate of pathogenic variants in MECP2, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene.",
"label": "PS2",
"ns": "036",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* 1 occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180599",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180599",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxlo----"
},
{
"entContent": {
"_uniqueProp": "036_PP3_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "036",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\n\n* For missense variants use REVEL with a score ≥ 0.644.\n* For splice site variants use SpliceAI with a score ≥ 0.2.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180597",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180597",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxlli---"
},
{
"entContent": {
"_uniqueProp": "036_BS3_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "036",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for other functional studies.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180593",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180593",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxlou---"
},
{
"entContent": {
"_uniqueProp": "036_PM2_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "036",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180590",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180590",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxliu---"
},
{
"entContent": {
"_uniqueProp": "036_PVS1_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "Initiation codon variants are not applicable due to the MECP2E1 alternative isoform that excludes exon 1 with an alterante start codon.\n\nFor intragenic deletions/duplications that are predicted to result in a product that preserves reading frame:\n\n* For single exon in-frame deletions, assign the same strength (PVS1 or PVS1\\_moderate) as for splice site variants that preserve reading frame indicated above.\n* For multiple exon in-frame deletions, PVS1 can be assigned to deletions that include single in-frame exons in the PVS1 category listed in the splice site section above OR if the exon contains a functionally important domain as specified in PM1.\n* Given the extensive data available for MECP2, classifications for single or multi-exon in-frame deletions are assigned as PVS1 or PVS1\\_strong. Refer to PVS1 flow chart for additional guidance.",
"label": "PVS1",
"ns": "036",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable for:\n * Null variants up to p.E472\n * Any frameshift variant that results in a read-through of the stop codon\n * Canonical splice site variants predicted to result in an out-of-frame product\n * Canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 3)\n * A full gene deletion\n* PVS1 is **not** applicable for initiation codons.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* PVS1\\_Strong is applicable for:\n * Canonical splice site variants or deletions (single exon to full gene deletion) resulting in exon skipping or use of a cryptic splice site that disrupts reading frame and is **NOT** predicted to undergo NMD, but the truncated/altered region is critical to protein function (exon 4).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* PVS1\\_Moderate is applicable for any truncating variant distal of p.E472.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180613",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180613",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxlj----"
},
{
"entContent": {
"_uniqueProp": "036_BP4_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "036",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\n\n* For missense variants use REVEL with a score ≤ 0.290.\n* For splice site variants use SpliceAI with a score ≤ 0.1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180611",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180611",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxljS---"
},
{
"entContent": {
"_uniqueProp": "036_BP2_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "Knock out of MECP2 results in embryonic lethality/drastic phenotype.[1](#PMID_11242117)",
"label": "BP2",
"ns": "036",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180608",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180608",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxljm---"
},
{
"entContent": {
"_uniqueProp": "036_BS1_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoffs are based on MECP2 expected disease allele frequency divided by 10-fold. MECP2 is the most prevalent of the genes covered in the Rett/Angelman-like working group and was chosen as most conservative number.",
"label": "BS1",
"ns": "036",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0000083 (0.00083%) and \\<0.000083 (0.0083%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180602",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180602",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxlnm---"
},
{
"entContent": {
"_uniqueProp": "036_PM3_nuclear_MECP2",
"additionalComments": "Not applicable for MECP2.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "036",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180601",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180601",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxliK---"
},
{
"entContent": {
"_uniqueProp": "036_PS4_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "* Detailed phenotype not needed. Need to confirm patient is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.\n* Patient can be published OR an internal case OR observed at an outside lab (i.e. via ClinVar) OR described in the reputable databases (RettBASE). However, independent case has to be confirmed to be a different patient than yours (compare gender/age).\n* Do not use this criterion for variants where BS1 is applied or where PM2 does not apply.",
"label": "PS4",
"ns": "036",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180598",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180598",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxlj2---"
},
{
"entContent": {
"_uniqueProp": "036_PS1_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "036",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180607",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180607",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxlnW---"
},
{
"entContent": {
"_uniqueProp": "036_PM4_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "036",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Protein length changes due to stop-loss variants.\n\n* PM4\\_Strong is applicable to stop-loss variants in _MECP2_, as several stop loss variants in this gene has been described in affected individuals.[2](#PMID_11469283)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n\n* Do not use PM4 for in-frame deletions/insertions in the Proline-rich region of gene (p.381-p.405)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180603",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180603",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxlpu---"
},
{
"entContent": {
"_uniqueProp": "036_PP5_nuclear_MECP2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "036",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180616",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180616",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxlmW---"
},
{
"entContent": {
"_uniqueProp": "036_BP3_nuclear_MECP2",
"additionalComments": "BP3 is applicable if there are repetitive regions in population databases (eg. gnomAD) that have in-frame deletions/duplications that are observed at frequencies commensurate with the BA1 threshold for this gene. \n",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP3",
"ns": "036",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function. \n\n* BP3 is applicable if there are in-frame deletions/duplications in a repetitive region where other in-frame deletions/duplications have been observed with an overall frequency commensurate with the BA1 threshold for this gene.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180609",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180609",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxlpe---"
},
{
"entContent": {
"_uniqueProp": "036_PM6_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "Because of the very high de novo rate of pathogenic variants in MECP2, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene.",
"label": "PM6",
"ns": "036",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* ≥4 independent occurrences of PM6. \n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* 1 occurrence of PM6.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180606",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180606",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxll----"
},
{
"entContent": {
"_uniqueProp": "036_BS4_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"label": "BS4",
"ns": "036",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"status": {
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"completed": true
}
},
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"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
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{
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{
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],
"status": "approved",
"strength": "Strong",
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},
{
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"text": "",
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{
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"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
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"type": "EvidenceLineStrength"
}
]
},
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"modifier": "gmillikin",
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},
{
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"applicability": "Not applicable",
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"evidenceCategory": "Functional Data",
"gene": [
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],
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}
},
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0049",
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"status": "not approved",
"strength": "Very Strong",
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0034",
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"modifier": "gmillikin",
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{
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}
},
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0015",
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"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "006",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n\n* Methyl-DNA binding (MBD): aa 90-162\n* Transcirptional repression domain (TRD): aa 302-306",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180595",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180595",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxloW---"
},
{
"entContent": {
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"additionalComments": "",
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
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}
},
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"id": "0234",
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"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0047",
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"text": "",
"type": "EvidenceLineStrength"
},
{
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"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
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"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180594",
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"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxll2---"
},
{
"entContent": {
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"additionalComments": "",
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"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "* Should be applied in cases where the healthy adult is devoid of neurodevelopmental phenotypes.\n* Best to use with internal curated data that includes clinical information or published patients that have been phenotyped.",
"label": "BS2",
"ns": "036",
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"sepioID": "SEPIO-CG:99040",
"specificationType": [
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],
"status": {
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"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0091",
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 2 unaffected (related or unrelated) heterozygotes or hemizygotes.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 1 unaffected (related or unrelated) heterozygote or hemizygote",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180592",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180592",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxlkK---"
},
{
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PP4",
"ns": "036",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
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],
"status": {
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"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0239",
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
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"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxlp----"
},
{
"entContent": {
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"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "",
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{
"id": "29543229",
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"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
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"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180615",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180615",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxlmm---"
},
{
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PS3",
"ns": "036",
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"sepioID": "SEPIO-CG:99025",
"specificationType": [
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],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
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"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an out-offrame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
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"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See included table for approved functional studies.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1572180610",
"modified": "2025-07-30T16:39:03.453Z",
"modifier": "gmillikin",
"rev": "_kDuxlpO---"
}
],
"Disease": [
{
"entContent": {
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"lbl": "Rett syndrome",
"meta": {
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"val": "https://github.com/monarch-initiative/mondo/issues/3680"
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{
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{
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},
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2025-07-30T16:39:39.675Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2026-04-03T20:09:50.208Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"037"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for UBE3A Version 6.0.0",
"type": "Richards et.al., 2015 - Combining rules",
"version": "6.0.0",
"versioned": true
},
"entId": "GN037",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "037_PP5_nuclear_UBE3A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "037",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266908",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266908",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJgu---"
},
{
"entContent": {
"_uniqueProp": "037_PVS1_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "Refer to PVS1 flow chart for additional guidance.\n\nFor intragenic deletions/duplications that are predicted to result in a product that preserves reading frame:\n\n* For single exon in-frame deletions assign the same strength (PVS1, PVS1\\_strong, or PVS1\\_moderate) as for splice site variants that preserve reading frame indicated above.\n* For multiple exon in-frame deletions PVS1 can be assigned to deletions that include single in-frame exons in the PVS1 category (listed above) OR if the exon contains a functionally important domain as specified in PM1.\n* Given the extensive data available for _UBE3A_, classifications for single or multi-exon in-frame deletions are assigned as PVS1 or PVS1\\_strong. Refer to PVS1 flow chart for additional guidance.",
"label": "PVS1",
"ns": "037",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable for:\n * Any truncating variant up to p.K841[3](#PMID_9887341)\n * Any frameshift variant that results in a read-through of the stop codon\n * Initiation codon variants\n * Canonical splice site variants predicted to result in an out-of-frame product\n * Intragenic deletions/duplications predicted to result in an out-of-frame product.\n * Full gene deletion",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Strong is applicable for:\n * Any truncating variant from p.A842 to p.G850 \n * Canonical splice site variants that flank exons 7, 8 (in-frame exons)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Moderate is applicable for any truncating variant distal of p.G850.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266905",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266905",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJhu---"
},
{
"entContent": {
"_uniqueProp": "037_PM4_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PM4",
"ns": "037",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Protein length changes due to stop-loss variants.\n\n* PM4\\_Strong is applicable to stop-loss variants in UBE3A, as several stop loss variants in this gene has been described in affected individuals.[4](#PMID_25212744)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n\n* Smaller in-frame events (\\< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domain for this gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266895",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266895",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJcK---"
},
{
"entContent": {
"_uniqueProp": "037_PS2_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable to all genes in affected individuals identified as mosaic for the variant (as the presence of a variant in the mosaic state is confirmatory of the variant being de novo). \n\nBecause of the very high de novo rate of pathogenic variants in UBE3A, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene.",
"label": "PS2",
"ns": "037",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* 1 occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266891",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266891",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJce---"
},
{
"entContent": {
"_uniqueProp": "037_PP2_nuclear_UBE3A",
"additionalComments": "Not applicable for UBE3A.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "037",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266888",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266888",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJeK---"
},
{
"entContent": {
"_uniqueProp": "037_PM1_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "037",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n\n* 3’ cysteine binding site: aa 820[3](#PMID_9887341)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266887",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266887",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJcu---"
},
{
"entContent": {
"_uniqueProp": "037_PP1_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"label": "PP1",
"ns": "037",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n\n* ≥5 informative meiosis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 3-4 informative meiosis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 2 informative meiosis.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266904",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266904",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJey---"
},
{
"entContent": {
"_uniqueProp": "037_PM6_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "Because of the very high de novo rate of pathogenic variants in _UBE3A_, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene.",
"label": "PM6",
"ns": "037",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Assumed de novo without confirmation of paternity and maternity.\n\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Assumed de novo without confirmation of paternity and maternity.\n\n* ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo without confirmation of paternity and maternity.\n\n* 1 occurrence of PM6.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266898",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266898",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJb6---"
},
{
"entContent": {
"_uniqueProp": "037_BA1_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoffs are based on MECP2 expected disease allele frequency (1 in 10,000 for the disease prevalence / (1.5 alleles \\[assumes 50/50 male/female ratio\\] \\* 0.8 for 80% penetrance)). MECP2 is the most prevalent of the genes covered in the Rett/Angelman-like working group and was chosen as most conservative number.",
"label": "BA1",
"ns": "037",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.000083 (0.0083%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266892",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266892",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJi6---"
},
{
"entContent": {
"_uniqueProp": "037_PS4_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "* Detailed phenotype not needed. Need to confirm patient is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.\n* Patient can be published OR an internal case OR observed at an outside lab (i.e. via ClinVar) OR described in the reputable databases (LOVD). However, the independent case has to be confirmed to be a different patient than yours (compare gender/age).\n* Do not use this criterion for variants where BS1 is applied or where PM2 does not apply.",
"label": "PS4",
"ns": "037",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266890",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266890",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJfm---"
},
{
"entContent": {
"_uniqueProp": "037_BS3_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "037",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for other functional studies.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266885",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266885",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJaa---"
},
{
"entContent": {
"_uniqueProp": "037_BP5_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "* For example if a variant in _UBE3A_ is identified in a patient with lissencephaly in whom a pathogenic variant is identified in the _PAFAH1B1_ gene.\n* Variant should also be maternally inherited in the case with an alternate molecular basis for disease for this criteria to be used.\n* Do not apply if variant is de novo.",
"label": "BP5",
"ns": "037",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Variant found in a case with an alternate molecular basis for disease. \n\n* 2 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\n\n* 1 case with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266906",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266906",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJha---"
},
{
"entContent": {
"_uniqueProp": "037_BP3_nuclear_UBE3A",
"additionalComments": "Not applicable for UBE3A.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "037",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function.\n\n* BP3 is applicable if there are in-frame deletions/duplications in a repetitive region where other in-frame deletions/duplications have been observed with an overall frequency commensurate with the BA1 threshold for this gene.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266901",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266901",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJbm---"
},
{
"entContent": {
"_uniqueProp": "037_BS2_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "- Should be applied in cases where the healthy adult is devoid of neurodevelopmental phenotypes. \n- Best to use with internal curated data that includes clinical information or published patients that have been phenotyped.",
"label": "BS2",
"ns": "037",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 4 unaffected (related and maternally inherited or unrelated) heterozygotes",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 3 unaffected (related and maternally inherited or unrelated) heterozygotes",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 2 unaffected (related and maternally inherited or unrelated) heterozygotes",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266884",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266884",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJc6---"
},
{
"entContent": {
"_uniqueProp": "037_PP4_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "037",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266883",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266883",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJga---"
},
{
"entContent": {
"_uniqueProp": "037_BP7_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "For silent variants BP4 and BP7 can be added.",
"label": "BP7",
"ns": "037",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score \\<1 and/or PhyloP score \\<0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.\n* For splice site variants use SpliceAI with a score ≤ 0.1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266909",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266909",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJau---"
},
{
"entContent": {
"_uniqueProp": "037_BP4_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "037",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc).\n\n* For missense variants use REVEL with a score ≤ 0.290.\n* For splice site variants use SpliceAI with a score ≤ 0.1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266903",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266903",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJbO---"
},
{
"entContent": {
"_uniqueProp": "037_BP2_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "Knock out of _UBE3A_ results in disease but viable phenotype.[5](#PMID_9808466)",
"label": "BP2",
"ns": "037",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n\n* BP2 is not applicable for UBE3A _in trans_ state.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266900",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266900",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJfC---"
},
{
"entContent": {
"_uniqueProp": "037_PS1_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "037",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266899",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266899",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJZ6---"
},
{
"entContent": {
"_uniqueProp": "037_BS4_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"label": "BS4",
"ns": "037",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member, when seen in two or more families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266897",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266897",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJdi---"
},
{
"entContent": {
"_uniqueProp": "037_BS1_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoffs are based on MECP2 expected disease allele frequency divided by 10-fold. MECP2 is the most prevalent of the genes covered in the Rett/Angelman-like working group and was chosen as most conservative number.",
"label": "BS1",
"ns": "037",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0000083 (0.00083%) and \\<0.000083 (0.0083%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266894",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266894",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJiG---"
},
{
"entContent": {
"_uniqueProp": "037_PP3_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "037",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.\n\n* For missense variants use REVEL with a score ≥ 0.644.\n* For splice site variants use SpliceAI with a score ≥ 0.2.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266889",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266889",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJdy---"
},
{
"entContent": {
"_uniqueProp": "037_PM2_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "037",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266882",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266882",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJei---"
},
{
"entContent": {
"_uniqueProp": "037_BP6_nuclear_UBE3A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "037",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266907",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266907",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJhC---"
},
{
"entContent": {
"_uniqueProp": "037_PS3_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "037",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an out-of-frame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See included table for acceptable functional studies.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266902",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266902",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJdO---"
},
{
"entContent": {
"_uniqueProp": "037_BP1_nuclear_UBE3A",
"additionalComments": "Not applicable for UBE3A.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "037",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266896",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533266896",
"modified": "2025-07-30T16:39:40.188Z",
"modifier": "gmillikin",
"rev": "_kDuyJfW---"
},
{
"entContent": {
"_uniqueProp": "037_PM3_nuclear_UBE3A",
"additionalComments": "Not applicable for UBE3A.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "037",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
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"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
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"shortTitle": "ACMG variant classification (RASopathy)",
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"additionalComments": "Previously established variant must be established as pathogenic per these criteria. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes. This evidence rule can also be used for pathogenic missense variants seen in the same analogous residue position in highly analogous groupings below:\nGroup 1: HRAS, NRAS, KRAS\nGroup 2: MAP2K1, MAP2K2\nGroup 3: SOS1, SOS2\n\nThis rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a “mutational hot-spot”. For example, Gly12 in HRAS is listed as a hot-spot for PM1 usage. In these situations, only PM1 should be used when combining criteria for final variant classification in order to avoid premature designation of a likely pathogenic classification in the absence of other evidence for pathogenicity.",
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"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
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"text": "",
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"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥2 different \\[likely\\] pathogenic residues changes at the same codon observed in ≥5 probands.",
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"strengthSepioID": "SEPIO:0000216",
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"type": "EvidenceLineStrength"
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"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
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"label": "BA1",
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"sepioID": "SEPIO-CG:99038",
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"status": "not approved",
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"text": "",
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"text": "",
"type": "EvidenceLineStrength"
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"text": "",
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"creator": "cspecAdministrator",
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"additionalComments": "Requires only one informative meiosis and does not require an additional piece of supporting evidence to classify variant as likely benign.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"SHOC2"
],
"geneType": "nuclear",
"instructionsToUse": "Lack of segregation in affected members of a family.",
"label": "BS4",
"ns": "038",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Requires only one informative meiosis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828333101",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828333101",
"modified": "2024-12-03T00:07:12.037Z",
"modifier": "RFWebb",
"rev": "_i2lVoHu---"
},
{
"created": "2024-08-03T01:22:42.658Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "038_PS2_nuclear_SHOC2",
"additionalComments": "PS2_Very Strong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"SHOC2"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PM6 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS2",
"ns": "038",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828333099",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828333099",
"modified": "2024-12-03T00:07:12.037Z",
"modifier": "RFWebb",
"rev": "_i2lVoTm---"
},
{
"created": "2024-08-03T01:22:42.658Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "038_PP1_nuclear_SHOC2",
"additionalComments": "PP1_Moderate: ≥5 informative meioses\nPP1_Strong: ≥7 informative meioses",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"SHOC2"
],
"geneType": "nuclear",
"instructionsToUse": "Segregation in more than one family is recommended.",
"label": "PP1",
"ns": "038",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥7 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥5 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥3 informative meioses.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828333098",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828333098",
"modified": "2024-12-03T00:07:12.037Z",
"modifier": "RFWebb",
"rev": "_i2lVoCa---"
},
{
"created": "2024-08-03T01:22:42.658Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "038_BS2_nuclear_SHOC2",
"additionalComments": "Due to variable expressivity and severity, extensive clinical workup for RASopathy spectrum features is warranted, thus general population data should not be used for this criterion. Clinical laboratories are encouraged to accumulate more than 3 instances of well phenotyped family members before applying this strong criterion.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SHOC2"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring based on phenotypic specifications. Phenotypic specifications: based on healthy homozygote or heterozygote individuals, reduced points for apparently unaffected heterozygous individuals, applicable to parent or sibling samples during clinical family evaluations.",
"label": "BS2",
"ns": "038",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "\\-4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "\\-1 Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828333115",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828333115",
"modified": "2024-12-03T00:07:12.037Z",
"modifier": "RFWebb",
"rev": "_i2lVoVi---"
},
{
"created": "2024-08-03T01:22:42.658Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "038_PP3_nuclear_SHOC2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SHOC2"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"label": "PP3",
"ns": "038",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828333105",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828333105",
"modified": "2024-12-03T00:07:12.037Z",
"modifier": "RFWebb",
"rev": "_i2lVoAq---"
},
{
"created": "2024-08-03T01:22:42.658Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "038_PP4_nuclear_SHOC2",
"additionalComments": "Not applicable, see PS4.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SHOC2"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "038",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828333103",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828333103",
"modified": "2024-12-03T00:07:12.037Z",
"modifier": "RFWebb",
"rev": "_i2lVoSy---"
},
{
"created": "2024-08-03T01:22:42.658Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "038_BP7_nuclear_SHOC2",
"additionalComments": "This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SHOC2"
],
"geneType": "nuclear",
"instructionsToUse": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"label": "BP7",
"ns": "038",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828333119",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828333119",
"modified": "2024-12-03T00:07:12.037Z",
"modifier": "RFWebb",
"rev": "_i2lVoKK---"
},
{
"created": "2024-08-03T01:22:42.658Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "038_PM2_nuclear_SHOC2",
"additionalComments": "The variant must be completely absent from all population databases.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"SHOC2"
],
"geneType": "nuclear",
"instructionsToUse": "The variant must be absent from controls (gnomAD).",
"label": "PM2",
"ns": "038",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The variant must be absent from controls (gnomAD).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828333100",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828333100",
"modified": "2024-12-03T00:07:12.037Z",
"modifier": "RFWebb",
"rev": "_i2lVoBW---"
},
{
"created": "2024-08-03T01:22:42.658Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "038_BP6_nuclear_SHOC2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SHOC2"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "038",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828333095",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828333095",
"modified": "2024-12-03T00:07:12.037Z",
"modifier": "RFWebb",
"rev": "_i2lVoXe---"
},
{
"created": "2024-08-03T01:22:42.658Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "038_BP5_nuclear_SHOC2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SHOC2"
],
"geneType": "nuclear",
"instructionsToUse": "Points are awarded for an alternative molecular cause of a RASopathy in a different gene (and/or in conjunction with BP2) and the phenotype is consistent with expected severity of the RASopathy. Points are also awarded for phenotypes inconsistent with a RASopathy and fully explained by a different causative variant (e.g. WES testing).",
"label": "BP5",
"ns": "038",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828333117",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828333117",
"modified": "2024-12-03T00:07:12.037Z",
"modifier": "RFWebb",
"rev": "_i2lVoGu---"
},
{
"created": "2024-08-03T01:22:42.658Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "038_PM1_nuclear_SHOC2",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"SHOC2"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "038",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": "Analogous Gene",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828333116",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828333116",
"modified": "2024-12-03T00:07:12.037Z",
"modifier": "RFWebb",
"rev": "_i2lVoOK---"
},
{
"created": "2024-08-03T01:22:42.658Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "038_BP4_nuclear_SHOC2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SHOC2"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≤0.3. For splicing variants: predicted outcome is negligible or does not match disease mechanism.",
"label": "BP4",
"ns": "038",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "For missense variants: REVEL ≤0.3.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828333112",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828333112",
"modified": "2024-12-03T00:07:12.037Z",
"modifier": "RFWebb",
"rev": "_i2lVoP----"
},
{
"created": "2024-08-03T01:22:42.658Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "038_PM3_nuclear_SHOC2",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"SHOC2"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "038",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828333104",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828333104",
"modified": "2024-12-03T00:07:12.037Z",
"modifier": "RFWebb",
"rev": "_i2lVoKy---"
},
{
"created": "2024-08-03T01:22:42.658Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "038_PVS1_nuclear_SHOC2",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SHOC2"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "038",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0244",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828333096",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828333096",
"modified": "2024-12-03T00:07:12.037Z",
"modifier": "RFWebb",
"rev": "_i2lVoUm---"
},
{
"created": "2024-08-03T01:22:42.658Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "038_PP5_nuclear_SHOC2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SHOC2"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "038",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828333120",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828333120",
"modified": "2024-12-03T00:07:12.037Z",
"modifier": "RFWebb",
"rev": "_i2lVoI6---"
},
{
"created": "2024-08-03T01:22:42.658Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "038_PS1_nuclear_SHOC2",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria for germline RASopathy variants. This evidence rule can also be applied for the any observed analogous residue positions/regions throughout the gene in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SHOC2"
],
"geneType": "nuclear",
"instructionsToUse": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"label": "PS1",
"ns": "038",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant in _SHOC2_ regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828333114",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828333114",
"modified": "2024-12-03T00:07:12.037Z",
"modifier": "RFWebb",
"rev": "_i2lVn7u---"
},
{
"created": "2024-08-03T01:22:42.658Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "038_BP2_nuclear_SHOC2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"SHOC2"
],
"geneType": "nuclear",
"instructionsToUse": "Points are awarded for an alternative molecular cause of a RASopathy in the same gene (and/or in conjunction with BP5) and the phenotype is consistent with expected severity of the RASopathy.",
"label": "BP2",
"ns": "038",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828333111",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828333111",
"modified": "2024-12-03T00:07:12.037Z",
"modifier": "RFWebb",
"rev": "_i2lVoQS---"
},
{
"created": "2024-08-03T01:22:42.658Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "038_BP3_nuclear_SHOC2",
"additionalComments": "No known benign repetitive areas in RASopathy genes.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SHOC2"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "038",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": "None",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828333109",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828333109",
"modified": "2024-12-03T00:07:12.037Z",
"modifier": "RFWebb",
"rev": "_i2lVoQ2--A"
},
{
"created": "2024-08-03T01:22:42.658Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "038_PP2_nuclear_SHOC2",
"additionalComments": "Not applicable because missense z score is <3.09 in gnomAD.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"SHOC2"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "038",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
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},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 \\[likely\\] pathogenic residue change at the same codon.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332360",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332360",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWcfS---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_PM1_nuclear_NRAS",
"additionalComments": "See supplemental material for approved functional domains and residues. This evidence rule can also be applied for the same analogous residue positions/regions in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
"label": "PM1",
"ns": "039",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable only to critical and well-established functional domains available in the supplementary table (P-loop \\[AA 10-17\\], SW1 \\[AA 25-40\\], SW2 \\[AA 57-64\\], SAK \\[AA 145-156\\]). Not applicable to specific amino acid residues (see PM5).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332358",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332358",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWcgq---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_BS2_nuclear_NRAS",
"additionalComments": "Due to variable expressivity and severity, extensive clinical workup for RASopathy spectrum features is warranted, thus general population data should not be used for this criterion. Clinical laboratories are encouraged to accumulate more than 3 instances of well phenotyped family members before applying this strong criterion.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring based on phenotypic specifications. Phenotypic specifications: based on healthy homozygote or heterozygote individuals, reduced points for apparently unaffected heterozygous individuals, applicable to parent or sibling samples during clinical family evaluations.",
"label": "BS2",
"ns": "039",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "\\-4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "\\-1 Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332357",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332357",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWcvm---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_PS2_nuclear_NRAS",
"additionalComments": "PS2_Very Strong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PM6 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS2",
"ns": "039",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332341",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332341",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWcke---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_BP1_nuclear_NRAS",
"additionalComments": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Truncating, LOF variant in a gene for which primarily missense, GOF variants are known to cause disease.",
"label": "BP1",
"ns": "039",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332355",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332355",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWcnW---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_BP2_nuclear_NRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Points are awarded for an alternative molecular cause of a RASopathy in the same gene (and/or in conjunction with BP5) and the phenotype is consistent with expected severity of the RASopathy.",
"label": "BP2",
"ns": "039",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332353",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332353",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWc5----"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_BA1_nuclear_NRAS",
"additionalComments": "An allele frequency ≥0.05% was approved. See supplemental material for additional frequency information.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"instructionsToUse": "GnomAD filtering allele frequency ≥0.05%.",
"label": "BA1",
"ns": "039",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "GnomAD filtering allele frequency ≥0.05%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332352",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332352",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWc1W---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_PP2_nuclear_NRAS",
"additionalComments": "Not applicable because missense z score is <3.09 in gnomAD.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "039",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332350",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332350",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWcw2---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_PM4_nuclear_NRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"label": "PM4",
"ns": "039",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "No known repetitive areas in gene. Use as described.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332344",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332344",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWcjC---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_PM2_nuclear_NRAS",
"additionalComments": "The variant must be completely absent from all population databases.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"instructionsToUse": "The variant must be absent from controls (gnomAD).",
"label": "PM2",
"ns": "039",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": "General",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The variant must be absent from controls (gnomAD).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332342",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332342",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWcrq---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_BP6_nuclear_NRAS",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "039",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332337",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332337",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWczW---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_BP7_nuclear_NRAS",
"additionalComments": "This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"instructionsToUse": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"label": "BP7",
"ns": "039",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332361",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332361",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWcuu---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_BP5_nuclear_NRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Points are awarded for an alternative molecular cause of a RASopathy in a different gene (and/or in conjunction with BP2) and the phenotype is consistent with expected severity of the RASopathy. Points are also awarded for phenotypes inconsistent with a RASopathy and fully explained by a different causative variant (e.g. WES testing).",
"label": "BP5",
"ns": "039",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332359",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332359",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWc0u---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_PM3_nuclear_NRAS",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "039",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332346",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332346",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWc3m---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_PP4_nuclear_NRAS",
"additionalComments": "Not applicable, see PS4.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "039",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332345",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332345",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWc6K---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_PP1_nuclear_NRAS",
"additionalComments": "PP1_Moderate: ≥5 informative meioses\nPP1_Strong: ≥7 informative meioses",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Segregation in more than one family is recommended.",
"label": "PP1",
"ns": "039",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥7 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥5 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥3 informative meioses.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332340",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332340",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWclG---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_PP5_nuclear_NRAS",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "039",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332362",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332362",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWcte---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_PS1_nuclear_NRAS",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria for germline RASopathy variants. This evidence rule can also be applied for the any observed analogous residue positions/regions throughout the gene in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"label": "PS1",
"ns": "039",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous pathogenic residue positions in _HRAS, KRAS, MRAS, NRAS, RIT1,_ and _RRAS2._",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332356",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332356",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWchS---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_BP4_nuclear_NRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≤0.3. For splicing variants: predicted outcome is negligible or does not match disease mechanism.",
"label": "BP4",
"ns": "039",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "For missense variants: REVEL ≤0.3.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332354",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332354",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWcoO---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_BP3_nuclear_NRAS",
"additionalComments": "No known benign repetitive areas in RASopathy genes.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "039",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": "None",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332351",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332351",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWc2a---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_PM6_nuclear_NRAS",
"additionalComments": "PM6_Strong: ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.\nPS2_VeryStrong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PS2 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PM6",
"ns": "039",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 Points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332349",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332349",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWcxe--_"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
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"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"label": "BS3",
"ns": "039",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332336",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332336",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWcmK---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_BS1_nuclear_NRAS",
"additionalComments": "An allele frequency ≥0.025% was approved. See supplemental material for additional frequency information.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "GnomAD filtering allele frequency ≥0.025%.",
"label": "BS1",
"ns": "039",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "GnomAD filtering allele frequency ≥0.025%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332363",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332363",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWcsu---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_PS3_nuclear_NRAS",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Approved assays are available in the supplemental materials.",
"label": "PS3",
"ns": "039",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Two or more different approved assays.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One approved assay.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332348",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332348",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWcpW---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_PP3_nuclear_NRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"label": "PP3",
"ns": "039",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332347",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332347",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWciG---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_BS4_nuclear_NRAS",
"additionalComments": "Requires only one informative meiosis and does not require an additional piece of supporting evidence to classify variant as likely benign.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Lack of segregation in affected members of a family.",
"label": "BS4",
"ns": "039",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Requires only one informative meiosis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332343",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332343",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWcqq---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_PS4_nuclear_NRAS",
"additionalComments": "PS4: ≥5 independent occurrences\nPS4_Moderate: ≥3 independent occurrences\nPS4_Supporting: ≥1 independent occurrences",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring for autosomal dominant cases with phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS4",
"ns": "039",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥5 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥3 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥1 points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828332339",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828332339",
"modified": "2024-12-03T00:08:05.872Z",
"modifier": "RFWebb",
"rev": "_i2lWcy2---"
},
{
"created": "2024-08-03T01:21:55.372Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "039_PVS1_nuclear_NRAS",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"NRAS"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "039",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0244",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
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"type": "EvidenceLineStrength"
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"text": "",
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"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828331600",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828331600",
"modified": "2024-12-03T02:17:32.839Z",
"modifier": "RFWebb",
"rev": "_i2nM9bS---"
},
{
"created": "2024-08-03T01:21:07.500Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "040_PM1_nuclear_RAF1",
"additionalComments": "See supplemental material for approved functional domains and residues. This evidence rule can also be applied for the same analogous residue positions/regions in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"RAF1"
],
"geneType": "nuclear",
"instructionsToUse": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
"label": "PM1",
"ns": "040",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable only to critical and well-established functional domains available in the supplementary table (CR2 domain \\[AA 251-266/exon7\\], exon 14, exon 17). Not applicable to specific amino acid residues (see PM5).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828331597",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828331597",
"modified": "2024-12-03T02:17:32.839Z",
"modifier": "RFWebb",
"rev": "_i2nM9va---"
},
{
"created": "2024-08-03T01:21:07.500Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "040_BS2_nuclear_RAF1",
"additionalComments": "Due to variable expressivity and severity, extensive clinical workup for RASopathy spectrum features is warranted, thus general population data should not be used for this criterion. Clinical laboratories are encouraged to accumulate more than 3 instances of well phenotyped family members before applying this strong criterion.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"RAF1"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring based on phenotypic specifications. Phenotypic specifications: based on healthy homozygote or heterozygote individuals, reduced points for apparently unaffected heterozygous individuals, applicable to parent or sibling samples during clinical family evaluations.",
"label": "BS2",
"ns": "040",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "\\-4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "\\-1 Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828331596",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828331596",
"modified": "2024-12-03T02:17:32.839Z",
"modifier": "RFWebb",
"rev": "_i2nM9jm---"
},
{
"created": "2024-08-03T01:21:07.500Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "040_BP4_nuclear_RAF1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RAF1"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≤0.3. For splicing variants: predicted outcome is negligible or does not match disease mechanism.",
"label": "BP4",
"ns": "040",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "For missense variants: REVEL ≤0.3.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828331593",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828331593",
"modified": "2024-12-03T02:17:32.839Z",
"modifier": "RFWebb",
"rev": "_i2nM9ga---"
},
{
"created": "2024-08-03T01:21:07.500Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "040_BP3_nuclear_RAF1",
"additionalComments": "No known benign repetitive areas in RASopathy genes.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RAF1"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "040",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": "None",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828331590",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828331590",
"modified": "2024-12-03T02:17:32.839Z",
"modifier": "RFWebb",
"rev": "_i2nM9mK---"
},
{
"created": "2024-08-03T01:21:07.500Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "040_PM6_nuclear_RAF1",
"additionalComments": "PM6_Strong: ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.\nPS2_VeryStrong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"RAF1"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PS2 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PM6",
"ns": "040",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 Points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828331588",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828331588",
"modified": "2024-12-03T02:17:32.839Z",
"modifier": "RFWebb",
"rev": "_i2nM9oa---"
},
{
"created": "2024-08-03T01:21:07.500Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "040_PM3_nuclear_RAF1",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"RAF1"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "040",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828331585",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828331585",
"modified": "2024-12-03T02:17:32.839Z",
"modifier": "RFWebb",
"rev": "_i2nM9xG--F"
},
{
"created": "2024-08-03T01:21:07.500Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "040_BP6_nuclear_RAF1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"RAF1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "040",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828331576",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828331576",
"modified": "2024-12-03T02:17:32.839Z",
"modifier": "RFWebb",
"rev": "_i2nM91m---"
},
{
"created": "2024-08-03T01:21:07.500Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "040_PP5_nuclear_RAF1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"RAF1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "040",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828331601",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828331601",
"modified": "2024-12-03T02:17:32.839Z",
"modifier": "RFWebb",
"rev": "_i2nM9sy---"
},
{
"created": "2024-08-03T01:21:07.500Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "040_PM5_nuclear_RAF1",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes. This evidence rule can also be used for pathogenic missense variants seen in the same analogous residue position in highly analogous groupings below:\nGroup 1: HRAS, NRAS, KRAS\nGroup 2: MAP2K1, MAP2K2\nGroup 3: SOS1, SOS2\n\nThis rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a “mutational hot-spot”. For example, Gly12 in HRAS is listed as a hot-spot for PM1 usage. In these situations, only PM1 should be used when combining criteria for final variant classification in order to avoid premature designation of a likely pathogenic classification in the absence of other evidence for pathogenicity.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RAF1"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable for observed analogous residue positions in _BRAF_ and _RAF1_. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
"label": "PM5",
"ns": "040",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥2 different \\[likely\\] pathogenic residues changes at the same codon observed in ≥5 probands.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 \\[likely\\] pathogenic residue change at the same codon.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828331599",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828331599",
"modified": "2024-12-03T02:17:32.839Z",
"modifier": "RFWebb",
"rev": "_i2nM9ea---"
},
{
"created": "2024-08-03T01:21:07.500Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "040_PS3_nuclear_RAF1",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Approved assays are available in the supplemental materials.",
"label": "PS3",
"ns": "040",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
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"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Two or more different approved assays.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One approved assay.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828331587",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828331587",
"modified": "2024-12-03T02:17:32.839Z",
"modifier": "RFWebb",
"rev": "_i2nM9pm---"
},
{
"created": "2024-08-03T01:21:07.500Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "040_PP3_nuclear_RAF1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"label": "PP3",
"ns": "040",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828331586",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828331586",
"modified": "2024-12-03T02:17:32.839Z",
"modifier": "RFWebb",
"rev": "_i2nM9wm---"
},
{
"created": "2024-08-03T01:21:07.500Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "040_PP4_nuclear_RAF1",
"additionalComments": "Not applicable, see PS4.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"RAF1"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "040",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828331584",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828331584",
"modified": "2024-12-03T02:17:32.839Z",
"modifier": "RFWebb",
"rev": "_i2nM9yK--K"
},
{
"created": "2024-08-03T01:21:07.500Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "040_PM2_nuclear_RAF1",
"additionalComments": "The variant must be completely absent from all population databases.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"RAF1"
],
"geneType": "nuclear",
"instructionsToUse": "The variant must be absent from controls (gnomAD).",
"label": "PM2",
"ns": "040",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The variant must be absent from controls (gnomAD).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828331581",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828331581",
"modified": "2024-12-03T02:17:32.839Z",
"modifier": "RFWebb",
"rev": "_i2nM9iS---"
},
{
"created": "2024-08-03T01:21:07.500Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "040_PS4_nuclear_RAF1",
"additionalComments": "PS4: ≥5 independent occurrences\nPS4_Moderate: ≥3 independent occurrences\nPS4_Supporting: ≥1 independent occurrences",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"RAF1"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring for autosomal dominant cases with phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS4",
"ns": "040",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥5 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥3 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥1 points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828331578",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828331578",
"modified": "2024-12-03T02:17:32.839Z",
"modifier": "RFWebb",
"rev": "_i2nM91----"
},
{
"created": "2024-08-03T01:21:07.500Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "040_PS1_nuclear_RAF1",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria for germline RASopathy variants. This evidence rule can also be applied for the any observed analogous residue positions/regions throughout the gene in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RAF1"
],
"geneType": "nuclear",
"instructionsToUse": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"label": "PS1",
"ns": "040",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in _BRAF_ and _RAF1._",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828331595",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828331595",
"modified": "2024-12-03T02:17:32.839Z",
"modifier": "RFWebb",
"rev": "_i2nM9ku---"
},
{
"created": "2024-08-03T01:21:07.500Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "040_BP1_nuclear_RAF1",
"additionalComments": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RAF1"
],
"geneType": "nuclear",
"instructionsToUse": "Truncating, LOF variant in a gene for which primarily missense, GOF variants are known to cause disease.",
"label": "BP1",
"ns": "040",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828331594",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828331594",
"modified": "2024-12-03T02:17:32.839Z",
"modifier": "RFWebb",
"rev": "_i2nM9fu---"
},
{
"created": "2024-08-03T01:21:07.500Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "040_PP2_nuclear_RAF1",
"additionalComments": "Not applicable because missense z score is <3.09 in gnomAD.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"RAF1"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "040",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828331589",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828331589",
"modified": "2024-12-03T02:17:32.839Z",
"modifier": "RFWebb",
"rev": "_i2nM9nm---"
},
{
"created": "2024-08-03T01:21:07.500Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "040_PM4_nuclear_RAF1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RAF1"
],
"geneType": "nuclear",
"instructionsToUse": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"label": "PM4",
"ns": "040",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
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"text": "",
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"text": "",
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"applicability": "Not Applicable",
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],
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},
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"text": "",
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"text": "",
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"text": "",
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"text": "",
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"text": "",
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"text": "",
"type": "EvidenceLineStrength"
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"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
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"id": "0100",
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"status": "not approved",
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"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
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"strength": "Supporting",
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{
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{
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},
{
"current": true,
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],
"tagNameSpaces": [
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"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SOS1 Version 2.3.0",
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},
"entId": "GN041",
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"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
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"text": "",
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"text": "",
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"applicability": "Not applicable",
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"text": "",
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{
"applicability": "Not applicable",
"id": "0089",
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"text": "",
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"entType": "CriteriaCode",
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"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
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{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_BP3_nuclear_SOS1",
"additionalComments": "No known benign repetitive areas in RASopathy genes.",
"applicability": "Not applicable",
"baseStrength": "Benign",
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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"text": "",
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{
"applicability": "Not applicable",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0211",
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"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0081",
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"specificationType": "None",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
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]
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"entType": "CriteriaCode",
"ldhId": "1828334137",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334137",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
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{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
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"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Applicable",
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"sepioID": "SEPIO-CG:99025",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"id": "0031",
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"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0052",
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"specificationType": [
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],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
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"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Two or more different approved assays.",
"type": "EvidenceLineStrength"
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{
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"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One approved assay.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334134",
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"modified": "2024-12-03T02:19:17.555Z",
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{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
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"additionalComments": "Not applicable.",
"applicability": "Not applicable",
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"evidenceCategory": "Allelic Data",
"gene": [
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"label": "PM3",
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"sepioID": "SEPIO-CG:99029",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334132",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334132",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOjxS---"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_PVS1_nuclear_SOS1",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PVS1",
"ns": "041",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
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"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0244",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334124",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334124",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOkES---"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_BP7_nuclear_SOS1",
"additionalComments": "This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
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"geneType": "nuclear",
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"sepioID": "SEPIO-CG:99049",
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"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0221",
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334147",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334147",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOj1i---"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_PP2_nuclear_SOS1",
"additionalComments": "Not applicable because missense z score is <3.09 in gnomAD.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PP2",
"ns": "041",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
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"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334136",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334136",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOkA2---"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_PM6_nuclear_SOS1",
"additionalComments": "PM6_Strong: ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.\nPS2_VeryStrong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"SOS1"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PS2 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PM6",
"ns": "041",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 Points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334135",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334135",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOjwO---"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_PP3_nuclear_SOS1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SOS1"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"label": "PP3",
"ns": "041",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334133",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334133",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOkBa--F"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_PS2_nuclear_SOS1",
"additionalComments": "PS2_Very Strong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"SOS1"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PM6 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS2",
"ns": "041",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334127",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334127",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOkCK--L"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_BP6_nuclear_SOS1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SOS1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "041",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334123",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334123",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOj1----"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_PM5_nuclear_SOS1",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes. This evidence rule can also be used for pathogenic missense variants seen in the same analogous residue position in highly analogous groupings below:\nGroup 1: HRAS, NRAS, KRAS\nGroup 2: MAP2K1, MAP2K2\nGroup 3: SOS1, SOS2\n\nThis rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a “mutational hot-spot”. For example, Gly12 in HRAS is listed as a hot-spot for PM1 usage. In these situations, only PM1 should be used when combining criteria for final variant classification in order to avoid premature designation of a likely pathogenic classification in the absence of other evidence for pathogenicity.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SOS1"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable for observed analogous residue positions in _SOS1_ and _SOS2_. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
"label": "PM5",
"ns": "041",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥2 different \\[likely\\] pathogenic residues changes at the same codon observed in ≥5 probands.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 \\[likely\\] pathogenic residue change at the same codon.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334146",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334146",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOjtC---"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_BP5_nuclear_SOS1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SOS1"
],
"geneType": "nuclear",
"instructionsToUse": "Points are awarded for an alternative molecular cause of a RASopathy in a different gene (and/or in conjunction with BP2) and the phenotype is consistent with expected severity of the RASopathy. Points are also awarded for phenotypes inconsistent with a RASopathy and fully explained by a different causative variant (e.g. WES testing).",
"label": "BP5",
"ns": "041",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334145",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334145",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOjt2---"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_PM1_nuclear_SOS1",
"additionalComments": "Not applicable for SOS1.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"SOS1"
],
"geneType": "nuclear",
"instructionsToUse": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
"label": "PM1",
"ns": "041",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable only to critical and well-established functional domains available in the supplementary table (PH domain \\[AA 420-500\\]). Not applicable to specific amino acid residues (see PM5).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334144",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334144",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOj4u---"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_BP4_nuclear_SOS1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SOS1"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≤0.3. For splicing variants: predicted outcome is negligible or does not match disease mechanism.",
"label": "BP4",
"ns": "041",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "For missense variants: REVEL ≤0.3.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334140",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334140",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOk_q---"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_PM4_nuclear_SOS1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SOS1"
],
"geneType": "nuclear",
"instructionsToUse": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"label": "PM4",
"ns": "041",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "No known repetitive areas in gene. Use as described.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334130",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334130",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOk-G---"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_PM2_nuclear_SOS1",
"additionalComments": "The variant must be completely absent from all population databases.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"SOS1"
],
"geneType": "nuclear",
"instructionsToUse": "The variant must be absent from controls (gnomAD).",
"label": "PM2",
"ns": "041",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": "General",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The variant must be absent from controls (gnomAD).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334128",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334128",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOjz2---"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_BS3_nuclear_SOS1",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SOS1"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"label": "BS3",
"ns": "041",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334122",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334122",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOkEy---"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_BS2_nuclear_SOS1",
"additionalComments": "Due to variable expressivity and severity, extensive clinical workup for RASopathy spectrum features is warranted, thus general population data should not be used for this criterion. Clinical laboratories are encouraged to accumulate more than 3 instances of well phenotyped family members before applying this strong criterion.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SOS1"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring based on phenotypic specifications. Phenotypic specifications: based on healthy homozygote or heterozygote individuals, reduced points for apparently unaffected heterozygous individuals, applicable to parent or sibling samples during clinical family evaluations.",
"label": "BS2",
"ns": "041",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "\\-4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "\\-1 Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334143",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334143",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOj5O---"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_BP2_nuclear_SOS1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"SOS1"
],
"geneType": "nuclear",
"instructionsToUse": "Points are awarded for an alternative molecular cause of a RASopathy in the same gene (and/or in conjunction with BP5) and the phenotype is consistent with expected severity of the RASopathy.",
"label": "BP2",
"ns": "041",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334139",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334139",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOjvC---"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_PP4_nuclear_SOS1",
"additionalComments": "Not applicable, see PS4.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SOS1"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "041",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334131",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334131",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOjyC---"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_PP1_nuclear_SOS1",
"additionalComments": "PP1_Moderate: ≥5 informative meioses\nPP1_Strong: ≥7 informative meioses",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"SOS1"
],
"geneType": "nuclear",
"instructionsToUse": "Segregation in more than one family is recommended.",
"label": "PP1",
"ns": "041",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥7 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥5 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥3 informative meioses.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334126",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334126",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOkDW---"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_PP5_nuclear_SOS1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SOS1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "041",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334148",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334148",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOjra---"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_PS1_nuclear_SOS1",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria for germline RASopathy variants. This evidence rule can also be applied for the any observed analogous residue positions/regions throughout the gene in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SOS1"
],
"geneType": "nuclear",
"instructionsToUse": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"label": "PS1",
"ns": "041",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in _SOS1_ and _SOS2._",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334142",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334142",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOj6S---"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_BP1_nuclear_SOS1",
"additionalComments": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SOS1"
],
"geneType": "nuclear",
"instructionsToUse": "Truncating, LOF variant in a gene for which primarily missense, GOF variants are known to cause disease.",
"label": "BP1",
"ns": "041",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828334141",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828334141",
"modified": "2024-12-03T02:19:17.555Z",
"modifier": "RFWebb",
"rev": "_i2nOj7e---"
},
{
"created": "2024-08-03T01:27:44.935Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "041_BS4_nuclear_SOS1",
"additionalComments": "Requires only one informative meiosis and does not require an additional piece of supporting evidence to classify variant as likely benign.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"SOS1"
],
"geneType": "nuclear",
"instructionsToUse": "Lack of segregation in affected members of a family.",
"label": "BS4",
"ns": "041",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
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"created": "2024-08-03T01:20:22.072Z",
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"text": "",
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"text": "",
"type": "EvidenceLineStrength"
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"status": "not approved",
"strength": "Strong",
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"text": "",
"type": "EvidenceLineStrength"
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"status": "not approved",
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"text": "",
"type": "EvidenceLineStrength"
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"specificationType": [
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"strengthSepioID": "SEPIO:0000327",
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"ldhId": "1828330857",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330857",
"modified": "2024-12-03T02:39:51.352Z",
"modifier": "RFWebb",
"rev": "_i2nhY3q---"
},
{
"created": "2024-08-03T01:20:22.072Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "042_PM5_nuclear_SOS2",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes. This evidence rule can also be used for pathogenic missense variants seen in the same analogous residue position in highly analogous groupings below:\nGroup 1: HRAS, NRAS, KRAS\nGroup 2: MAP2K1, MAP2K2\nGroup 3: SOS1, SOS2\n\nThis rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a “mutational hot-spot”. For example, Gly12 in HRAS is listed as a hot-spot for PM1 usage. In these situations, only PM1 should be used when combining criteria for final variant classification in order to avoid premature designation of a likely pathogenic classification in the absence of other evidence for pathogenicity.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SOS2"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable for observed analogous residue positions in _SOS1_ and _SOS2_. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
"label": "PM5",
"ns": "042",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥2 different \\[likely\\] pathogenic residues changes at the same codon observed in ≥5 probands.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 \\[likely\\] pathogenic residue change at the same codon.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330856",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330856",
"modified": "2024-12-03T02:39:51.352Z",
"modifier": "RFWebb",
"rev": "_i2nhYxu---"
},
{
"created": "2024-08-03T01:20:22.072Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "042_BP3_nuclear_SOS2",
"additionalComments": "No known benign repetitive areas in RASopathy genes.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SOS2"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "042",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": "None",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330847",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330847",
"modified": "2024-12-03T02:39:51.352Z",
"modifier": "RFWebb",
"rev": "_i2nhYry---"
},
{
"created": "2024-08-03T01:20:22.072Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "042_PP3_nuclear_SOS2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SOS2"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"label": "PP3",
"ns": "042",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330843",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330843",
"modified": "2024-12-03T02:39:51.352Z",
"modifier": "RFWebb",
"rev": "_i2nhY8C---"
},
{
"created": "2024-08-03T01:20:22.072Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "042_PS4_nuclear_SOS2",
"additionalComments": "PS4: ≥5 independent occurrences\nPS4_Moderate: ≥3 independent occurrences\nPS4_Supporting: ≥1 independent occurrences",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"SOS2"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring for autosomal dominant cases with phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS4",
"ns": "042",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥5 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥3 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥1 points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330835",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330835",
"modified": "2024-12-03T02:39:51.352Z",
"modifier": "RFWebb",
"rev": "_i2nhZ-K---"
},
{
"created": "2024-08-03T01:20:22.072Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "042_BS1_nuclear_SOS2",
"additionalComments": "An allele frequency ≥0.025% was approved. See supplemental material for additional frequency information.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SOS2"
],
"geneType": "nuclear",
"instructionsToUse": "GnomAD filtering allele frequency ≥0.025%.",
"label": "BS1",
"ns": "042",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "GnomAD filtering allele frequency ≥0.025%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330859",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330859",
"modified": "2024-12-03T02:39:51.352Z",
"modifier": "RFWebb",
"rev": "_i2nhY2W--C"
},
{
"created": "2024-08-03T01:20:22.072Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "042_PP5_nuclear_SOS2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SOS2"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "042",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330858",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330858",
"modified": "2024-12-03T02:39:51.352Z",
"modifier": "RFWebb",
"rev": "_i2nhYwi---"
},
{
"created": "2024-08-03T01:20:22.072Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "042_PP2_nuclear_SOS2",
"additionalComments": "Not applicable because missense z score is <3.09 in gnomAD.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"SOS2"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "042",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330846",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330846",
"modified": "2024-12-03T02:39:51.352Z",
"modifier": "RFWebb",
"rev": "_i2nhYs2---"
},
{
"created": "2024-08-03T01:20:22.072Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "042_PM6_nuclear_SOS2",
"additionalComments": "PM6_Strong: ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.\nPS2_VeryStrong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"SOS2"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PS2 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PM6",
"ns": "042",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 Points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330845",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330845",
"modified": "2024-12-03T02:39:51.352Z",
"modifier": "RFWebb",
"rev": "_i2nhYuC---"
},
{
"created": "2024-08-03T01:20:22.072Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "042_PS3_nuclear_SOS2",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SOS2"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Approved assays are available in the supplemental materials.",
"label": "PS3",
"ns": "042",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Two or more different approved assays.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One approved assay.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330844",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330844",
"modified": "2024-12-03T02:39:51.352Z",
"modifier": "RFWebb",
"rev": "_i2nhYmm---"
},
{
"created": "2024-08-03T01:20:22.072Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "042_PP4_nuclear_SOS2",
"additionalComments": "Not applicable, see PS4.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SOS2"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "042",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330841",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330841",
"modified": "2024-12-03T02:39:51.352Z",
"modifier": "RFWebb",
"rev": "_i2nhYnu---"
},
{
"created": "2024-08-03T01:20:22.072Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "042_PM4_nuclear_SOS2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SOS2"
],
"geneType": "nuclear",
"instructionsToUse": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"label": "PM4",
"ns": "042",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "No known repetitive areas in gene. Use as described.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330840",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330840",
"modified": "2024-12-03T02:39:51.352Z",
"modifier": "RFWebb",
"rev": "_i2nhYp----"
},
{
"created": "2024-08-03T01:20:22.072Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "042_PM2_nuclear_SOS2",
"additionalComments": "The variant must be completely absent from all population databases.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"SOS2"
],
"geneType": "nuclear",
"instructionsToUse": "The variant must be absent from controls (gnomAD).",
"label": "PM2",
"ns": "042",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": "General",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The variant must be absent from controls (gnomAD).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330838",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330838",
"modified": "2024-12-03T02:39:51.352Z",
"modifier": "RFWebb",
"rev": "_i2nhYum---"
},
{
"created": "2024-08-03T01:20:22.072Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "042_PVS1_nuclear_SOS2",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SOS2"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "042",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0244",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330834",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330834",
"modified": "2024-12-03T02:39:51.352Z",
"modifier": "RFWebb",
"rev": "_i2nhYva---"
},
{
"created": "2024-08-03T01:20:22.072Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "042_BP6_nuclear_SOS2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SOS2"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "042",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330833",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330833",
"modified": "2024-12-03T02:39:51.352Z",
"modifier": "RFWebb",
"rev": "_i2nhZ-2---"
},
{
"created": "2024-08-03T01:20:22.072Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "042_PS1_nuclear_SOS2",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria for germline RASopathy variants. This evidence rule can also be applied for the any observed analogous residue positions/regions throughout the gene in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SOS2"
],
"geneType": "nuclear",
"instructionsToUse": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"label": "PS1",
"ns": "042",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in _SOS1_ and _SOS2._",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330852",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330852",
"modified": "2024-12-03T02:39:51.352Z",
"modifier": "RFWebb",
"rev": "_i2nhY6O---"
},
{
"created": "2024-08-03T01:20:22.072Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "042_BP1_nuclear_SOS2",
"additionalComments": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SOS2"
],
"geneType": "nuclear",
"instructionsToUse": "Truncating, LOF variant in a gene for which primarily missense, GOF variants are known to cause disease.",
"label": "BP1",
"ns": "042",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330851",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330851",
"modified": "2024-12-03T02:39:51.352Z",
"modifier": "RFWebb",
"rev": "_i2nhYqC---"
},
{
"created": "2024-08-03T01:20:22.072Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "042_BP5_nuclear_SOS2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SOS2"
],
"geneType": "nuclear",
"instructionsToUse": "Points are awarded for an alternative molecular cause of a RASopathy in a different gene (and/or in conjunction with BP2) and the phenotype is consistent with expected severity of the RASopathy. Points are also awarded for phenotypes inconsistent with a RASopathy and fully explained by a different causative variant (e.g. WES testing).",
"label": "BP5",
"ns": "042",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330855",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330855",
"modified": "2024-12-03T02:39:51.352Z",
"modifier": "RFWebb",
"rev": "_i2nhYyy---"
},
{
"created": "2024-08-03T01:20:22.072Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "042_BS2_nuclear_SOS2",
"additionalComments": "Due to variable expressivity and severity, extensive clinical workup for RASopathy spectrum features is warranted, thus general population data should not be used for this criterion. Clinical laboratories are encouraged to accumulate more than 3 instances of well phenotyped family members before applying this strong criterion.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SOS2"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring based on phenotypic specifications. Phenotypic specifications: based on healthy homozygote or heterozygote individuals, reduced points for apparently unaffected heterozygous individuals, applicable to parent or sibling samples during clinical family evaluations.",
"label": "BS2",
"ns": "042",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "\\-4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
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{
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{
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{
"val": "Orphanet:536391"
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{
"current": false,
"event": {
"modifiedBy": "RFWebb",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-12-02T21:12:08.270Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"043"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0",
"version": "2.3.0",
"versioned": true
},
"entId": "GN043",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_PM5_nuclear_PTPN11",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes. This evidence rule can also be used for pathogenic missense variants seen in the same analogous residue position in highly analogous groupings below:\nGroup 1: HRAS, NRAS, KRAS\nGroup 2: MAP2K1, MAP2K2\nGroup 3: SOS1, SOS2\n\nThis rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a “mutational hot-spot”. For example, Gly12 in HRAS is listed as a hot-spot for PM1 usage. In these situations, only PM1 should be used when combining criteria for final variant classification in order to avoid premature designation of a likely pathogenic classification in the absence of other evidence for pathogenicity.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable for observed analogous residue positions in _PTPN11_. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
"label": "PM5",
"ns": "043",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥2 different \\[likely\\] pathogenic residues changes at the same codon observed in ≥5 probands.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 \\[likely\\] pathogenic residue change at the same codon.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330079",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330079",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9cG---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_PS1_nuclear_PTPN11",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria for germline RASopathy variants. This evidence rule can also be applied for the any observed analogous residue positions/regions throughout the gene in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"label": "PS1",
"ns": "043",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant in _PTPN11_ regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330075",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330075",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9W----"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_PP3_nuclear_PTPN11",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"label": "PP3",
"ns": "043",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330066",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330066",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9Zi---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_PM4_nuclear_PTPN11",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"label": "PM4",
"ns": "043",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "No known repetitive areas in gene. Use as described.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330063",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330063",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9IW---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_PM2_nuclear_PTPN11",
"additionalComments": "The variant must be completely absent from all population databases.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "The variant must be absent from controls (gnomAD).",
"label": "PM2",
"ns": "043",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": "General",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The variant must be absent from controls (gnomAD).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330061",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330061",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9N2---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_PS2_nuclear_PTPN11",
"additionalComments": "PS2_Very Strong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PM6 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS2",
"ns": "043",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330060",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330060",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9da---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_PVS1_nuclear_PTPN11",
"additionalComments": "LOF and/or haploinsufficiency has not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype, therefore in general this rule is not applicable. Note that PTPN11 is currently the only gene with a confirmed association to another non-RASopathy disorder due to LOF alleles. Variants in PTPN11 with predicted LOF should not be evaluated by these RASopathy specific criteria, but should defer to non-adjusted criteria. Given that some historical LOF variants (e.g. canonical splice sites) could potentially result in a gain of function, users should assess using these criteria and non-adjusted criteria to identify the highest likelihood of pathogenicity for all associated diseases. We recommend that the ClinGen Dosage Sensitivity Map Status (http://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/index.shtml) be reviewed for any new apparently LOF disease associations prior to classification assessment.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "043",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0244",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330057",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330057",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9JC---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_BP7_nuclear_PTPN11",
"additionalComments": "This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"label": "BP7",
"ns": "043",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330080",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330080",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9Qe---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_PM1_nuclear_PTPN11",
"additionalComments": "See supplemental material for approved functional domains and residues. This evidence rule can also be applied for the same analogous residue positions/regions in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
"label": "PM1",
"ns": "043",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable only to critical and well-established functional domains available in the supplementary table (Directly interacting residues between N-SH2 and PTPN domains \\[AA 4, AA 7-9, AA 58-63, AA 69-77, AA 247, AA 251, AA 255, AA 256, AA 258, AA 261, AA 265, AA 278-281, AA 284\\]). Not applicable to specific amino acid residues (see PM5).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330077",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330077",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9K6---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_BP1_nuclear_PTPN11",
"additionalComments": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "Truncating, LOF variant in a gene for which primarily missense, GOF variants are known to cause disease.",
"label": "BP1",
"ns": "043",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330074",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330074",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9RS---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_BP4_nuclear_PTPN11",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≤0.3. For splicing variants: predicted outcome is negligible or does not match disease mechanism.",
"label": "BP4",
"ns": "043",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "For missense variants: REVEL ≤0.3.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330073",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330073",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9R6---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_BP3_nuclear_PTPN11",
"additionalComments": "No known benign repetitive areas in RASopathy genes.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "043",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": "None",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330070",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330070",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9S6---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_PS3_nuclear_PTPN11",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Approved assays are available in the supplemental materials.",
"label": "PS3",
"ns": "043",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Two or more different approved assays.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One approved assay.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330067",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330067",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9Yq---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_PM3_nuclear_PTPN11",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "043",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330065",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330065",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9Ga---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_PP4_nuclear_PTPN11",
"additionalComments": "Not applicable, see PS4.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "043",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330064",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330064",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9HK---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_BS3_nuclear_PTPN11",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"label": "BS3",
"ns": "043",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330055",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330055",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9ee---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_PP5_nuclear_PTPN11",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "043",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330081",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330081",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9U6---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_BP5_nuclear_PTPN11",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "Points are awarded for an alternative molecular cause of a RASopathy in a different gene (and/or in conjunction with BP2) and the phenotype is consistent with expected severity of the RASopathy. Points are also awarded for phenotypes inconsistent with a RASopathy and fully explained by a different causative variant (e.g. WES testing).",
"label": "BP5",
"ns": "043",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330078",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330078",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9Jy---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_BA1_nuclear_PTPN11",
"additionalComments": "An allele frequency ≥0.05% was approved. See supplemental material for additional frequency information.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "GnomAD filtering allele frequency ≥0.05%.",
"label": "BA1",
"ns": "043",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "GnomAD filtering allele frequency ≥0.05%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330071",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330071",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9Fe---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_PP2_nuclear_PTPN11",
"additionalComments": "PP2 is applicable to all RASopathy genes described and curated herein.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"label": "PP2",
"ns": "043",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense z score is >3.09 in gnomAD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330069",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330069",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9Mq---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_BS4_nuclear_PTPN11",
"additionalComments": "Requires only one informative meiosis and does not require an additional piece of supporting evidence to classify variant as likely benign.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "Lack of segregation in affected members of a family.",
"label": "BS4",
"ns": "043",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Requires only one informative meiosis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330062",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330062",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9T2---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_PP1_nuclear_PTPN11",
"additionalComments": "PP1_Moderate: ≥5 informative meioses\nPP1_Strong: ≥7 informative meioses",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "Segregation in more than one family is recommended.",
"label": "PP1",
"ns": "043",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥7 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥5 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥3 informative meioses.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330059",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330059",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9Om---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_BS1_nuclear_PTPN11",
"additionalComments": "An allele frequency ≥0.025% was approved. See supplemental material for additional frequency information.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "GnomAD filtering allele frequency ≥0.025%.",
"label": "BS1",
"ns": "043",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "GnomAD filtering allele frequency ≥0.025%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330082",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330082",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9be---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_BP2_nuclear_PTPN11",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "Points are awarded for an alternative molecular cause of a RASopathy in the same gene (and/or in conjunction with BP5) and the phenotype is consistent with expected severity of the RASopathy.",
"label": "BP2",
"ns": "043",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330072",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330072",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9W6---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_BS2_nuclear_PTPN11",
"additionalComments": "Due to variable expressivity and severity, extensive clinical workup for RASopathy spectrum features is warranted, thus general population data should not be used for this criterion. Clinical laboratories are encouraged to accumulate more than 3 instances of well phenotyped family members before applying this strong criterion.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring based on phenotypic specifications. Phenotypic specifications: based on healthy homozygote or heterozygote individuals, reduced points for apparently unaffected heterozygous individuals, applicable to parent or sibling samples during clinical family evaluations.",
"label": "BS2",
"ns": "043",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "\\-4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "\\-1 Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330076",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330076",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9L2---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_PM6_nuclear_PTPN11",
"additionalComments": "PM6_Strong: ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.\nPS2_VeryStrong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PS2 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PM6",
"ns": "043",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 Points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828330068",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828330068",
"modified": "2024-12-03T02:44:50.889Z",
"modifier": "RFWebb",
"rev": "_i2nl9X2---"
},
{
"created": "2024-08-03T01:19:36.915Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "043_PS4_nuclear_PTPN11",
"additionalComments": "PS4: ≥5 independent occurrences\nPS4_Moderate: ≥3 independent occurrences\nPS4_Supporting: ≥1 independent occurrences",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"PTPN11"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring for autosomal dominant cases with phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
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"additionalComments": "This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
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"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
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"geneType": "nuclear",
"instructionsToUse": "Applicable for observed analogous residue positions in _HRAS_, _KRAS_, _MRAS_, _NRAS_, _RIT1_, and _RRAS2_. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
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"strength": "Strong",
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"strength": "Moderate",
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"status": "approved",
"strength": "Supporting",
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"type": "EvidenceLineStrength"
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"created": "2024-08-03T01:18:35.562Z",
"creator": "cspecAdministrator",
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"additionalComments": "No known benign repetitive areas in RASopathy genes.",
"applicability": "Not applicable",
"baseStrength": "Benign",
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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"geneType": "nuclear",
"label": "BP3",
"ns": "044",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
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"id": "0210",
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
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"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": "None",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
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]
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"modified": "2024-12-03T02:47:49.605Z",
"modifier": "RFWebb",
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"created": "2024-08-03T01:18:35.562Z",
"creator": "cspecAdministrator",
"entContent": {
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"additionalComments": "PP1_Moderate: ≥5 informative meioses\nPP1_Strong: ≥7 informative meioses",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "Segregation in more than one family is recommended.",
"label": "PP1",
"ns": "044",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥7 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥5 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥3 informative meioses.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828329255",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828329255",
"modified": "2024-12-03T02:47:49.605Z",
"modifier": "RFWebb",
"rev": "_i2nosAa---"
},
{
"created": "2024-08-03T01:18:35.562Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "044_BS1_nuclear_KRAS",
"additionalComments": "An allele frequency ≥0.025% was approved. See supplemental material for additional frequency information.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"KRAS"
],
"geneType": "nuclear",
"instructionsToUse": "GnomAD filtering allele frequency ≥0.025%.",
"label": "BS1",
"ns": "044",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "GnomAD filtering allele frequency ≥0.025%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828329278",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828329278",
"modified": "2024-12-03T02:47:49.605Z",
"modifier": "RFWebb",
"rev": "_i2norxq---"
},
{
"created": "2024-08-03T01:18:35.562Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "044_PP5_nuclear_KRAS",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"KRAS"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "044",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828329277",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828329277",
"modified": "2024-12-03T02:47:49.605Z",
"modifier": "RFWebb",
"rev": "_i2normm---"
},
{
"created": "2024-08-03T01:18:35.562Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "044_BP1_nuclear_KRAS",
"additionalComments": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"KRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Truncating, LOF variant in a gene for which primarily missense, GOF variants are known to cause disease.",
"label": "BP1",
"ns": "044",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828329270",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828329270",
"modified": "2024-12-03T02:47:49.605Z",
"modifier": "RFWebb",
"rev": "_i2nor3a---"
},
{
"created": "2024-08-03T01:18:35.562Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "044_BP2_nuclear_KRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"KRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Points are awarded for an alternative molecular cause of a RASopathy in the same gene (and/or in conjunction with BP5) and the phenotype is consistent with expected severity of the RASopathy.",
"label": "BP2",
"ns": "044",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828329268",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828329268",
"modified": "2024-12-03T02:47:49.605Z",
"modifier": "RFWebb",
"rev": "_i2norni---"
},
{
"created": "2024-08-03T01:18:35.562Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "044_BA1_nuclear_KRAS",
"additionalComments": "An allele frequency ≥0.05% was approved. See supplemental material for additional frequency information.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"KRAS"
],
"geneType": "nuclear",
"instructionsToUse": "GnomAD filtering allele frequency ≥0.05%.",
"label": "BA1",
"ns": "044",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "GnomAD filtering allele frequency ≥0.05%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828329267",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828329267",
"modified": "2024-12-03T02:47:49.605Z",
"modifier": "RFWebb",
"rev": "_i2norzi---"
},
{
"created": "2024-08-03T01:18:35.562Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "044_PS3_nuclear_KRAS",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"KRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Approved assays are available in the supplemental materials.",
"label": "PS3",
"ns": "044",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Two or more different approved assays.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One approved assay.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828329263",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828329263",
"modified": "2024-12-03T02:47:49.605Z",
"modifier": "RFWebb",
"rev": "_i2nor0e---"
},
{
"created": "2024-08-03T01:18:35.562Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "044_PM4_nuclear_KRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"KRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"label": "PM4",
"ns": "044",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "No known repetitive areas in gene. Use as described.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828329259",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828329259",
"modified": "2024-12-03T02:47:49.605Z",
"modifier": "RFWebb",
"rev": "_i2nor1K---"
},
{
"created": "2024-08-03T01:18:35.562Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "044_BS3_nuclear_KRAS",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"KRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"label": "BS3",
"ns": "044",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828329251",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828329251",
"modified": "2024-12-03T02:47:49.605Z",
"modifier": "RFWebb",
"rev": "_i2norwq---"
},
{
"created": "2024-08-03T01:18:35.562Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "044_PM1_nuclear_KRAS",
"additionalComments": "See supplemental material for approved functional domains and residues. This evidence rule can also be applied for the same analogous residue positions/regions in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"KRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
"label": "PM1",
"ns": "044",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable only to critical and well-established functional domains available in the supplementary table (P-loop \\[AA 10-17\\], SW1 \\[AA 25-40\\], SW2 \\[AA 57-64\\], SAK \\[AA 145-156\\]). Not applicable to specific amino acid residues (see PM5).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828329273",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828329273",
"modified": "2024-12-03T02:47:49.605Z",
"modifier": "RFWebb",
"rev": "_i2norvC---"
},
{
"created": "2024-08-03T01:18:35.562Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "044_BS2_nuclear_KRAS",
"additionalComments": "Due to variable expressivity and severity, extensive clinical workup for RASopathy spectrum features is warranted, thus general population data should not be used for this criterion. Clinical laboratories are encouraged to accumulate more than 3 instances of well phenotyped family members before applying this strong criterion.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"KRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring based on phenotypic specifications. Phenotypic specifications: based on healthy homozygote or heterozygote individuals, reduced points for apparently unaffected heterozygous individuals, applicable to parent or sibling samples during clinical family evaluations.",
"label": "BS2",
"ns": "044",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "\\-4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "\\-1 Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828329272",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828329272",
"modified": "2024-12-03T02:47:49.605Z",
"modifier": "RFWebb",
"rev": "_i2nor9m---"
},
{
"created": "2024-08-03T01:18:35.562Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "044_PP2_nuclear_KRAS",
"additionalComments": "Not applicable because missense z score is <3.09 in gnomAD.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"KRAS"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "044",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828329265",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828329265",
"modified": "2024-12-03T02:47:49.605Z",
"modifier": "RFWebb",
"rev": "_i2nor4W---"
},
{
"created": "2024-08-03T01:18:35.562Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "044_PM6_nuclear_KRAS",
"additionalComments": "PM6_Strong: ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.\nPS2_VeryStrong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"KRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PS2 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PM6",
"ns": "044",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 Points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828329264",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828329264",
"modified": "2024-12-03T02:47:49.605Z",
"modifier": "RFWebb",
"rev": "_i2noroq---"
},
{
"created": "2024-08-03T01:18:35.562Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "044_BS4_nuclear_KRAS",
"additionalComments": "Requires only one informative meiosis and does not require an additional piece of supporting evidence to classify variant as likely benign.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"KRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Lack of segregation in affected members of a family.",
"label": "BS4",
"ns": "044",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Requires only one informative meiosis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828329258",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828329258",
"modified": "2024-12-03T02:47:49.605Z",
"modifier": "RFWebb",
"rev": "_i2norsG---"
},
{
"created": "2024-08-03T01:18:35.562Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "044_PS2_nuclear_KRAS",
"additionalComments": "PS2_Very Strong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"KRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PM6 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS2",
"ns": "044",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828329256",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828329256",
"modified": "2024-12-03T02:47:49.605Z",
"modifier": "RFWebb",
"rev": "_i2nors2---"
},
{
"created": "2024-08-03T01:18:35.562Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "044_PS4_nuclear_KRAS",
"additionalComments": "PS4: ≥5 independent occurrences\nPS4_Moderate: ≥3 independent occurrences\nPS4_Supporting: ≥1 independent occurrences",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"KRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring for autosomal dominant cases with phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS4",
"ns": "044",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥5 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥3 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥1 points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828329254",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828329254",
"modified": "2024-12-03T02:47:49.605Z",
"modifier": "RFWebb",
"rev": "_i2nortm---"
},
{
"created": "2024-08-03T01:18:35.562Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "044_PVS1_nuclear_KRAS",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"KRAS"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "044",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0244",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828329253",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828329253",
"modified": "2024-12-03T02:47:49.605Z",
"modifier": "RFWebb",
"rev": "_i2nor6q---"
},
{
"created": "2024-08-03T01:18:35.562Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "044_PS1_nuclear_KRAS",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria for germline RASopathy variants. This evidence rule can also be applied for the any observed analogous residue positions/regions throughout the gene in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"KRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"label": "PS1",
"ns": "044",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in _HRAS, KRAS, MRAS, NRAS, RIT1,_ and _RRAS2._",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
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{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in _MAP2K1_ and _MAP2K2_.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328435",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328435",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7Ki---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_PP2_nuclear_MAP2K1",
"additionalComments": "PP2 is applicable to all RASopathy genes described and curated herein.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"label": "PP2",
"ns": "045",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense z score is >3.09 in gnomAD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328429",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328429",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7C2---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_PS3_nuclear_MAP2K1",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Approved assays are available in the supplemental materials.",
"label": "PS3",
"ns": "045",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Two or more different approved assays.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One approved assay.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328427",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328427",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7a2---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_PS2_nuclear_MAP2K1",
"additionalComments": "PS2_Very Strong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PM6 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS2",
"ns": "045",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328420",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328420",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7GS---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_PP5_nuclear_MAP2K1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "045",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328441",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328441",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7Z----"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_BP7_nuclear_MAP2K1",
"additionalComments": "This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"label": "BP7",
"ns": "045",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328440",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328440",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7Ma---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_PM5_nuclear_MAP2K1",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes. This evidence rule can also be used for pathogenic missense variants seen in the same analogous residue position in highly analogous groupings below:\nGroup 1: HRAS, NRAS, KRAS\nGroup 2: MAP2K1, MAP2K2\nGroup 3: SOS1, SOS2\n\nThis rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a “mutational hot-spot”. For example, Gly12 in HRAS is listed as a hot-spot for PM1 usage. In these situations, only PM1 should be used when combining criteria for final variant classification in order to avoid premature designation of a likely pathogenic classification in the absence of other evidence for pathogenicity.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable for observed analogous residue positions in _MAP2K1_ and _MAP2K2_. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
"label": "PM5",
"ns": "045",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥2 different \\[likely\\] pathogenic residues changes at the same codon observed in ≥5 probands.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 \\[likely\\] pathogenic residue change at the same codon.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328439",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328439",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7Zy---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_PP3_nuclear_MAP2K1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"label": "PP3",
"ns": "045",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328426",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328426",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7Si--C"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_BS1_nuclear_MAP2K1",
"additionalComments": "An allele frequency ≥0.025% was approved. See supplemental material for additional frequency information.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "GnomAD filtering allele frequency ≥0.025%.",
"label": "BS1",
"ns": "045",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "GnomAD filtering allele frequency ≥0.025%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328442",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328442",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7YC---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_BS2_nuclear_MAP2K1",
"additionalComments": "Due to variable expressivity and severity, extensive clinical workup for RASopathy spectrum features is warranted, thus general population data should not be used for this criterion. Clinical laboratories are encouraged to accumulate more than 3 instances of well phenotyped family members before applying this strong criterion.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring based on phenotypic specifications. Phenotypic specifications: based on healthy homozygote or heterozygote individuals, reduced points for apparently unaffected heterozygous individuals, applicable to parent or sibling samples during clinical family evaluations.",
"label": "BS2",
"ns": "045",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "\\-4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "\\-1 Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328436",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328436",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7JG---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_BP1_nuclear_MAP2K1",
"additionalComments": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "Truncating, LOF variant in a gene for which primarily missense, GOF variants are known to cause disease.",
"label": "BP1",
"ns": "045",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328434",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328434",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7OK---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_BP3_nuclear_MAP2K1",
"additionalComments": "No known benign repetitive areas in RASopathy genes.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "045",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": "None",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328430",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328430",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7Pa---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_PM6_nuclear_MAP2K1",
"additionalComments": "PM6_Strong: ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.\nPS2_VeryStrong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PS2 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PM6",
"ns": "045",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 Points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328428",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328428",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7Du---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_PP1_nuclear_MAP2K1",
"additionalComments": "PP1_Moderate: ≥5 informative meioses\nPP1_Strong: ≥7 informative meioses",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "Segregation in more than one family is recommended.",
"label": "PP1",
"ns": "045",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥7 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥5 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥3 informative meioses.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328419",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328419",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7Ha---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_PVS1_nuclear_MAP2K1",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "045",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0244",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328417",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328417",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7WG---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_BP6_nuclear_MAP2K1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "045",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328416",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328416",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7b6---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_BP5_nuclear_MAP2K1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "Points are awarded for an alternative molecular cause of a RASopathy in a different gene (and/or in conjunction with BP2) and the phenotype is consistent with expected severity of the RASopathy. Points are also awarded for phenotypes inconsistent with a RASopathy and fully explained by a different causative variant (e.g. WES testing).",
"label": "BP5",
"ns": "045",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328438",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328438",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7B----"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_PM1_nuclear_MAP2K1",
"additionalComments": "See supplemental material for approved functional domains and residues. This evidence rule can also be applied for the same analogous residue positions/regions in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
"label": "PM1",
"ns": "045",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable only to critical and well-established functional domains available in the supplementary table (AA 43-61, AA 124-134). Not applicable to specific amino acid residues (see PM5).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328437",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328437",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7Ni---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_BP4_nuclear_MAP2K1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≤0.3. For splicing variants: predicted outcome is negligible or does not match disease mechanism.",
"label": "BP4",
"ns": "045",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "For missense variants: REVEL ≤0.3.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328433",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328433",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7Ra--D"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_BA1_nuclear_MAP2K1",
"additionalComments": "An allele frequency ≥0.05% was approved. See supplemental material for additional frequency information.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "GnomAD filtering allele frequency ≥0.05%.",
"label": "BA1",
"ns": "045",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "GnomAD filtering allele frequency ≥0.05%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328431",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328431",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7CC---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_PM3_nuclear_MAP2K1",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "045",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328425",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328425",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7FG---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_PM4_nuclear_MAP2K1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"label": "PM4",
"ns": "045",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "No known repetitive areas in gene. Use as described.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328423",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328423",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7TW---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_PM2_nuclear_MAP2K1",
"additionalComments": "The variant must be completely absent from all population databases.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "The variant must be absent from controls (gnomAD).",
"label": "PM2",
"ns": "045",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": "General",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The variant must be absent from controls (gnomAD).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328421",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328421",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7VS---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_BS3_nuclear_MAP2K1",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"label": "BS3",
"ns": "045",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328415",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328415",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7XO---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_BP2_nuclear_MAP2K1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "Points are awarded for an alternative molecular cause of a RASopathy in the same gene (and/or in conjunction with BP5) and the phenotype is consistent with expected severity of the RASopathy.",
"label": "BP2",
"ns": "045",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328432",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328432",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7LK---"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_PP4_nuclear_MAP2K1",
"additionalComments": "Not applicable, see PS4.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "045",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328424",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328424",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7Qi--A"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_BS4_nuclear_MAP2K1",
"additionalComments": "Requires only one informative meiosis and does not require an additional piece of supporting evidence to classify variant as likely benign.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "Lack of segregation in affected members of a family.",
"label": "BS4",
"ns": "045",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Requires only one informative meiosis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828328422",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828328422",
"modified": "2024-12-03T02:50:16.450Z",
"modifier": "RFWebb",
"rev": "_i2nq7UO--G"
},
{
"created": "2024-08-03T01:16:16.410Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "045_PS4_nuclear_MAP2K1",
"additionalComments": "PS4: ≥5 independent occurrences\nPS4_Moderate: ≥3 independent occurrences\nPS4_Supporting: ≥1 independent occurrences",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"MAP2K1"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring for autosomal dominant cases with phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
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],
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]
}
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"entType": "RuleSet",
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],
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},
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"created": "2024-08-03T01:15:05.085Z",
"creator": "cspecAdministrator",
"entContent": {
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"additionalComments": "See supplemental material for approved functional domains and residues. This evidence rule can also be applied for the same analogous residue positions/regions in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
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"strength": "Stand Alone",
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
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"strength": "Very Strong",
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"text": "",
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"id": "0028",
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],
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"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable only to critical and well-established functional domains available in the supplementary table (P-loop \\[AA 10-17\\], SW1 \\[AA 25-40\\], SW2 \\[AA 57-64\\], SAK \\[AA 145-156\\]). Not applicable to specific amino acid residues (see PM5).",
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"id": "0054",
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"status": "not approved",
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"strengthSepioID": "SEPIO:0000329",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
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"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0019",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
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"status": "not approved",
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"text": "",
"type": "EvidenceLineStrength"
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"status": "approved",
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"evidenceCategory": "Other Data",
"gene": [
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],
"geneType": "nuclear",
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"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
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"text": "",
"type": "EvidenceLineStrength"
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"text": "",
"type": "EvidenceLineStrength"
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"strength": "Strong",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
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"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
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"applicability": "Not applicable",
"id": "0063",
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"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
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"geneType": "nuclear",
"instructionsToUse": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"label": "PM4",
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"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
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"status": {
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
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"specificationType": [
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],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "No known repetitive areas in gene. Use as described.",
"type": "EvidenceLineStrength"
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"status": "not approved",
"strength": "Supporting",
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"creator": "cspecAdministrator",
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"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "Segregation in more than one family is recommended.",
"label": "PP1",
"ns": "046",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"instructionsToUse": "",
"specificationType": [
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"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥7 informative meioses.",
"type": "EvidenceLineStrength"
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{
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"specificationType": [
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"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥5 informative meioses.",
"type": "EvidenceLineStrength"
},
{
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"specificationType": [
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"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥3 informative meioses.",
"type": "EvidenceLineStrength"
}
]
},
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"ldhId": "1828327643",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828327643",
"modified": "2024-12-03T02:51:34.732Z",
"modifier": "RFWebb",
"rev": "_i2nsH2e---"
},
{
"created": "2024-08-03T01:15:05.085Z",
"creator": "cspecAdministrator",
"entContent": {
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"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
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"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
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"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "046",
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"references": [
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"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
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],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828327665",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828327665",
"modified": "2024-12-03T02:51:34.732Z",
"modifier": "RFWebb",
"rev": "_i2nsHdm---"
},
{
"created": "2024-08-03T01:15:05.085Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "046_BP7_nuclear_HRAS",
"additionalComments": "This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HRAS"
],
"geneType": "nuclear",
"instructionsToUse": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"label": "BP7",
"ns": "046",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828327664",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828327664",
"modified": "2024-12-03T02:51:34.732Z",
"modifier": "RFWebb",
"rev": "_i2nsHwC---"
},
{
"created": "2024-08-03T01:15:05.085Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "046_PP2_nuclear_HRAS",
"additionalComments": "Not applicable because missense z score is <3.09 in gnomAD.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"HRAS"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "046",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828327653",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828327653",
"modified": "2024-12-03T02:51:34.732Z",
"modifier": "RFWebb",
"rev": "_i2nsHjC---"
},
{
"created": "2024-08-03T01:15:05.085Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "046_PS3_nuclear_HRAS",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"HRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Approved assays are available in the supplemental materials.",
"label": "PS3",
"ns": "046",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Two or more different approved assays.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One approved assay.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828327651",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828327651",
"modified": "2024-12-03T02:51:34.732Z",
"modifier": "RFWebb",
"rev": "_i2nsHeK---"
},
{
"created": "2024-08-03T01:15:05.085Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "046_PM3_nuclear_HRAS",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"HRAS"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "046",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828327649",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828327649",
"modified": "2024-12-03T02:51:34.732Z",
"modifier": "RFWebb",
"rev": "_i2nsHp2---"
},
{
"created": "2024-08-03T01:15:05.085Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "046_PS2_nuclear_HRAS",
"additionalComments": "PS2_Very Strong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"HRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PM6 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS2",
"ns": "046",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828327644",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828327644",
"modified": "2024-12-03T02:51:34.732Z",
"modifier": "RFWebb",
"rev": "_i2nsHx2---"
},
{
"created": "2024-08-03T01:15:05.085Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "046_PS4_nuclear_HRAS",
"additionalComments": "PS4: ≥5 independent occurrences\nPS4_Moderate: ≥3 independent occurrences\nPS4_Supporting: ≥1 independent occurrences",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"HRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring for autosomal dominant cases with phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS4",
"ns": "046",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥5 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥3 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥1 points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828327642",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828327642",
"modified": "2024-12-03T02:51:34.732Z",
"modifier": "RFWebb",
"rev": "_i2nsH32---"
},
{
"created": "2024-08-03T01:15:05.085Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "046_PVS1_nuclear_HRAS",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HRAS"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "046",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0244",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828327641",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828327641",
"modified": "2024-12-03T02:51:34.732Z",
"modifier": "RFWebb",
"rev": "_i2nsHvC---"
},
{
"created": "2024-08-03T01:15:05.085Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "046_BP6_nuclear_HRAS",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"HRAS"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "046",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828327640",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828327640",
"modified": "2024-12-03T02:51:34.732Z",
"modifier": "RFWebb",
"rev": "_i2nsHfK---"
},
{
"created": "2024-08-03T01:15:05.085Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "046_BS1_nuclear_HRAS",
"additionalComments": "An allele frequency ≥0.025% was approved. See supplemental material for additional frequency information.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"HRAS"
],
"geneType": "nuclear",
"instructionsToUse": "GnomAD filtering allele frequency ≥0.025%.",
"label": "BS1",
"ns": "046",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "GnomAD filtering allele frequency ≥0.025%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828327666",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828327666",
"modified": "2024-12-03T02:51:34.732Z",
"modifier": "RFWebb",
"rev": "_i2nsHz----"
},
{
"created": "2024-08-03T01:15:05.085Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "046_BP5_nuclear_HRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"HRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Points are awarded for an alternative molecular cause of a RASopathy in a different gene (and/or in conjunction with BP2) and the phenotype is consistent with expected severity of the RASopathy. Points are also awarded for phenotypes inconsistent with a RASopathy and fully explained by a different causative variant (e.g. WES testing).",
"label": "BP5",
"ns": "046",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828327662",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828327662",
"modified": "2024-12-03T02:51:34.732Z",
"modifier": "RFWebb",
"rev": "_i2nsHly---"
},
{
"created": "2024-08-03T01:15:05.085Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "046_BS2_nuclear_HRAS",
"additionalComments": "Due to variable expressivity and severity, extensive clinical workup for RASopathy spectrum features is warranted, thus general population data should not be used for this criterion. Clinical laboratories are encouraged to accumulate more than 3 instances of well phenotyped family members before applying this strong criterion.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"HRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring based on phenotypic specifications. Phenotypic specifications: based on healthy homozygote or heterozygote individuals, reduced points for apparently unaffected heterozygous individuals, applicable to parent or sibling samples during clinical family evaluations.",
"label": "BS2",
"ns": "046",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "\\-4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "\\-1 Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828327660",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828327660",
"modified": "2024-12-03T02:51:34.732Z",
"modifier": "RFWebb",
"rev": "_i2nsHgO---"
},
{
"created": "2024-08-03T01:15:05.085Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "046_BA1_nuclear_HRAS",
"additionalComments": "An allele frequency ≥0.05% was approved. See supplemental material for additional frequency information.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"HRAS"
],
"geneType": "nuclear",
"instructionsToUse": "GnomAD filtering allele frequency ≥0.05%.",
"label": "BA1",
"ns": "046",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "GnomAD filtering allele frequency ≥0.05%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828327655",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828327655",
"modified": "2024-12-03T02:51:34.732Z",
"modifier": "RFWebb",
"rev": "_i2nsHhO---"
},
{
"created": "2024-08-03T01:15:05.085Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "046_BS4_nuclear_HRAS",
"additionalComments": "Requires only one informative meiosis and does not require an additional piece of supporting evidence to classify variant as likely benign.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"HRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Lack of segregation in affected members of a family.",
"label": "BS4",
"ns": "046",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Requires only one informative meiosis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828327646",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828327646",
"modified": "2024-12-03T02:51:34.732Z",
"modifier": "RFWebb",
"rev": "_i2nsHt---M"
},
{
"created": "2024-08-03T01:15:05.085Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "046_PM2_nuclear_HRAS",
"additionalComments": "The variant must be completely absent from all population databases.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"HRAS"
],
"geneType": "nuclear",
"instructionsToUse": "The variant must be absent from controls (gnomAD).",
"label": "PM2",
"ns": "046",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": "General",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The variant must be absent from controls (gnomAD).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828327645",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828327645",
"modified": "2024-12-03T02:51:34.732Z",
"modifier": "RFWebb",
"rev": "_i2nsHt2---"
},
{
"created": "2024-08-03T01:15:05.085Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "046_BP2_nuclear_HRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"HRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Points are awarded for an alternative molecular cause of a RASopathy in the same gene (and/or in conjunction with BP5) and the phenotype is consistent with expected severity of the RASopathy.",
"label": "BP2",
"ns": "046",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828327656",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828327656",
"modified": "2024-12-03T02:51:34.732Z",
"modifier": "RFWebb",
"rev": "_i2nsH1y---"
},
{
"created": "2024-08-03T01:15:05.085Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "046_PM6_nuclear_HRAS",
"additionalComments": "PM6_Strong: ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.\nPS2_VeryStrong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"HRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PS2 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PM6",
"ns": "046",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 Points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828327652",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828327652",
"modified": "2024-12-03T02:51:34.732Z",
"modifier": "RFWebb",
"rev": "_i2nsHo2---"
},
{
"created": "2024-08-03T01:15:05.085Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "046_BS3_nuclear_HRAS",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"HRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"label": "BS3",
"ns": "046",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828327639",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828327639",
"modified": "2024-12-03T02:51:34.732Z",
"modifier": "RFWebb",
"rev": "_i2nsHl----"
},
{
"created": "2024-08-03T01:15:05.085Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "046_PM5_nuclear_HRAS",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes. This evidence rule can also be used for pathogenic missense variants seen in the same analogous residue position in highly analogous groupings below:\nGroup 1: HRAS, NRAS, KRAS\nGroup 2: MAP2K1, MAP2K2\nGroup 3: SOS1, SOS2\n\nThis rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a “mutational hot-spot”. For example, Gly12 in HRAS is listed as a hot-spot for PM1 usage. In these situations, only PM1 should be used when combining criteria for final variant classification in order to avoid premature designation of a likely pathogenic classification in the absence of other evidence for pathogenicity.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable for observed analogous residue positions in _HRAS_, _KRAS_, _MRAS_, _NRAS_, _RIT1_, and _RRAS2_. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
"label": "PM5",
"ns": "046",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
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"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326904",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326904",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nthxW---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_BP4_nuclear_RIT1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≤0.3. For splicing variants: predicted outcome is negligible or does not match disease mechanism.",
"label": "BP4",
"ns": "047",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "For missense variants: REVEL ≤0.3.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326896",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326896",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nth1m---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_PVS1_nuclear_RIT1",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "047",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0244",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326880",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326880",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nti-e---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_BS3_nuclear_RIT1",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"label": "BS3",
"ns": "047",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326878",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326878",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nthte---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_PM1_nuclear_RIT1",
"additionalComments": "See supplemental material for approved functional domains and residues. This evidence rule can also be applied for the same analogous residue positions/regions in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
"label": "PM1",
"ns": "047",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable only to critical and well-established functional domains available in the supplementary table (P-loop \\[AA 28-35\\], SW1 \\[AA 43-58\\], SW2 \\[AA 75-82\\], no SAK). Not applicable to specific amino acid residues (see PM5).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326900",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326900",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nthze---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_PS1_nuclear_RIT1",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria for germline RASopathy variants. This evidence rule can also be applied for the any observed analogous residue positions/regions throughout the gene in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"label": "PS1",
"ns": "047",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in _HRAS, KRAS, MRAS, NRAS, RIT1,_ and _RRAS2._",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326898",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326898",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nth0i---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_BP1_nuclear_RIT1",
"additionalComments": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "Truncating, LOF variant in a gene for which primarily missense, GOF variants are known to cause disease.",
"label": "BP1",
"ns": "047",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326897",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326897",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nth42--A"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_BP2_nuclear_RIT1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "Points are awarded for an alternative molecular cause of a RASopathy in the same gene (and/or in conjunction with BP5) and the phenotype is consistent with expected severity of the RASopathy.",
"label": "BP2",
"ns": "047",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326895",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326895",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nthry---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_BS1_nuclear_RIT1",
"additionalComments": "An allele frequency ≥0.025% was approved. See supplemental material for additional frequency information.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "GnomAD filtering allele frequency ≥0.025%.",
"label": "BS1",
"ns": "047",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "GnomAD filtering allele frequency ≥0.025%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326905",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326905",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nti_O---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_PM5_nuclear_RIT1",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes. This evidence rule can also be used for pathogenic missense variants seen in the same analogous residue position in highly analogous groupings below:\nGroup 1: HRAS, NRAS, KRAS\nGroup 2: MAP2K1, MAP2K2\nGroup 3: SOS1, SOS2\n\nThis rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a “mutational hot-spot”. For example, Gly12 in HRAS is listed as a hot-spot for PM1 usage. In these situations, only PM1 should be used when combining criteria for final variant classification in order to avoid premature designation of a likely pathogenic classification in the absence of other evidence for pathogenicity.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable for observed analogous residue positions in HRAS, KRAS, MRAS, NRAS, RIT1, and RRAS2. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
"label": "PM5",
"ns": "047",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥2 different \\[likely\\] pathogenic residues changes at the same codon observed in ≥5 probands.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 \\[likely\\] pathogenic residue change at the same codon.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326902",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326902",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nth4O--D"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_PP3_nuclear_RIT1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"label": "PP3",
"ns": "047",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326889",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326889",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nthva---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_PM2_nuclear_RIT1",
"additionalComments": "The variant must be completely absent from all population databases.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "The variant must be absent from controls (gnomAD).",
"label": "PM2",
"ns": "047",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The variant must be absent from controls (gnomAD).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326884",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326884",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nth8W---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_PS4_nuclear_RIT1",
"additionalComments": "PS4: ≥5 independent occurrences\nPS4_Moderate: ≥3 independent occurrences\nPS4_Supporting: ≥1 independent occurrences",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring for autosomal dominant cases with phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS4",
"ns": "047",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥5 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥3 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥1 point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326881",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326881",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nthwe---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_BP3_nuclear_RIT1",
"additionalComments": "No known benign repetitive areas in RASopathy genes.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "047",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": "None",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326893",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326893",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nth2W---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_PP2_nuclear_RIT1",
"additionalComments": "Not applicable because missense z score is <3.09 in gnomAD.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "047",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326892",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326892",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2ntiB----"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_PM6_nuclear_RIT1",
"additionalComments": "PM6_Strong: ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.\nPS2_VeryStrong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PS2 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PM6",
"ns": "047",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 Points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326891",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326891",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nth6i---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_PM3_nuclear_RIT1",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "047",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326888",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326888",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nth7y---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_PP4_nuclear_RIT1",
"additionalComments": "Not applicable, see PS4.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "047",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326887",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326887",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2ntiD----"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_PM4_nuclear_RIT1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"label": "PM4",
"ns": "047",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "No known repetitive areas in gene. Use as described.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326886",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326886",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nth3a---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_PS2_nuclear_RIT1",
"additionalComments": "PS2_Very Strong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PM6 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS2",
"ns": "047",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326883",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326883",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2ntiDq---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_PP1_nuclear_RIT1",
"additionalComments": "PP1_Moderate: ≥5 informative meioses\nPP1_Strong: ≥7 informative meioses",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "Segregation in more than one family is recommended.",
"label": "PP1",
"ns": "047",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥7 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥5 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥3 informative meioses.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326882",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326882",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nth9W---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_BP7_nuclear_RIT1",
"additionalComments": "This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"label": "BP7",
"ns": "047",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326903",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326903",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nthyS---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_BP5_nuclear_RIT1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "Points are awarded for an alternative molecular cause of a RASopathy in a different gene (and/or in conjunction with BP2) and the phenotype is consistent with expected severity of the RASopathy. Points are also awarded for phenotypes inconsistent with a RASopathy and fully explained by a different causative variant (e.g. WES testing).",
"label": "BP5",
"ns": "047",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326901",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326901",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nthuW---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_BS2_nuclear_RIT1",
"additionalComments": "Due to variable expressivity and severity, extensive clinical workup for RASopathy spectrum features is warranted, thus general population data should not be used for this criterion. Clinical laboratories are encouraged to accumulate more than 3 instances of well phenotyped family members before applying this strong criterion.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring based on phenotypic specifications. Phenotypic specifications: based on healthy homozygote or heterozygote individuals, reduced points for apparently unaffected heterozygous individuals, applicable to parent or sibling samples during clinical family evaluations.",
"label": "BS2",
"ns": "047",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "\\-4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "\\-1 Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326899",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326899",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2ntiAG---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_BA1_nuclear_RIT1",
"additionalComments": "An allele frequency ≥0.05% was approved. See supplemental material for additional frequency information.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "GnomAD filtering allele frequency ≥0.05%.",
"label": "BA1",
"ns": "047",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "GnomAD filtering allele frequency ≥0.05%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326894",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326894",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2nth6C---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_PS3_nuclear_RIT1",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Approved assays are available in the supplemental materials.",
"label": "PS3",
"ns": "047",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Two or more different approved assays.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One approved assay.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326890",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326890",
"modified": "2024-12-03T02:53:07.122Z",
"modifier": "RFWebb",
"rev": "_i2ntiB6---"
},
{
"created": "2024-08-03T01:14:11.111Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "047_BS4_nuclear_RIT1",
"additionalComments": "Requires only one informative meiosis and does not require an additional piece of supporting evidence to classify variant as likely benign.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"RIT1"
],
"geneType": "nuclear",
"instructionsToUse": "Lack of segregation in affected members of a family.",
"label": "BS4",
"ns": "047",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Requires only one informative meiosis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
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"text": "",
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"text": "",
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"text": "",
"type": "EvidenceLineStrength"
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"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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"text": "One approved assay.",
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"defaultStrength": "Pathogenic Moderate",
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"instructionsToUse": "Applicable for observed analogous residue positions in _MAP2K1_ and _MAP2K2_. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
"label": "PM5",
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"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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"id": "0047",
"instructionsToUse": "",
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"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥2 different \\[likely\\] pathogenic residues changes at the same codon observed in ≥5 probands.",
"type": "EvidenceLineStrength"
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"strengthSepioID": "SEPIO:0000216",
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"type": "EvidenceLineStrength"
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"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
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"entType": "CriteriaCode",
"ldhId": "1828326132",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326132",
"modified": "2024-12-03T02:42:20.827Z",
"modifier": "RFWebb",
"rev": "_i2njqru---"
},
{
"created": "2024-08-03T01:13:05.596Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "048_PP1_nuclear_MAP2K2",
"additionalComments": "PP1_Moderate: ≥5 informative meioses\nPP1_Strong: ≥7 informative meioses",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"MAP2K2"
],
"geneType": "nuclear",
"instructionsToUse": "Segregation in more than one family is recommended.",
"label": "PP1",
"ns": "048",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥7 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥5 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥3 informative meioses.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326112",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326112",
"modified": "2024-12-03T02:42:20.827Z",
"modifier": "RFWebb",
"rev": "_i2njq0S---"
},
{
"created": "2024-08-03T01:13:05.596Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "048_BS3_nuclear_MAP2K2",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"MAP2K2"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"label": "BS3",
"ns": "048",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326108",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326108",
"modified": "2024-12-03T02:42:20.827Z",
"modifier": "RFWebb",
"rev": "_i2njqnK---"
},
{
"created": "2024-08-03T01:13:05.596Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "048_PP5_nuclear_MAP2K2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"MAP2K2"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "048",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326134",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326134",
"modified": "2024-12-03T02:42:20.827Z",
"modifier": "RFWebb",
"rev": "_i2njqoS---"
},
{
"created": "2024-08-03T01:13:05.596Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "048_BP7_nuclear_MAP2K2",
"additionalComments": "This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MAP2K2"
],
"geneType": "nuclear",
"instructionsToUse": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"label": "BP7",
"ns": "048",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326133",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326133",
"modified": "2024-12-03T02:42:20.827Z",
"modifier": "RFWebb",
"rev": "_i2njq1W---"
},
{
"created": "2024-08-03T01:13:05.596Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "048_PS1_nuclear_MAP2K2",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria for germline RASopathy variants. This evidence rule can also be applied for the any observed analogous residue positions/regions throughout the gene in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MAP2K2"
],
"geneType": "nuclear",
"instructionsToUse": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"label": "PS1",
"ns": "048",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in _MAP2K1_ and _MAP2K2._",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326128",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326128",
"modified": "2024-12-03T02:42:20.827Z",
"modifier": "RFWebb",
"rev": "_i2njqi6---"
},
{
"created": "2024-08-03T01:13:05.596Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "048_BP3_nuclear_MAP2K2",
"additionalComments": "No known benign repetitive areas in RASopathy genes.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MAP2K2"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "048",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": "None",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326123",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326123",
"modified": "2024-12-03T02:42:20.827Z",
"modifier": "RFWebb",
"rev": "_i2njqmO---"
},
{
"created": "2024-08-03T01:13:05.596Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "048_PP3_nuclear_MAP2K2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MAP2K2"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"label": "PP3",
"ns": "048",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326119",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326119",
"modified": "2024-12-03T02:42:20.827Z",
"modifier": "RFWebb",
"rev": "_i2njqui---"
},
{
"created": "2024-08-03T01:13:05.596Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "048_PP4_nuclear_MAP2K2",
"additionalComments": "Not applicable, see PS4.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"MAP2K2"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "048",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326117",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326117",
"modified": "2024-12-03T02:42:20.827Z",
"modifier": "RFWebb",
"rev": "_i2njqyS---"
},
{
"created": "2024-08-03T01:13:05.596Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "048_PVS1_nuclear_MAP2K2",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MAP2K2"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "048",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0244",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326110",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326110",
"modified": "2024-12-03T02:42:20.827Z",
"modifier": "RFWebb",
"rev": "_i2njqwa---"
},
{
"created": "2024-08-03T01:13:05.596Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "048_BS1_nuclear_MAP2K2",
"additionalComments": "An allele frequency ≥0.025% was approved. See supplemental material for additional frequency information.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"MAP2K2"
],
"geneType": "nuclear",
"instructionsToUse": "GnomAD filtering allele frequency ≥0.025%.",
"label": "BS1",
"ns": "048",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "GnomAD filtering allele frequency ≥0.025%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326135",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326135",
"modified": "2024-12-03T02:42:20.827Z",
"modifier": "RFWebb",
"rev": "_i2njqh6---"
},
{
"created": "2024-08-03T01:13:05.596Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "048_BP5_nuclear_MAP2K2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"MAP2K2"
],
"geneType": "nuclear",
"instructionsToUse": "Points are awarded for an alternative molecular cause of a RASopathy in a different gene (and/or in conjunction with BP2) and the phenotype is consistent with expected severity of the RASopathy. Points are also awarded for phenotypes inconsistent with a RASopathy and fully explained by a different causative variant (e.g. WES testing).",
"label": "BP5",
"ns": "048",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326131",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326131",
"modified": "2024-12-03T02:42:20.827Z",
"modifier": "RFWebb",
"rev": "_i2njqo6---"
},
{
"created": "2024-08-03T01:13:05.596Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "048_BP1_nuclear_MAP2K2",
"additionalComments": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MAP2K2"
],
"geneType": "nuclear",
"instructionsToUse": "Truncating, LOF variant in a gene for which primarily missense, GOF variants are known to cause disease.",
"label": "BP1",
"ns": "048",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326127",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326127",
"modified": "2024-12-03T02:42:20.827Z",
"modifier": "RFWebb",
"rev": "_i2njqjq---"
},
{
"created": "2024-08-03T01:13:05.596Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "048_BP4_nuclear_MAP2K2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MAP2K2"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≤0.3. For splicing variants: predicted outcome is negligible or does not match disease mechanism.",
"label": "BP4",
"ns": "048",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "For missense variants: REVEL ≤0.3.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326126",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326126",
"modified": "2024-12-03T02:42:20.827Z",
"modifier": "RFWebb",
"rev": "_i2njqp2---"
},
{
"created": "2024-08-03T01:13:05.596Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "048_PM3_nuclear_MAP2K2",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"MAP2K2"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "048",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326118",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326118",
"modified": "2024-12-03T02:42:20.827Z",
"modifier": "RFWebb",
"rev": "_i2njq3u---"
},
{
"created": "2024-08-03T01:13:05.596Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "048_PM4_nuclear_MAP2K2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MAP2K2"
],
"geneType": "nuclear",
"instructionsToUse": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"label": "PM4",
"ns": "048",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "No known repetitive areas in gene. Use as described.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326116",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326116",
"modified": "2024-12-03T02:42:20.827Z",
"modifier": "RFWebb",
"rev": "_i2njq5----"
},
{
"created": "2024-08-03T01:13:05.596Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "048_PM2_nuclear_MAP2K2",
"additionalComments": "The variant must be completely absent from all population databases.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"MAP2K2"
],
"geneType": "nuclear",
"instructionsToUse": "The variant must be absent from controls (gnomAD).",
"label": "PM2",
"ns": "048",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": "General",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The variant must be absent from controls (gnomAD).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326114",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326114",
"modified": "2024-12-03T02:42:20.827Z",
"modifier": "RFWebb",
"rev": "_i2njq5y---"
},
{
"created": "2024-08-03T01:13:05.596Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "048_PS2_nuclear_MAP2K2",
"additionalComments": "PS2_Very Strong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"MAP2K2"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PM6 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS2",
"ns": "048",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326113",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326113",
"modified": "2024-12-03T02:42:20.827Z",
"modifier": "RFWebb",
"rev": "_i2njqzG---"
},
{
"created": "2024-08-03T01:13:05.596Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "048_PS4_nuclear_MAP2K2",
"additionalComments": "PS4: ≥5 independent occurrences\nPS4_Moderate: ≥3 independent occurrences\nPS4_Supporting: ≥1 independent occurrences",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"MAP2K2"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring for autosomal dominant cases with phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS4",
"ns": "048",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥5 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥3 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥1 points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828326111",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828326111",
"modified": "2024-12-03T02:42:20.827Z",
"modifier": "RFWebb",
"rev": "_i2njqvq---"
},
{
"created": "2024-08-03T01:13:05.596Z",
"creator": "cspecAdministrator",
"entContent": {
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"text": "",
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"versioned": true
},
"entId": "GN049",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_PM5_nuclear_BRAF",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes. This evidence rule can also be used for pathogenic missense variants seen in the same analogous residue position in highly analogous groupings below:\nGroup 1: HRAS, NRAS, KRAS\nGroup 2: MAP2K1, MAP2K2\nGroup 3: SOS1, SOS2\n\nThis rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a “mutational hot-spot”. For example, Gly12 in HRAS is listed as a hot-spot for PM1 usage. In these situations, only PM1 should be used when combining criteria for final variant classification in order to avoid premature designation of a likely pathogenic classification in the absence of other evidence for pathogenicity.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable for observed analogous residue positions in _BRAF_ and _RAF1_. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
"label": "PM5",
"ns": "049",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥2 different \\[likely\\] pathogenic residues changes at the same codon observed in ≥5 probands.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 \\[likely\\] pathogenic residue change at the same codon.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325252",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325252",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpQS---"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_BP1_nuclear_BRAF",
"additionalComments": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "Truncating, LOF variant in a gene for which primarily missense, GOF variants are known to cause disease.",
"label": "BP1",
"ns": "049",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325247",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325247",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpYK---"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_BP4_nuclear_BRAF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≤0.3. For splicing variants: predicted outcome is negligible or does not match disease mechanism.",
"label": "BP4",
"ns": "049",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "For missense variants: REVEL ≤0.3.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325246",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325246",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpby---"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_PS2_nuclear_BRAF",
"additionalComments": "PS2_Very Strong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PM6 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS2",
"ns": "049",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325233",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325233",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUphK--_"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_PP5_nuclear_BRAF",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "049",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325254",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325254",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpW----"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_BP2_nuclear_BRAF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "Points are awarded for an alternative molecular cause of a RASopathy in the same gene (and/or in conjunction with BP5) and the phenotype is consistent with expected severity of the RASopathy.",
"label": "BP2",
"ns": "049",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325245",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325245",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpRm---"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_PP2_nuclear_BRAF",
"additionalComments": "PP2 is applicable to all RASopathy genes described and curated herein.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"label": "PP2",
"ns": "049",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense z score is >3.09 in gnomAD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325242",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325242",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpZS---"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_BS3_nuclear_BRAF",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"label": "BS3",
"ns": "049",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325228",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325228",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpVG---"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_PM1_nuclear_BRAF",
"additionalComments": "See supplemental material for approved functional domains and residues. This evidence rule can also be applied for the same analogous residue positions/regions in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
"label": "PM1",
"ns": "049",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable only to critical and well-established functional domains available in the supplementary table (exon 6, exon 11, P-loop \\[AA 459-474\\], CR3 activation segment \\[AA 594-627\\]). Not applicable to specific amino acid residues (see PM5).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325250",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325250",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpf----"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_PP3_nuclear_BRAF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"label": "PP3",
"ns": "049",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325239",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325239",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpMK---"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_BP5_nuclear_BRAF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "Points are awarded for an alternative molecular cause of a RASopathy in a different gene (and/or in conjunction with BP2) and the phenotype is consistent with expected severity of the RASopathy. Points are also awarded for phenotypes inconsistent with a RASopathy and fully explained by a different causative variant (e.g. WES testing).",
"label": "BP5",
"ns": "049",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325251",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325251",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpdy---"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_PM3_nuclear_BRAF",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "049",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325238",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325238",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpNW---"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_PP4_nuclear_BRAF",
"additionalComments": "Not applicable, see PS4.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "049",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325237",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325237",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpaO---"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_PM4_nuclear_BRAF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"label": "PM4",
"ns": "049",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "No known repetitive areas in gene. Use as described.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325236",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325236",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpbG---"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_BS4_nuclear_BRAF",
"additionalComments": "Requires only one informative meiosis and does not require an additional piece of supporting evidence to classify variant as likely benign.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "Lack of segregation in affected members of a family.",
"label": "BS4",
"ns": "049",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Requires only one informative meiosis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325235",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325235",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpTK---"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_PM2_nuclear_BRAF",
"additionalComments": "The variant must be completely absent from all population databases.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "The variant must be absent from controls (gnomAD).",
"label": "PM2",
"ns": "049",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The variant must be absent from controls (gnomAD).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325234",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325234",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpgG---"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_BP6_nuclear_BRAF",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "049",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325229",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325229",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpU----"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_BS1_nuclear_BRAF",
"additionalComments": "An allele frequency ≥0.025% was approved. See supplemental material for additional frequency information.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "GnomAD filtering allele frequency ≥0.025%.",
"label": "BS1",
"ns": "049",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "GnomAD filtering allele frequency ≥0.025%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325255",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325255",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpOO---"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_BP7_nuclear_BRAF",
"additionalComments": "This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"label": "BP7",
"ns": "049",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325253",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325253",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpPa---"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_BS2_nuclear_BRAF",
"additionalComments": "Due to variable expressivity and severity, extensive clinical workup for RASopathy spectrum features is warranted, thus general population data should not be used for this criterion. Clinical laboratories are encouraged to accumulate more than 3 instances of well phenotyped family members before applying this strong criterion.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring based on phenotypic specifications. Phenotypic specifications: based on healthy homozygote or heterozygote individuals, reduced points for apparently unaffected heterozygous individuals, applicable to parent or sibling samples during clinical family evaluations.",
"label": "BS2",
"ns": "049",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "\\-4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "\\-1 Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325249",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325249",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpJC---"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_PS1_nuclear_BRAF",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria for germline RASopathy variants. This evidence rule can also be applied for the any observed analogous residue positions/regions throughout the gene in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"label": "PS1",
"ns": "049",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in _BRAF_ and _RAF1_.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325248",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325248",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpX----"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_BA1_nuclear_BRAF",
"additionalComments": "An allele frequency ≥0.05% was approved. See supplemental material for additional frequency information.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "GnomAD filtering allele frequency ≥0.05%.",
"label": "BA1",
"ns": "049",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "GnomAD filtering allele frequency ≥0.05%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325244",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325244",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpKC---"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_BP3_nuclear_BRAF",
"additionalComments": "No known benign repetitive areas in RASopathy genes.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "049",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": "None",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325243",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325243",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpdO---"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_PM6_nuclear_BRAF",
"additionalComments": "PM6_Strong: ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.\nPS2_VeryStrong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PS2 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PM6",
"ns": "049",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 Points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325241",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325241",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpSS---"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_PS3_nuclear_BRAF",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Approved assays are available in the supplemental materials.",
"label": "PS3",
"ns": "049",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Two or more different approved assays.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One approved assay.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325240",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325240",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpL----"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_PP1_nuclear_BRAF",
"additionalComments": "PP1_Moderate: ≥5 informative meioses\nPP1_Strong: ≥7 informative meioses",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "Segregation in more than one family is recommended.",
"label": "PP1",
"ns": "049",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥7 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥5 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥3 informative meioses.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828325232",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828325232",
"modified": "2024-12-03T02:25:56.358Z",
"modifier": "RFWebb",
"rev": "_i2nUpiG--_"
},
{
"created": "2024-08-03T01:10:06.892Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "049_PS4_nuclear_BRAF",
"additionalComments": "PS4: ≥5 independent occurrences\nPS4_Moderate: ≥3 independent occurrences\nPS4_Supporting: ≥1 independent occurrences",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"BRAF"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring for autosomal dominant cases with phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS4",
"ns": "049",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥5 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
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"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 points** will arrive at **Very Strong**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110683",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110683",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtfue---"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BS1",
"ns": "067",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not Applicable",
"id": "0090",
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"specificationType": [],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency is above 0.0004% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110678",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110678",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtf3----"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_BS2_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "067",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in a healthy adult individual.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110668",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110668",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtf6----"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_BS4_nuclear_SCN1A",
"additionalComments": "Reduced penetrance, variable expressivity and phenocopies",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "067",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Not applicable",
"id": "0071",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110665",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110665",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtgI6---"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PM5_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"instructionsToUse": "The paralogous sodium channels genes associated with neurodevelomental disorders (SCN1A, SCN2A, SCN3A, SCN8A) share >77% sequence identity (PMID:33531663). In other words, the sodium channel genes share 87.7% (SCN2A), 84.7% (SCN3A), and 77.0% (SCN8A) amino acid sequence similarly with SCN1A (Ensembl). \n\nThe four functional homologous domains with voltage sensor and pore region remains largely preserved across the channels. Differences lie within the terminal regions and cytoplasmic loops. When these regions are excluded from analysis, homology increases to >90% (PMID:33531663; PMID:16382098). \n\nAs such, Pathogenic and Likely Pathogenic variants in paralogous genes can be considered for PM5.\n\n**Rule Combining Stipulation**: If PM5\\_Strong is reached, and the variant falls within a PM1 region, then do not add PM1 with PM5\\_Strong.",
"label": "PM5",
"ns": "067",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene).",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Novel missense change at an amino acid residue in the same gene where a different missense variant was determined to be Pathogenic.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Novel missense change at an amino acid residue where a different missense change determined to be **Likely Pathogenic** has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. \n* \\>1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be **Pathogenic** or **Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110663",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110663",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtfz6---"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PS4_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"instructionsToUse": "*Clinical Criteria for Dravet Syndrome: Based on Li et al, 2021 (PMID: 34338318)
Major features
-Fever-sensitive seizures,
-Hemiclonic or tonic-clonic seizures,
-Status epilepticus
Minor criteria (at least 3)
-Normal development prior to seizure onset
-Seizure onset <=12m
-Developmental impairment by age 5y
-Intellectual disability",
"label": "PS4",
"ns": "067",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **16+ points** will arrive at **Very Strong**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4-15.5 points** will arrive at **Strong**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2-3.5 points** will arrive at **Moderate**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1-1.5 points** will arrive at **Supporting**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110661",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110661",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtgH----"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PM4_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "067",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110659",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110659",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtgAi---"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PM6_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"instructionsToUse": "*Clinical Criteria for Dravet Syndrome: Based on Li et al, 2021 (PMID: 34338318)
Major features
-Fever-sensitive seizures,
-Hemiclonic or tonic-clonic seizures,
-Status epilepticus
Minor criteria (at least 3)
-Normal development prior to seizure onset
-Seizure onset <=12m
-Developmental impairment by age 5y
-Intellectual disability",
"label": "PM6",
"ns": "067",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. Total of **4 points** will arrive at **Very Strong**. \n\nDravet\\*: 1 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 0.5 points\n\nDevelopmental and Epileptic Encephalopathy: 0.5 points\n\nHemiplegic migraine: 0.25 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\nDravet\\*: 1 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 0.5 points\n\nDevelopmental and Epileptic Encephalopathy: 0.5 points\n\nHemiplegic migraine: 0.25 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\nDravet\\*: 1 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 0.5 points\n\nDevelopmental and Epileptic Encephalopathy: 0.5 points\n\nHemiplegic migraine: 0.25 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110674",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110674",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtg-S---"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
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"additionalComments": "Benign missense variants are common. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "067",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110667",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110667",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtgFW---"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PP1_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "067",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n\n\\>=7 independent meioses",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n\n5-6 independent meioses",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"May be used as stronger evidence with increasing segregation data"
]
},
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n\n3-4 independent meioses",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110680",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110680",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtf9O---"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_BP5_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "067",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110679",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110679",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtgCK---"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PP3_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP3",
"ns": "067",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)) using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)) using REVEL as the computational tool, with the following stipulations: with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110676",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110676",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtf3q---"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_BP7_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "067",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110675",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110675",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtgIK---"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PM1_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"instructionsToUse": "Pathogenic Enriched Regions (PERs): Regions that are enriched for Pathogenic variants (ClinVar/HGMD) across gene families, lack population (gnomAD) variants. Pérez-Palma, 2020 [PMID: 31871067](https://pubmed.ncbi.nlm.nih.gov/31871067/) & Lal et al, 2020 [PMID: 32183904](https://pubmed.ncbi.nlm.nih.gov/32183904/)",
"label": "PM1",
"ns": "067",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table\".",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110671",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110671",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtfvu---"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PP5_nuclear_SCN1A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "067",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110669",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110669",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtfwm---"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_BS3_nuclear_SCN1A",
"additionalComments": "Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "067",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
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"strength": "Moderate",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0085",
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"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
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"modifier": "laceysmith",
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},
{
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"creator": "laceysmith",
"entContent": {
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"applicability": "Not Applicable for this VCEP",
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"evidenceCategory": "Other Database",
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"references": [
{
"id": "29543229",
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],
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"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
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"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
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"ldhId": "1746110685",
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"modifier": "laceysmith",
"rev": "_jCDtf1u---"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
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"additionalComments": "Phenotypic specificity incorporated into PS2, PM6, PS4",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PP4",
"ns": "067",
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"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0018",
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"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0063",
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"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110682",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtgBO---"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
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"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "If a variant is found to have differences from wildtype of multiple levels of strength (example: strong level of evidence in peak current and moderate level of evidence in persistent current), use the highest level of evidence (capping at strong). If a variant has been studied in multiple publications, use the strongest level of evidence available.",
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"ns": "067",
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"sepioID": "SEPIO-CG:99025",
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"strengthDescriptor": [
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"id": "0242",
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"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"id": "0031",
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"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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{
"additionalComments": {
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"applicability": "Applicable",
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"specificationType": [
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"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 72.7% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 135% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.2 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 4.1 mV (absolute value).\n* Mouse knock-in model displays spontaneous seizures.",
"type": "EvidenceLineStrength"
},
{
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"id": "0039",
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"specificationType": [
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"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 80.6% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 125% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.1 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 3.0 mV (absolute value).\n* Mouse knock-in model displays induced seizures\n* Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies",
"type": "EvidenceLineStrength"
},
{
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"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110677",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110677",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtgDS---"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
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"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BA1",
"ns": "067",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
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"status": {
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"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
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"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency is above 0.02% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
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"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtg_q---"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
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"additionalComments": "SCN1A is associated with autosomal dominant inheritance. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PM3",
"ns": "067",
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"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
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"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
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]
},
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
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"ldhId": "1746110670",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110670",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtgEC---"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_BP2_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BP2",
"ns": "067",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
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"Pilot Rules In Prep": {
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"id": "0209",
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"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110662",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110662",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtgGa---"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_BP4_nuclear_SCN1A",
"additionalComments": "Replicating methodologies by Pejaver et al, 2022 and Johnston et al, 2021 (PMID: 33767344), REVEL scores could not be obtained for Benign calculations. ",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BP4",
"ns": "067",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
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},
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"strengthDescriptor": [
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"id": "0215",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0213",
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"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0066",
"instructionsToUse": "",
"status": "approved",
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"text": "",
"type": "EvidenceLineStrength"
},
{
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"specificationType": [
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],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)) using REVEL as the computational tool.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
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]
},
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"id": "0080",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)) using REVEL as the computational tool.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110686",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110686",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
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{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
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"evidenceCategory": "Computational And Predictive Data",
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"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
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"completed": true
},
"Pilot Rules In Prep": {
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"status": "approved",
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"text": "",
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{
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"id": "0210",
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"status": "approved",
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"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0074",
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"status": "approved",
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"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
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{
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"status": "approved",
"strength": "Moderate",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"specificationType": [
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"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In frame-deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110681",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746110681",
"modified": "2025-01-07T15:43:35.621Z",
"modifier": "laceysmith",
"rev": "_jCDtf8----"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)) using REVEL as the computational tool.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111570",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111570",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
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},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PP1",
"ns": "068",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
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"completed": true
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"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "\\>=7 independent meioses",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "5-6 independent meioses",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"May be used as stronger evidence with increasing segregation data"
]
},
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "3-4 independent meioses",
"type": "EvidenceLineStrength"
}
]
},
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"ldhId": "1746111564",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111564",
"modified": "2025-01-07T15:44:56.416Z",
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"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "068",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
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},
"Pilot Rules In Prep": {
"completed": true
}
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"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111563",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111563",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuuwG---"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PM6_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "Complex Neurodevelopmental Disorder (MONDO:0100038), as further described by Helbig et al, 2018 (PMID: 30311377), represents the broad and overlapping clinical spectrum that can include epilepsy, developmental delay, intellectual disability and autism spectrum disorder.",
"label": "PM6",
"ns": "068",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. Total of **4 points** will arrive at **Very Strong**. \n\n* Complex Neurodevelopmental Disorder: 0.5 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\n* Complex Neurodevelopmental Disorder: 0.5 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\n* Complex Neurodevelopmental Disorder: 0.5 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111558",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111558",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuvB----"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PM1_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "Pathogenic Enriched Regions (PERs): Regions that are enriched for Pathogenic variants (ClinVar/HGMD) across gene families, lack population (gnomAD) variants. Pérez-Palma, 2020 [PMID: 31871067](https://pubmed.ncbi.nlm.nih.gov/31871067/) & Lal et al, 2020 [PMID: 32183904](https://pubmed.ncbi.nlm.nih.gov/32183904/)",
"label": "PM1",
"ns": "068",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table\".",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111555",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111555",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuuny---"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BS4_nuclear_SCN2A",
"additionalComments": "Reduced penetrance and phenocopies",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "068",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Not applicable",
"id": "0071",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111549",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111549",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuurK---"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PS2_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "Complex Neurodevelopmental Disorder (MONDO:0100038), as further described by Helbig et al, 2018 (PMID: 30311377), represents the broad and overlapping clinical spectrum that can include epilepsy, developmental delay, intellectual disability and autism spectrum disorder.",
"label": "PS2",
"ns": "068",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 points** will arrive at **Very Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111567",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111567",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuu4----"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BS1_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "068",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency is above 0.0002% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111562",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111562",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuuwu---"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PP3_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "068",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111560",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111560",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuvA----"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BP7_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "068",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111559",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111559",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuux6---"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BA1_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "Allele frequency is above 0.02% in GnomAD or other large population database. ",
"label": "BA1",
"ns": "068",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency is above **0.01%** is gnomAD or other large population databases, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111557",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111557",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuvCO---"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PM3_nuclear_SCN2A",
"additionalComments": "SCN2A is associated with autosomal dominant inheritance. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "068",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"This requires testing of parents (or offspring) to determine phase."
]
},
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111554",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111554",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuupC---"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BS3_nuclear_SCN2A",
"additionalComments": "Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic ID/ASD, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "068",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111548",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111548",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuur6---"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PS4_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "Complex Neurodevelopmental Disorder (MONDO:0100038), as further described by Helbig et al, 2018 (PMID: 30311377), represents the broad and overlapping clinical spectrum that can include epilepsy, developmental delay, intellectual disability and autism spectrum disorder.",
"label": "PS4",
"ns": "068",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **16+ points** will arrive at **Very Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 - 15.5 points** will arrive at **Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 - 3.5 points** will arrive at **Moderate**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 - 1.5 points** will arrive at **Supporting**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111545",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111545",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuuzu---"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PM2_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "068",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Population data for insertions/deletions may be poorly called by next-generation sequencing."
]
},
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Other"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111544",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111544",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuv_W---"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PS1_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "The paralogous sodium channel genes associated with neurodevelopmental disorders (SCN1A, SCN2A, SCN3A, SCN8A) share >77% sequence identity (PMID:33531663). The four homologous domains with voltage sensor and pore region remain largely preserved across the channels. Differences lie within the terminal regions and cytoplasmic loops. When these regions are excluded from analysis, homology increases to >90% (PMID:33531663; PMID:16382098). As such, Pathogenic and Likely Pathogenic variants in paralogous genes can be considered for PS1.\n\nPS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859.",
"label": "PS1",
"ns": "068",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n* **\\>1** Identical amino acid change in paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). \n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Likely Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* A single identical amino acid change in a paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111568",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111568",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuu2y---"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PS3_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "If a variant is found to have differences from wildtype of multiple levels of strength (example: strong level of evidence in peak current and moderate level of evidence in persistent current), use the highest level of evidence (capping at strong). If a variant has been studied in multiple publications, use the strongest level of evidence available.",
"label": "PS3",
"ns": "068",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 72.7% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 135% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.2 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 4.1 mV (absolute value).\n* Mouse knock-in model displays spontaneous seizures.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 80.6% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 125% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.1 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 3.0 mV (absolute value).\n* Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111561",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111561",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuu46---"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BP1_nuclear_SCN2A",
"additionalComments": "Missense variants are common cause of disease. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "068",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111550",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111550",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuu5u---"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PP4_nuclear_SCN2A",
"additionalComments": "Phenotypic specificity incorporated into PS2, PM6, PS4",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "068",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111566",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111566",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuu7K---"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BP3_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "068",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0074",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In frame-deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111565",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111565",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuu7y---"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PVS1_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "Most terminal codon expected to undergo nonsense-mediated decay: p.Thr1591\n\nFor splice sites, this criterion should not be applied with PP3. \n\nFor a full gene deletion, a pathogenic classification is warranted.",
"label": "PVS1",
"ns": "068",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111556",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111556",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuu82---"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BS2_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "068",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in a healthy adult individual with full penetrance expected at an early age.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111552",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111552",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuu9y---"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PM5_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "The paralogous sodium channel genes associated with neurodevelomental disorders (SCN1A, SCN2A, SCN3A, SCN8A) share >77% sequence identity (PMID:33531663). The four homologous domains with voltage sensor and pore region remains largely preserved across the channels. Differences lie within the terminal regions and cytoplasmic loops. When these regions are excluded from analysis, homology increases to >90% (PMID:33531663; PMID:16382098). \n\nAs such, Pathogenic and Likely Pathogenic variants in paralogous genes can be considered for PM5.\n\n**Rule Combining Stipulation**: If PM5\\_Strong is reached, and the variant falls within a PM1 region, then do not add PM1 with PM5\\_Strong.",
"label": "PM5",
"ns": "068",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene).\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Novel missense change at an amino acid residue where a different missense change determined to be Pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Novel missense change at an amino acid residue where a different missense change determined to be **Likely Pathogenic** has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. \n* \\>1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be **Pathogenic**or **Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111547",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746111547",
"modified": "2025-01-07T15:44:56.416Z",
"modifier": "laceysmith",
"rev": "_jCDuus2---"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BP6_nuclear_SCN2A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "068",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
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{
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},
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],
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"generalComments": "Please disregard section on \"Rules for combining criteria\" section. Instead, please refer to \"Combining Rules\" attachment, as we have incorporated the points-based system. ",
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{
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{
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{
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],
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},
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],
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{
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},
{
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"event": {
"modifiedBy": "tsneddon",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
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"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "dazzarit",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2025-04-24T20:36:11.592Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "laceysmith",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2025-04-28T13:24:10.476Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "cspec-reopened",
"prevState": "Released",
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"name": "Pilot Rules In Prep"
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"current": false,
"event": {
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"name": "pilot-rules-withdrawn",
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],
"tagNameSpaces": [
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],
"title": "ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN3A Version 2.1.0",
"version": "2.1.0",
"versioned": true
},
"entId": "GN069",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
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"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
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"applicability": "Applicable",
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"evidenceCategory": "De novo Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PS2",
"ns": "069",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
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"status": {
"Classification Rules In Prep": {
"completed": true
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"Pilot Rules In Prep": {
"completed": true
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"strengthDescriptor": [
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"id": "0241",
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"strength": "Stand Alone",
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"specificationType": [
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],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 points** will arrive at **Very Strong**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
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"specificationType": [
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"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
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"strengthSepioID": "SEPIO:0000216",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
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"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
}
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},
"entType": "CriteriaCode",
"ldhId": "1746112475",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746112475",
"modified": "2025-04-28T13:24:11.066Z",
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"created": "2024-03-19T18:42:37.986Z",
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"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
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"geneType": "nuclear",
"label": "PP1",
"ns": "069",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
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"applicability": "Not applicable",
"id": "0236",
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"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "\\>=7 independent meioses",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "5-6 independent meioses",
"type": "EvidenceLineStrength"
},
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"additionalComments": {
"Notes": [
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]
},
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "3-4 independent meioses",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112472",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746112472",
"modified": "2025-04-28T13:24:11.066Z",
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"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BS1",
"ns": "069",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
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"strengthDescriptor": [
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"applicability": "Not Applicable",
"id": "0090",
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"specificationType": [],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency is above 0.0002% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112470",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746112470",
"modified": "2025-04-28T13:24:11.066Z",
"modifier": "laceysmith",
"rev": "_jlwPwNC---"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PM6_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PM6",
"ns": "069",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
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},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. Total of **4 points** will arrive at **Very Strong**. \n\nDevelopmental and Epileptic Encephalopathy: 0.5 points\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\nDevelopmental and Epileptic Encephalopathy: 0.5 points\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\nDevelopmental and Epileptic Encephalopathy: 0.5 points\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112466",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746112466",
"modified": "2025-04-28T13:24:11.066Z",
"modifier": "laceysmith",
"rev": "_jlwPwTK---"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PVS1_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"instructionsToUse": "Most terminal codon expected to undergo NMD: p.Thr1586 \n\nFor splice sites, this criterion should not be applied with PP3. \n\nFor a full gene deletion, a pathogenic classification is warranted.",
"label": "PVS1",
"ns": "069",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112464",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746112464",
"modified": "2025-04-28T13:24:11.066Z",
"modifier": "laceysmith",
"rev": "_jlwPwU----"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PM5_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "The paralogous sodium channel genes associated with neurodevelomental disorders (SCN1A, SCN2A, SCN3A, SCN8A) share >77% sequence identity (PMID:33531663). The four homologous domains with voltage sensor and pore region remains largely preserved across the channels. Differences lie within the terminal regions and cytoplasmic loops. When these regions are excluded from analysis, homology increases to >90% (PMID:33531663; PMID:16382098). \n\nAs such, Pathogenic and Likely Pathogenic variants in paralogous genes can be considered for PM5.\n\n**Rule Combining Stipulation**: If PM5\\_Strong is reached, and the variant falls within a PM1 region, then do not add PM1 with PM5\\_Strong.",
"label": "PM5",
"ns": "069",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene).\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Novel missense change at an amino acid residue where a different missense change determined to be Pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Novel missense change at an amino acid residue where a different missense change determined to be **Likely Pathogenic** has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. \n* \\>1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be **Pathogenic**or **Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112455",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746112455",
"modified": "2025-04-28T13:24:11.066Z",
"modifier": "laceysmith",
"rev": "_jlwPwVW---"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_BP2_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "069",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112454",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746112454",
"modified": "2025-04-28T13:24:11.066Z",
"modifier": "laceysmith",
"rev": "_jlwPwR----"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_BP4_nuclear_SCN3A",
"additionalComments": "Replicating methodologies by Pejaver et al, 2022 and Johnston et al, 2021 (PMID: 33767344), REVEL scores could not be obtained for Benign calculations. ",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "069",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112478",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746112478",
"modified": "2025-04-28T13:24:11.066Z",
"modifier": "laceysmith",
"rev": "_jlwPwRu---"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PS1_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"instructionsToUse": "The paralogous sodium channel genes associated with neurodevelomental disorders (SCN1A, SCN2A, SCN3A, SCN8A) share >77% sequence identity (PMID:33531663). The four homologous domains with voltage sensor and pore region remain largely preserved across the channels. Differences lie within the terminal regions and cytoplasmic loops. When these regions are excluded from analysis, homology increases to >90% (PMID:33531663; PMID:16382098). \n\nAs such, Pathogenic and Likely Pathogenic variants in paralogous genes can be considered for PS1.",
"label": "PS1",
"ns": "069",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n* **\\>1** Identical amino acid change in paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Likely Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* A single identical amino acid change in a paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A).\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112476",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746112476",
"modified": "2025-04-28T13:24:11.066Z",
"modifier": "laceysmith",
"rev": "_jlwPwOu---"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_BP5_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "069",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112471",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746112471",
"modified": "2025-04-28T13:24:11.066Z",
"modifier": "laceysmith",
"rev": "_jlwPwSK---"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PS3_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"instructionsToUse": "If a variant is found to have differences from wildtype of multiple levels of strength (example: strong level of evidence in peak current and moderate level of evidence in persistent current), use the highest level of evidence (capping at strong). If a variant has been studied in multiple publications, use the strongest level of evidence available.",
"label": "PS3",
"ns": "069",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 72.7% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 135% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.2 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 4.1 mV (absolute value).\n* Mouse knock-in model displays spontaneous seizures.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 80.6% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 125% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.1 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 3.0 mV (absolute value).\n* Mouse knock-in model displays induced seizures\n* Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112469",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746112469",
"modified": "2025-04-28T13:24:11.066Z",
"modifier": "laceysmith",
"rev": "_jlwPwSu---"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_BP7_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "069",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112467",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746112467",
"modified": "2025-04-28T13:24:11.066Z",
"modifier": "laceysmith",
"rev": "_jlwPwNi---"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_BA1_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"instructionsToUse": "Allele frequency is above 0.02% in GnomAD or other large population database. ",
"label": "BA1",
"ns": "069",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency is above **0.01%** is gnomAD or other large population databases, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112465",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746112465",
"modified": "2025-04-28T13:24:11.066Z",
"modifier": "laceysmith",
"rev": "_jlwPwTm---"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_BS4_nuclear_SCN3A",
"additionalComments": "Reduced penetrance and phenocopies",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "069",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Not applicable",
"id": "0071",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
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"status": "approved",
"strength": "Supporting",
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"text": "",
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"text": "",
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"id": "0049",
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"status": "approved",
"strength": "Very Strong",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0033",
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"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0034",
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"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0061",
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"status": "approved",
"strength": "Supporting",
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"text": "",
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},
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"modified": "2025-04-28T13:24:11.066Z",
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"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
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"additionalComments": "Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n",
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"text": "",
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{
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"id": "0225",
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"strength": "Very Strong",
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"text": "",
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{
"applicability": "Not applicable",
"id": "0072",
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"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
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"text": "",
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{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
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},
"entType": "CriteriaCode",
"ldhId": "1746112456",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746112456",
"modified": "2025-04-28T13:24:11.066Z",
"modifier": "laceysmith",
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},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
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"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PS4",
"ns": "069",
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"sepioID": "SEPIO-CG:99026",
"specificationType": [],
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},
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"text": "",
"type": "EvidenceLineStrength"
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{
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"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **16+ points** will arrive at **Very Strong**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
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{
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},
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"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4-15.5 points** will arrive at **Strong**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
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{
"applicability": "Applicable",
"id": "0057",
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"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2-3.5 points** will arrive at **Moderate**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
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"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1-1.5 points** will arrive at **Supporting**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
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"modified": "2025-04-28T13:24:11.066Z",
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},
{
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"evidenceCategory": "Computational And Predictive Data",
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"text": "",
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{
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0074",
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"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0081",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In frame-deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112473",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746112473",
"modified": "2025-04-28T13:24:11.066Z",
"modifier": "laceysmith",
"rev": "_jlwPwMi---"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
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"ns": "069",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
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"completed": true
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"id": "0238",
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"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"id": "0019",
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"specificationType": [
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],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0025",
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"specificationType": [
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],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
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]
},
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"id": "0062",
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"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746112468",
"modified": "2025-04-28T13:24:11.066Z",
"modifier": "laceysmith",
"rev": "_jlwPwQS---"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
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"additionalComments": "SCN3A is associated with autosomal dominant inheritance. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PM3",
"ns": "069",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
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"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0058",
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"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
"additionalComments": {
"Notes": [
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]
},
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
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"modified": "2025-04-28T13:24:11.066Z",
"modifier": "laceysmith",
"rev": "_jlwPwUW---"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PP5_nuclear_SCN3A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "069",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112461",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746112461",
"modified": "2025-04-28T13:24:11.066Z",
"modifier": "laceysmith",
"rev": "_jlwPwW2---"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
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"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PM2",
"ns": "069",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
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{
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{
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]
},
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{
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}
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{
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{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
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],
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{
"applicability": "Not applicable",
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"type": "EvidenceLineStrength"
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{
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"strengthSepioID": "",
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},
{
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{
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]
},
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{
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"instructionsToUse": "Pathogenic Enriched Regions (PERs): Regions that are enriched for Pathogenic variants (ClinVar/HGMD) across gene families, lack population (gnomAD) variants. Pérez-Palma, 2020 [PMID: 31871067](https://pubmed.ncbi.nlm.nih.gov/31871067/) & Lal et al, 2020 [PMID: 32183904](https://pubmed.ncbi.nlm.nih.gov/32183904/)",
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{
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"status": "approved",
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{
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"status": "approved",
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},
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],
"comments": [
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],
"definition": {
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"xrefs": [
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]
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]
},
{
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}
],
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{
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{
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},
{
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},
{
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{
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]
},
"type": "CLASS"
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"name": "genetic developmental and epileptic encephalopathy"
},
"entId": "MONDO:0100062",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0100062",
"entType": "Disease",
"ldhId": "467881472",
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"modified": "2025-10-07T16:16:39.306Z",
"modifier": "cspecAdministrator",
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],
"Gene": [
{
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"agr": "HGNC:10590",
"alias_symbol": [
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],
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],
"date_approved_reserved": "1992-04-10",
"date_modified": "2021-05-26",
"date_name_changed": "2016-02-05",
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],
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"entrez_id": "6328",
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],
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"iuphar": "objectId:580",
"location": "2q24.3",
"location_sortable": "02q24.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
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],
"mgd_id": [
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],
"name": "sodium voltage-gated channel alpha subunit 3",
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],
"orphanet": 471032,
"prev_name": [
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"sodium channel, voltage-gated, type III, alpha subunit",
"sodium channel, voltage gated, type III alpha subunit"
],
"pubmed_id": [
9589372,
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],
"refseq_accession": [
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],
"rgd_id": [
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],
"status": "Approved",
"symbol": "SCN3A",
"symbol_report_tag": [
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],
"ucsc_id": "uc002ucx.4",
"uniprot_ids": [
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"vega_id": "OTTHUMG00000044171"
}
},
"entId": "SCN3A",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:10590",
"entType": "Gene",
"ldhId": "467855393",
"ldhIri": "https://cspec.genome.network/cspec/Gene/id/467855393",
"modified": "2021-10-14T11:37:07.088Z",
"modifier": "genbadmin",
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}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "069_nuclear_SCN3A",
"geneType": "nuclear",
"generalComments": "Please disregard the \"Rules for Combining Criteria\" section\". Instead, please refer to the \"Combining Rules\" attachment, as we have incorporated the points-based system. ",
"genes": [
{
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{
"adjective": "Autosomal dominant germline de novo mutation (HP:0025352)",
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"preferredMondoId": "MONDO:0100062",
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}
],
"gene": "SCN3A",
"preferredTranscript": "NM_006922.3"
}
],
"ns": "069",
"references": [],
"rules": {
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{
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{
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],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
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"PS1",
"PS2",
"PS3",
"PS4",
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],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
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"strength": "Very Strong",
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"text": "",
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{
"applicability": "Not applicable",
"id": "0058",
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"status": "approved",
"strength": "Strong",
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"text": "",
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{
"additionalComments": {
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]
},
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
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]
},
"entType": "CriteriaCode",
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"modified": "2025-01-07T15:49:04.105Z",
"modifier": "laceysmith",
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{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
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"applicability": "Not applicable",
"baseStrength": "Benign",
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"evidenceCategory": "Functional Data",
"gene": [
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"geneType": "nuclear",
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"sepioID": "SEPIO-CG:99041",
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"completed": true
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"completed": true
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"applicability": "Not applicable",
"id": "0226",
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"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0225",
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"status": "approved",
"strength": "Very Strong",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0072",
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"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0085",
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"text": "",
"type": "EvidenceLineStrength"
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},
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"modified": "2025-01-07T15:49:04.105Z",
"modifier": "laceysmith",
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{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BP3",
"ns": "070",
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"sepioID": "SEPIO-CG:99045",
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"completed": true
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"Pilot Rules In Prep": {
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"applicability": "Not applicable",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0210",
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"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"id": "0074",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In frame-deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113410",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746113410",
"modified": "2025-01-07T15:49:04.105Z",
"modifier": "laceysmith",
"rev": "_jCDyghm---"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PS3_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"instructionsToUse": "If a variant is found to have differences from wildtype of multiple levels of strength (example: strong level of evidence in peak current and moderate level of evidence in persistent current), use the highest level of evidence (capping at strong). If a variant has been studied in multiple publications, use the strongest level of evidence available.",
"label": "PS3",
"ns": "070",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
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"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
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]
},
"applicability": "Applicable",
"id": "0052",
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"specificationType": [
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"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 72.7% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 135% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.2 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 4.1 mV (absolute value).\n* Mouse knock-in model displays spontaneous seizures.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 80.6% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 125% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.1 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 3.0 mV (absolute value).\n* Mouse knock-in model displays induced seizures\n* Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113406",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746113406",
"modified": "2025-01-07T15:49:04.105Z",
"modifier": "laceysmith",
"rev": "_jCDyg4q---"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PP3_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "070",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [
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"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113405",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746113405",
"modified": "2025-01-07T15:49:04.105Z",
"modifier": "laceysmith",
"rev": "_jCDygk----"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PP5_nuclear_SCN8A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "070",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113398",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746113398",
"modified": "2025-01-07T15:49:04.105Z",
"modifier": "laceysmith",
"rev": "_jCDyguC---"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PP2_nuclear_SCN8A",
"additionalComments": "Benign missense variants are common. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "070",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113396",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746113396",
"modified": "2025-01-07T15:49:04.105Z",
"modifier": "laceysmith",
"rev": "_jCDygoS---"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PM5_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"instructionsToUse": "The paralogous sodium channel genes associated with neurodevelomental disorders (SCN1A, SCN2A, SCN3A, SCN8A) share >77% sequence identity (PMID:33531663). The four homologous domains with voltage sensor and pore region remains largely preserved across the channels. Differences lie within the terminal regions and cytoplasmic loops. When these regions are excluded from analysis, homology increases to >90% (PMID:33531663; PMID:16382098). \n\nAs such, Pathogenic and Likely Pathogenic variants in paralogous genes can be considered for PM5.\n\n**Rule Combining Stipulation**: If PM5\\_Strong is reached, and the variant falls within a PM1 region, then do not add PM1 with PM5\\_Strong.",
"label": "PM5",
"ns": "070",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene).\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Novel missense change at an amino acid residue where a different missense change determined to be Pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Novel missense change at an amino acid residue where a different missense change determined to be **Likely Pathogenic** has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. \n* \\>1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be **Pathogenic**or **Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113392",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746113392",
"modified": "2025-01-07T15:49:04.105Z",
"modifier": "laceysmith",
"rev": "_jCDygqG---"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
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"instructionsToUse": "Complex Neurodevelopmental Disorder (MONDO:0100038), as further described in Helbig et al, 2018 (PMID: 30311377), represents the broad and overlapping clinical spectrum that can include epilepsy, developmental delay, intellectual disability and autism spectrum disorder.",
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"text": "",
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"Disease-specific",
"Gene-specific",
"Strength"
],
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"strength": "Very Strong",
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"text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **16+ points** will arrive at **Very Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
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"strength": "Strong",
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"strengthSepioID": "SEPIO:0000216",
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"strength": "Supporting",
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{
"applicability": "Not Applicable",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0086",
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"text": "",
"type": "EvidenceLineStrength"
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{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
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{
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"id": "0207",
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"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
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{
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"id": "0068",
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"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
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{
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"status": "approved",
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"text": "",
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"specificationType": [
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"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
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]
},
"entType": "CriteriaCode",
"ldhId": "1746113391",
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"modified": "2025-01-07T15:49:04.105Z",
"modifier": "laceysmith",
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{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
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"applicability": "Not Applicable for this VCEP",
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"evidenceCategory": "Other Database",
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"strengthDescriptor": [
{
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"strength": "Stand Alone",
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"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
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},
{
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"strength": "Very Strong",
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"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
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"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
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},
{
"applicability": "Not applicable",
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"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
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]
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"ldhId": "1746113414",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746113414",
"modified": "2025-01-07T15:49:04.105Z",
"modifier": "laceysmith",
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{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
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"instructionsToUse": "Complex Neurodevelopmental Disorder (MONDO:0100038), as further described in Helbig et al, 2018 (PMID: 30311377), represents the broad and overlapping clinical spectrum that can include epilepsy, developmental delay, intellectual disability and autism spectrum disorder.",
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"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 points** will arrive at **Very Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
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"specificationType": [
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],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
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"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
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"specificationType": [
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"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
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]
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"modified": "2025-01-07T15:49:04.105Z",
"modifier": "laceysmith",
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"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
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"gene": [
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{
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"id": "005",
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{
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"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
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"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"instructionsToUse": "Complex Neurodevelopmental Disorder (MONDO:0100038), as further described in Helbig et al, 2018 (PMID: 30311377), represents the broad and overlapping clinical spectrum that can include epilepsy, developmental delay, intellectual disability and autism spectrum disorder.",
"label": "PM6",
"ns": "070",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. Total of **4 points** will arrive at **Very Strong**. \n\n* Complex Neurodevelopmental Disorder: 0.5 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\n* Complex Neurodevelopmental Disorder: 0.5 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\n* Complex Neurodevelopmental Disorder: 0.5 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113403",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746113403",
"modified": "2025-01-07T15:49:04.105Z",
"modifier": "laceysmith",
"rev": "_jCDygzC---"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PM1_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"instructionsToUse": "Pathogenic Enriched Regions (PERs): Regions that are enriched for Pathogenic variants (ClinVar/HGMD) across gene families, lack population (gnomAD) variants. Pérez-Palma, 2020 [PMID: 31871067](https://pubmed.ncbi.nlm.nih.gov/31871067/) & Lal et al, 2020 [PMID: 32183904](https://pubmed.ncbi.nlm.nih.gov/32183904/)",
"label": "PM1",
"ns": "070",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table\".",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113400",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746113400",
"modified": "2025-01-07T15:49:04.105Z",
"modifier": "laceysmith",
"rev": "_jCDyg56---"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_BS2_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "070",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in a healthy adult individual with full penetrance expected at an early age.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113397",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746113397",
"modified": "2025-01-07T15:49:04.105Z",
"modifier": "laceysmith",
"rev": "_jCDyg6i---"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_BS4_nuclear_SCN8A",
"additionalComments": "Reduced penetrance and phenocopies",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "070",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Not applicable",
"id": "0071",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113394",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746113394",
"modified": "2025-01-07T15:49:04.105Z",
"modifier": "laceysmith",
"rev": "_jCDyg0u---"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PS1_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"instructionsToUse": "The paralogous sodium channel genes associated with neurodevelomental disorders (SCN1A, SCN2A, SCN3A, SCN8A) share >77% sequence identity (PMID:33531663). The four homologous domains with voltage sensor and pore region remain largely preserved across the channels. Differences lie within the terminal regions and cytoplasmic loops. When these regions are excluded from analysis, homology increases to >90% (PMID:33531663; PMID:16382098). \n\nAs such, Pathogenic and Likely Pathogenic variants in paralogous genes can be considered for PS1.",
"label": "PS1",
"ns": "070",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n* **\\>1** Identical amino acid change in paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Likely Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* A single identical amino acid change in a paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A).\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113413",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746113413",
"modified": "2025-01-07T15:49:04.105Z",
"modifier": "laceysmith",
"rev": "_jCDyggu---"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_BP7_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "070",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113404",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746113404",
"modified": "2025-01-07T15:49:04.105Z",
"modifier": "laceysmith",
"rev": "_jCDygxy---"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PVS1_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"instructionsToUse": "Most terminal codon expected to undergo nonsense-mediated decay: p.Thr1582\n\nFor splice sites, this criterion should not be applied with PP3. \n\nFor a full gene deletion, a pathogenic classification is warranted.",
"label": "PVS1",
"ns": "070",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113401",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746113401",
"modified": "2025-01-07T15:49:04.105Z",
"modifier": "laceysmith",
"rev": "_jCDyg0G---"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_BP1_nuclear_SCN8A",
"additionalComments": "Missense variants are common cause of disease. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "070",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
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"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-30T16:51:25.460Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "leekristy",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2025-12-09T19:48:45.634Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "leekristy",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2025-12-09T19:48:22.476Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2025-10-02T15:39:48.918Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2026-01-13T21:29:43.535Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "leekristy",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2026-01-20T17:00:57.493Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "leekristy",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-09-06T11:49:00.799Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"071"
],
"title": "ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 2.0.0",
"type": "Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015",
"version": "2.0.0",
"versioned": true
},
"entId": "GN071",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BP7_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "Also applicable to non-canonical intronic variants. The use of BP7 with BP4 is allowed, as appropriate, to classify variants meeting both criteria as likely benign.",
"label": "BP7",
"ns": "071",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0065",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applicable for variants that have no observable splicing impact with RNA sequencing and/or minigene assay and a SpliceAI score of less than or equal to 0.1.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Splice AI should be used to suggest no splicing impact. Splicing prediction score of less than or equal to 0.1 is required. Conservation should be assess using PhyloP (cutoff less than 0.1) and PhastCons (cutoff less than 0.5).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362903",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362903",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLju---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PP2_nuclear_F8",
"additionalComments": "Not applicable for F8.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "071",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362901",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362901",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLei---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PM6_nuclear_F8",
"additionalComments": "This rule code is combined with PS2. Please combined assumed de novo cases with confirmed de novo cases and apply PS2 at the appropriate weight.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "Use ClinGen’s de novo point system for a highly specific phenotype.",
"label": "PM6",
"ns": "071",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 8,
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 4,
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 2,
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362889",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362889",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLfe---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PM4_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": ".",
"label": "PM4",
"ns": "071",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "009",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use code with no specification.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362884",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362884",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLb2---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PP5_nuclear_F8",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "071",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362908",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362908",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLa2---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BP6_nuclear_F8",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "071",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362907",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362907",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLdG---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BP1_nuclear_F8",
"additionalComments": "Not applicable for F8 gene.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "071",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362887",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362887",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLi----"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PM1_nuclear_F8",
"additionalComments": "Not applicable for CDH1.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "This rule is applicable to the variant residues noted above based on activity that is critical to the function of the factor VIII protein (PMID: 33592631, 35722946). Combined weight of codes PM1 and PM5 applied for a single variant can only equal strong.",
"label": "PM1",
"ns": "071",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0028",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This code can be applied at the strong level for variants involving the following residues: R391-S392, R759-S760, E1701-Q1705, R1708-S1709, Y1683, Y1689, Y737, Y742.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This code can be applied at the moderate level for variants involving the following residues: \n\nResidues affecting secretion: Arg1667, Arg1332\n\nFXa-binding residues: Gly2267-Gly2304 (with the exception of Ser2283)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362905",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362905",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLlC---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PP4_nuclear_F8",
"additionalComments": "Please use the PS4 code for probands meeting phenotype criteria.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "**Hemophilia A phenotype requirements:** \n\\-Abnormal factor VIII activity levels in the severe range (\\< 1% factor VIII activity level) are sufficient to confer a diagnosis of hemophilia A. \n\\-If the proband's factor VIII level is in the mild or moderate range (1-40% factor VIII activity level) there must be a clear pattern of X-linked inheritance (i.e. - more than a sibling pair). \n\\-If the proband is in the mild/moderate range and is a simplex case, there are only affected siblings, or no family history information is available, documentation that von Willebrand disease (VWD) type 2N was ruled out as a diagnosis is required. If this documentation is not available, the two following exceptions can be made:\n\n1. If VWD 2N is ruled out in at least one proband, all other probands can be counted, OR\n2. If there are 4 or more unrelated probands reported with mild or moderate hemophilia A, all probands can be counted.\n\n\\-Full gene sequencing and deletion/duplication analysis of the _F8_ gene is required to use this rule code.\n\n\\-This rule code is not eligible for any variants meeting BA1 criteria.\n\n\\-A probands used for PP4 cannot be used for PS4.",
"label": "PP4",
"ns": "071",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Proband must meet hemophilia A phenotype criteria AND have full gene sequencing and deletion/duplication analysis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "0063",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362904",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362904",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLeC---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PP3_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "Do not apply PP3 for variants that meet criteria for a PVS1\\_RNA rule code.",
"label": "PP3",
"ns": "071",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Code can be applied for variants where the REVEL score is greater than or equal to 0.6 or a SpliceAI score of greater than or equal to 0.2.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362902",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362902",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLf6---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BP4_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "none",
"label": "BP4",
"ns": "071",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -4,
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This code can be applied for variants reaching a REVEL score of 0.3 or below AND a Splice AI score of less than or equal to 0.1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362895",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362895",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLbW---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PS3_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PS3",
"ns": "071",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 8,
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Abnormal factor VIII activity (\\<40 IU/dL or 40%) via one-stage or two-stage chromogenic assay in a cell line and/or mouse model.\n\n\\--OR--\n\nAbsent or significantly reduced factor VIII antigen levels compared to wildtype in a cell line by quantitative assay.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362894",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362894",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLgq---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BP3_nuclear_F8",
"additionalComments": "Not applicable for F8 gene.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "071",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362893",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362893",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLn----"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PS2_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "Use ClinGen’s de novo modified point system for a highly specific phenotype (see guidance below). Probands must meet the PS4 phenotype criteria to apply this code. Combine all assumed and confirmed de novo cases for this code and use at the appropriate strength based on amount of points for all probands.",
"label": "PS2",
"ns": "071",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 8,
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use the SVI recommendations for de novo cases; 4 points. Use de novo guidance below to determine point value.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use the SVI recommendations for de novo cases; 2 points. Use de novo guidance below to determine point value.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use the SVI recommendations for de novo cases; 1 point. Use de novo guidance below to determine point value.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use the SVI recommendations for de novo cases; 0.5 point. Use de novo guidance below to determine point value.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362892",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362892",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLhK---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PM5_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "Combined weight of codes PM1 and PM5 applied for a single variant can only equal strong.",
"label": "PM5",
"ns": "071",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This evidence code can be applied when there is 1 pathogenic variant or 2 likely pathogenic variants at the same residue based on the _F8_ rule specifications from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This evidence code can be applied when there is 1 likely pathogenic variant at the same residue based on the _F8_ rule specifications from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362886",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362886",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLia---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BS3_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "none",
"label": "BS3",
"ns": "071",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This code can be used for _F8_ gene variants studied in a cell line or mouse model setting that confer a normal factor VIII activity level AND normal factor VIII antigen level OR normal Western Blot.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This code can be used for _F8_ gene variants studied in a cell line or mouse model setting that confer the following results: \n\n* Normal factor VIII activity level, OR\n* Abnormal factor VIII activity level with abnormal 2N binding assay suggesting a diagnosis of VWD Normandy (VWD 2N) instead of hemophilia A.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362885",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362885",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLj----"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BS2_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "This code is not applicable if there is a normal one stage factor VIII level and an abnormal factor VIII using a chromogenic assay or vice versa.",
"label": "BS2",
"ns": "071",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This evidence code can be used when a _F8_ variant is observed in a male with a normal factor VIII activity level (at least >40% IU or as defined by laboratory cut off) using a one stage and/or a chromogenic assay.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -1,
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362883",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362883",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLkq---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PM2_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "None",
"label": "PM2",
"ns": "071",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Variant must be absent in males in population databases, such as gnomAD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362906",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362906",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLdm---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BA1_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "99.99% CI; subpopulation must have a minimum of five variant alleles present. Males and females are included for this code.",
"label": "BA1",
"ns": "071",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"defaultPoint": "Not Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "MAF cutoff of greater or equal to 0.0333% (or 0.000333).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362900",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362900",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLgS---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BP5_nuclear_F8",
"additionalComments": "While unlikely, it is possible for males with hemophilia to also have a diagnosis of von Willebrand Normandy (or VWD 2N).",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "This applies if a P/LP variant is identified in an alternate gene known to cause HDGC (currently only CTNNA1).",
"label": "BP5",
"ns": "071",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362899",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362899",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLlm---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PVS1_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "Apply the ClinGen Coagulation Factor Deficiency VCEP/SVI decision tree to determine use and strength of the PVS1 rule. PVS1 (RNA): assays demonstrating a variant leads to aberrant splicing profile that can be used in the PVS1 decision tree as described in Walker et al. (PMID: 36865205) that was added to the v1 CFD-VCEP PVS1 flowchart. If using PVS1(RNA), do not apply PP3.",
"label": "PVS1",
"ns": "071",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 8,
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "001",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362898",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362898",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLmG---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PS4_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "**Hemophilia A phenotype requirements:** \n\\-Abnormal factor VIII activity levels in the severe range (\\< 1% factor VIII activity level) are sufficient to confer a diagnosis of hemophilia A. \n\\-If the proband's factor VIII level is in the mild or moderate range (1-40% factor VIII activity level) there must be a clear pattern of X-linked inheritance (i.e. - more than a sibling pair). \n\\-If the proband is in the mild/moderate range and is a simplex case, there are only affected siblings, or no family history information is available, documentation that von Willebrand disease (VWD) type 2N was ruled out as a diagnosis is required. If this documentation is not available, the two following exceptions can be made:\n\n1. If VWD 2N is ruled out in at least one proband, all other probands can be counted, OR\n2. If there are 4 or more unrelated probands reported with mild or moderate hemophilia A, all probands can be counted.\n\n\\- It is reasonable to expect that genomic data from individuals with hemophilia A could be used in population databases. Therefore, we decided to implement use of a ratio of hemizygotes found to harbor a variant of interest by the total number of alleles in XY individuals in that population database (**\\# of hemizygotes** with variant of interest/**total # of alleles from XY individuals** sequenced in the database) as a criteria for using the PS4 code. The PS4 code is only applicable to variants with a ratio lower than or equal to 1.26 x 10-5. This ratio was set by using the most frequently seen pathogenic variant, _F8_ c.1834C>T, p.Arg612Cys, in gnomAD that was studied in the Coagulation Factor Deficiency VCEP pilot _F8_ study.",
"label": "PS4",
"ns": "071",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 8,
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥8 probands meet criteria described below",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "4-7 probands meet criteria described below",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "2-3 probands meet criteria described below",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1 proband meets criteria described below",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362897",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362897",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLmm---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BP2_nuclear_F8",
"additionalComments": "Not being used at this time. There are reports of males with hemophilia having two suspicious pathogenic variants.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "Evidence code is dependent on the strength of data. Take consideration of the quality of sequencing data when applying code.",
"label": "BP2",
"ns": "071",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0084",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362891",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362891",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLhi---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BS4_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "none",
"label": "BS4",
"ns": "071",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This evidence code can be used when a _F8_ variant is observed in a male with a family history of hemophilia A and has a normal factor VIII activity level.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -1,
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362888",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362888",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
"rev": "_k7vYLkK---"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PP1_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "Base strength of rule code on number of meioses across one or more families.",
"label": "PP1",
"ns": "071",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The code is application when there are ≥4 meioses across ≥2 families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The code is application when there are at least 3 meioses across one or more families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The code is application when there are 2 meioses in one family **OR** 1 meiosis between 2 affected siblings.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362896",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620362896",
"modified": "2026-01-20T17:00:58.149Z",
"modifier": "leekristy",
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"text": "",
"type": "EvidenceLineStrength"
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},
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"text": "",
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{
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"id": "0228",
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"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0077",
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"status": "approved",
"strength": "Supporting",
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"text": "",
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},
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"creator": "laceysmith",
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"gene": [
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"id": "0090",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency is above **0.01%** in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
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"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0086",
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"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
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},
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"modified": "2025-01-07T15:50:05.370Z",
"modifier": "laceysmith",
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},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
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"geneType": "nuclear",
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"sepioID": "SEPIO-CG:99032",
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"completed": true
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"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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"applicability": "Not applicable",
"id": "0014",
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"text": "",
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"specificationType": [
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"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. Total of **4 points** will arrive at **Very Strong**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points",
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],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points",
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points",
"type": "EvidenceLineStrength"
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]
},
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"id": "0225",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0072",
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"status": "approved",
"strength": "Strong",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0100",
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"strength": "Moderate",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0085",
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"status": "approved",
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"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
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},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
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"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PM2",
"ns": "076",
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"sepioID": "SEPIO-CG:99028",
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"id": "0231",
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"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0044",
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"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Population data for insertions/deletions may be poorly called by next-generation sequencing."
]
},
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Other"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109662",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746109662",
"modified": "2025-01-07T15:50:05.370Z",
"modifier": "laceysmith",
"rev": "_jCDzciy---"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PS1_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PS1",
"ns": "076",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
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"Pilot Rules In Prep": {
"completed": true
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},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
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},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established **Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Same amino acid change as a previously established **Likely Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109686",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746109686",
"modified": "2025-01-07T15:50:05.370Z",
"modifier": "laceysmith",
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"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
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"geneType": "nuclear",
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"ns": "076",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
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"status": {
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"id": "0212",
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"text": "",
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{
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"id": "0210",
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"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"id": "0074",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In frame-deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109683",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746109683",
"modified": "2025-01-07T15:50:05.370Z",
"modifier": "laceysmith",
"rev": "_jCDzcci---"
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{
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"creator": "laceysmith",
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"applicability": "Applicable",
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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"geneType": "nuclear",
"label": "BP7",
"ns": "076",
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"sepioID": "SEPIO-CG:99049",
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"text": "",
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{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"id": "0065",
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"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
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"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109677",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746109677",
"modified": "2025-01-07T15:50:05.370Z",
"modifier": "laceysmith",
"rev": "_jCDzcuq---"
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{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BS2",
"ns": "076",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
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"Pilot Rules In Prep": {
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"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in a healthy adult individual.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109670",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746109670",
"modified": "2025-01-07T15:50:05.370Z",
"modifier": "laceysmith",
"rev": "_jCDzchi---"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "076",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This should say greater than or equal to 2 known pathogenic variants at same site as novel change.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Novel missense change at an amino acid residue where a different missense change determined to be **Pathogenic** has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Novel missense change at an amino acid residue where a different missense change determined to be **Likely Pathogenic** has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109665",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746109665",
"modified": "2025-01-07T15:50:05.370Z",
"modifier": "laceysmith",
"rev": "_jCDzcxS---"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "076",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 points** will arrive at **Very Strong**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109685",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746109685",
"modified": "2025-01-07T15:50:05.370Z",
"modifier": "laceysmith",
"rev": "_jCDzcVm---"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PP4_nuclear_SCN1B",
"additionalComments": "Phenotypic specificity incorporated into PS2, PM6, PS4",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "076",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109684",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746109684",
"modified": "2025-01-07T15:50:05.370Z",
"modifier": "laceysmith",
"rev": "_jCDzcWy---"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_BP5_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "076",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109681",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746109681",
"modified": "2025-01-07T15:50:05.370Z",
"modifier": "laceysmith",
"rev": "_jCDzclq---"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PP3_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "076",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109678",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746109678",
"modified": "2025-01-07T15:50:05.370Z",
"modifier": "laceysmith",
"rev": "_jCDzceS---"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_BA1_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BA1",
"ns": "076",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency is above **0.3%** in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109675",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746109675",
"modified": "2025-01-07T15:50:05.370Z",
"modifier": "laceysmith",
"rev": "_jCDzcqy---"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PVS1_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"instructionsToUse": "Most terminal codon expected to undergo NMD: p.Thr204\n\nFor splice sites, this criterion should not be applied with PP3. \n\nFor a full gene deletion, a pathogenic classification is warranted.",
"label": "PVS1",
"ns": "076",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109674",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746109674",
"modified": "2025-01-07T15:50:05.370Z",
"modifier": "laceysmith",
"rev": "_jCDzcfu---"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PM3_nuclear_SCN1B",
"additionalComments": "SCN1A is associated with autosomal dominant inheritance. ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "076",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "For recessive disorders, points-based system based on confirmation of phase and classification of other variant. Total of **4.0 points** will arrive at **Very Strong**. \n\n* Classification of other variant is Pathogenic/Likely Pathogenic\n * Confirmed in trans: 1 point\n * Phase unknown: 0.5 (P) or 0.25 (LP) points\n* Homozygous occurrence (max point 1.0)\n * Confirmed in trans: 0.5 points\n* Classification of other variant is Uncertain Significance \n * Confirmed in trans: 0.25 points\n * Phase unknown: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "For recessive disorders, points-based system based on confirmation of phase and classification of other variant. Total of **2.0 points** will arrive at **Strong**. \n\n* Classification of other variant is Pathogenic/Likely Pathogenic\n * Confirmed in trans: 1 point\n * Phase unknown: 0.5 (P) or 0.25 (LP) points\n* Homozygous occurrence (max point 1.0)\n * Confirmed in trans: 0.5 points\n* Classification of other variant is Uncertain Significance \n * Confirmed in trans: 0.25 points\n * Phase unknown: 0 points",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
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]
},
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "For recessive disorders, points-based system based on confirmation of phase and classification of other variant. Total of **1.0 point** will arrive at **Moderate**. \n\n* Classification of other variant is Pathogenic/Likely Pathogenic\n * Confirmed in trans: 1 point\n * Phase unknown: 0.5 (P) or 0.25 (LP) points\n* Homozygous occurrence (max point 1.0)\n * Confirmed in trans: 0.5 points\n* Classification of other variant is Uncertain Significance \n * Confirmed in trans: 0.25 points\n * Phase unknown: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For recessive disorders, points-based system based on confirmation of phase and classification of other variant. Total of **0.5 points** will arrive at **Supporting**. \n\n* Classification of other variant is Pathogenic/Likely Pathogenic\n * Confirmed in trans: 1 point\n * Phase unknown: 0.5 (P) or 0.25 (LP) points\n* Homozygous occurrence (max point 1.0)\n * Confirmed in trans: 0.5 points\n* Classification of other variant is Uncertain Significance \n * Confirmed in trans: 0.25 points\n * Phase unknown: 0 points",
"type": "EvidenceLineStrength"
}
]
},
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"modifier": "laceysmith",
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},
{
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"creator": "laceysmith",
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"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
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"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "076",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
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{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
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"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
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"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
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"modified": "2025-01-07T15:50:05.370Z",
"modifier": "laceysmith",
"rev": "_jCDzcs6---"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PM4",
"ns": "076",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
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"status": {
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"completed": true
},
"Pilot Rules In Prep": {
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}
},
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"id": "0233",
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"text": "",
"type": "EvidenceLineStrength"
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{
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{
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{
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],
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"strength": "Moderate",
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"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
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{
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"id": "0059",
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"status": "approved",
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},
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{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PM1_nuclear_SCN1B",
"additionalComments": "Currently, insufficient numbers of pathogenic variants have been reported in SCN1B to calculate “mutational hotspots”. SCN1B does not belong to a gene family to utilize PERs.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "076",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0015",
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"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109673",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746109673",
"modified": "2025-01-07T15:50:05.370Z",
"modifier": "laceysmith",
"rev": "_jCDzcgW---"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PP2_nuclear_SCN1B",
"additionalComments": "Benign missense variants are common. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "076",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109669",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746109669",
"modified": "2025-01-07T15:50:05.370Z",
"modifier": "laceysmith",
"rev": "_jCDzcti---"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_BP2_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "076",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
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}
},
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"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0207",
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"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109664",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746109664",
"modified": "2025-01-07T15:50:05.370Z",
"modifier": "laceysmith",
"rev": "_jCDzcoq---"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PS4_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "076",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
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}
},
"strengthDescriptor": [
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"id": "0243",
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"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
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"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **16+ points** will arrive at **Very Strong**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
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]
},
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"id": "0053",
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"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4-15.5 points** will arrive at **Strong**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points",
"type": "EvidenceLineStrength"
},
{
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"id": "0057",
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"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2-3.5 points** will arrive at **Moderate**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1-1.5 points** will arrive at **Supporting**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109663",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1746109663",
"modified": "2025-01-07T15:50:05.370Z",
"modifier": "laceysmith",
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}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0100062",
"lbl": "genetic developmental and epileptic encephalopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/19"
},
{
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"val": "https://github.com/monarch-initiative/mondo/issues/3680"
},
{
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"val": "https://www.malacards.org/card/early_infantile_epileptic_encephalopathy"
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"val": "http://purl.obolibrary.org/obo/MONDO_0005579"
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"val": "http://purl.obolibrary.org/obo/MONDO_0015921"
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"val": "http://purl.obolibrary.org/obo/MONDO_0024321"
},
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"val": "http://purl.obolibrary.org/obo/MONDO_0100022"
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{
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"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://purl.org/dc/elements/1.1/date",
"val": "2018-10-10T22:04:15Z"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0001-5208-3432"
},
{
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"val": "http://purl.obolibrary.org/obo/DOID_0112202"
},
{
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"val": "http://purl.obolibrary.org/obo/NCIT_C122814"
},
{
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"val": "https://omim.org/phenotypicSeries/PS308350"
}
],
"comments": [
"Individuals, both male and female, have been reported with variants in the GABRB3 gene. De novo and familial cases have been reported, with mostly missense and a few nonsense variants identified as causative. These patients have been described in the literature as having a range of phenotypes characterized as epileptic encephalopathy, Lennox-Gastaut syndrome, Dravet syndrome-like, and childhood absence epilepsy. Severity of intellectual disability is variable among reported probands, as is the age of onset of seizure phenotypes. In one case of epileptic encephalopathy, for example, the individual presented with severe intellectual disability while seizures onset at 12 years old. Additionally, individuals have been reported with the same de novo missense variants, and have been described with varying phenotypes. (PMID:26544041, PMID:26704558, PMID:26645412, PMID:26993267, PMID:27476654)"
],
"definition": {
"val": "A complex neurodevelopmental disorder characterized by a range of developmental delays and epileptic encephalopathy phenotypes. Seizure onset is variable and intellectual disability is variable in presence and severity.",
"xrefs": [
"PMID:28276062"
]
},
"subsets": [
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"http://purl.obolibrary.org/obo/mondo#gard_rare",
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"http://purl.obolibrary.org/obo/mondo#otar",
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],
"synonyms": [
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"releaseNotes": "Release notes v1.2\n\nProvided % for PM2 and clarified use of gnomAD v4 \nClarified when to assume in trans for PM3 \nProvided PP1 guidance for AR condition \nAdded SpliceAI thresholds for PP3 and BP4 \nClarified use of PP3/BP4 in the presence of RNA data \nUpdated MONDO from hereditary breast carcinoma and familial pancreatic carcinoma to PALB2-related cancer predisposition \nMinor formatting adjustments",
"shortTitle": "Hereditary Breast, Ovarian and Pancreatic Cancer Specification",
"specificationSource": "",
"states": [
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"current": false,
"event": {
"modifiedBy": "meganholdren",
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"name": "pilot-rules-approved",
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],
"tagNameSpaces": [
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],
"title": "ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PALB2 Version 1.2.0",
"type": "Richards et.al., 2015 - Combining rules",
"version": "1.2.0",
"versioned": true
},
"entId": "GN077",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "077_BS4_nuclear_PALB2",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "* Quantitative co-segregation analysis is mandated for more accurate assessment of causality for PALB2 alterations. It is strongly preferred that biocurators use a quantitative method that accommodates both pathologies of AD PALB2: breast cancer, ovarian cancer and pancreatic cancer. These methods may be conducted by biostatisticians, particularly if they are able to compute LR scores[9](#pmid_29300386) using multiple phenotypes. \n * PP1\\_Strong: LOD ≥1.26 or Bayes Factor (LR) ≥18:1 \n * PP1\\_Moderate: LOD ≥.60 or Bayes Factor (LR) ≥4:1\n * PP1: LOD ≥0.3 or Bayes Factor (LR) ≥2:1\n * BS4\\_Supporting: LOD ≤-.32 or Bayes Factor (LR) ≤.48\n * BS4\\_Moderate: LOD ≤ -.64 or Bayes Factor (LR) ≤.23\n * BS4: LOD ≤ -1.28 or Bayes Factor (LR) LR≤.053:1\n* A freely available tool, COOL (COsegregation OnLine) from Bing-Jian Feng’s laboratory can be used to calculate LoD scores for co-segregation analysis \n 1\\. Navigate to COOL (COsegregation OnLine)[11](#url_3e13dc73-4062-5d3f-b4aa-67f233ce7248) \n 2\\. Input ‘PALB2’ into the ‘Input a Gene Symbol’ field (the PALB2 defaults are approved by this VCEP) \n 3\\. Upload your Pedigree File (see COOL (COsegregation OnLine) manual[12](#url_02bc6e53-f375-5e2c-acc1-e4b5e6fce8f9) for formatting) \n 4\\. Leave all defaults as is. Select ‘Submit’ to obtain LR based on Full Likelihood Bayes (FLB)",
"label": "BS4",
"ns": "077",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "LOD ≤ -1.28 or Bayes Factor (LR) ≤.053:1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "LOD ≤ -.64 or Bayes Factor (LR) ≤.23",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "LOD ≤-.32 or Bayes Factor (LR) ≤.48",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584512",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584512",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVga----"
},
{
"entContent": {
"_uniqueProp": "077_PM4_nuclear_PALB2",
"additionalComments": "Do not use:\n●\tIn-frame deletions/insertions that are not already PVS1-eligible: no information is available to justify the application of this rule. \n●\tMissense and small in-frame indels: not yet confirmed as a mechanism of disease for PALB2.\n●\tStop-loss: lack of data on stop-loss variants. \n\n",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "Do not use for in-frame insertions or deletions less than a single exon; Use for stop-loss variants, only.",
"label": "PM4",
"ns": "077",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": "Gene-specific, General recommendation",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584500",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584500",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgXi--E"
},
{
"entContent": {
"_uniqueProp": "077_PM3_nuclear_PALB2",
"additionalComments": "Multiple such cases are additive, Phenotype considerations are detailed in the rules, frequency of >.01% should not use PM3; Observations in cis are not applicable. Source information is considered (laboratory vs database setting).",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "See **Fanconi Anemia PM3 tables** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points.\n\nFanconi Anemia (FA) of any subtype is generally considered an exceedingly rare, severe, early-onset disease with variable features. In the case of _BRCA2_, hypomorphic FA patients have been described who are diagnosed at older ages with less severe phenotypes. The criteria set forth in the tables below are designed to accommodate such hypomorphs and are recommended to be applied to all FA-associated genes which may not be as well described due to the extreme infrequency of their identification, and due to ascertainment bias (for severe phenotype) in the literature.\n\n* General Considerations\n * Variant may not exceed general population frequency >0.01%. \n * Consider other gene panel test results as potential explanation for phenotype.\n * Multiple unrelated cases are additive.\n\nPhenotype consistent: \n\n* Chromosomal breakage with 1 clinical feature OR \n * Ex. Chromosomal breakage testing + microcephaly / triangular face\n* At least 2 of 3 clinical features from separate categories without chromosomal breakage studies\n * Ex. (Without chromosomal breakage): Myelodysplastic Syndrome and microcephaly / triangular face.\n* Positive for chromosome breakage test:\n * Increased chromosome breakage and/or radial forms on cytogenetic testing of lymphocytes with diepoxybutane (DEB) or mitomycin C (MMC)\n* Clinical features indicative of FA, including \n * Physical features (in ~75% of affected persons), include: \n * prenatal and/or postnatal short stature\n * abnormal skin pigmentation (e.g., café au lait macules, hypo- pigmentation)\n * Skeletal malformations (e.g., hypoplastic thumb, hypoplastic radius)\n * Microcephaly, triangular face\n * Ophthalmic anomalies\n * Genitourinary tract anomalies.\n * See Orphanet [13](#url_e738c852-705f-5eda-9836-d72955882e91) for full list of >100 HPO terms (and their reported frequency).\n * Pathology findings and laboratory findings (non-cancer related) include\n * progressive bone marrow failure (unrelated to cancer treatment)\n * aplastic anemia\n * Myelodysplastic syndrome\n * Inordinate toxicities from chemotherapy or radiation\n * macrocytosis\n * cytopenia (especially thrombocytopenia, leukopenia, and neutropenia)\n * increased fetal hemoglobin (often precedes anemia). \n * Note: FA patients with very early onset cancer (≤5yr) may not present with hematologic disease, which is reported to have median age at onset of 7 years in FA patients in general[14](#pmid_27929686)\n * Cancer diagnosis ≤5yr, particularly\n * Blood cancers (AML)\n * Brain cancers (medulloblastoma, neuroblastoma)\n * Wilms Tumor\n\nSpecifications are adapted from definitions from GeneReviews (last revision June 3, 2021)",
"label": "PM3",
"ns": "077",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "PM3\\_VeryStrong **≥ 8** points\n\nSee Fanconi Anemia PM3 tables for approach to assign points per proband.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "PM3\\_Strong **≥ 4** points\n\nSee Fanconi Anemia PM3 tables for approach to assign points per proband.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "PM3 = **2** points\n\nSee Fanconi Anemia PM3 tables for approach to assign points per proband.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "PM3\\_Supporting = **1** point\n\nSee Fanconi Anemia PM3 tables for approach to assign points per proband.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584499",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584499",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgd----"
},
{
"entContent": {
"_uniqueProp": "077_BP6_nuclear_PALB2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP6",
"ns": "077",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584518",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584518",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgeK---"
},
{
"entContent": {
"_uniqueProp": "077_BP5_nuclear_PALB2",
"additionalComments": "Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2). In addition, PALB2 has moderate penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "077",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584517",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584517",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgea---"
},
{
"entContent": {
"_uniqueProp": "077_BP1_nuclear_PALB2",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "Based on published and unpublished functional studies, PALB2 has a low rate of missense variants that are non-functional in relevant assays. True missense pathogenic variants are not yet confirmed or refuted but are thought to be exceedingly rare. Given the very low likelihood that missense variants are pathogenic, this rule applies to all missense variants in PALB2.",
"label": "BP1",
"ns": "077",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": " Apply to all missense variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584513",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584513",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgfW---"
},
{
"entContent": {
"_uniqueProp": "077_BS3_nuclear_PALB2",
"additionalComments": "Do not use: \n●\tProtein functional studies (BS3) See PS3 for details \n●\tRNA functional studies (Use BP7_Variable(RNA))",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "For protein, see detailed notes on ATM-specific assays; For RNA use code BP7_O and modulate strength based on assay quality and quantity (curator discretion).",
"label": "BS3",
"ns": "077",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": "Gene-specific, Disease-specific, Strength, General Recommendation",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": "Gene-specific, Disease-specific, Strength, General Recommendation",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584511",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584511",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgWe---"
},
{
"entContent": {
"_uniqueProp": "077_BS2_nuclear_PALB2",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "See **Fanconi Anemia BS2 tables** for approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points.\n\n* Do not use for individuals in population based cohorts, such as gnomAD \n* VUA should not be bioinformatically predicted (or experimentally proven) to have a clinically important effect on protein or mRNA splicing. Co-occurrent P or LP variant should be assigned classification using VCEP specifications\n* Consider multiple instances of co-occurrence with the same variant are more likely to be in cis in unrelated individuals when assessing BS2 application",
"label": "BS2",
"ns": "077",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "BS2 **≥ 4** points\n\nSee Fanconi Anemia BS2 tables for approach to assign points per proband.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "BS2\\_Moderate = **2** points\n\nSee Fanconi Anemia BS2 tables for approach to assign points per proband.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "BS2\\_Supporting = **1** point\n\nSee Fanconi Anemia BS2 tables for approach to assign points per proband.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584510",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584510",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgfu---"
},
{
"entContent": {
"_uniqueProp": "077_BS1_nuclear_PALB2",
"additionalComments": "FAF is a statistical model that accounts for population size and founder populations.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "Follow all [SVI general guidance](https://clinicalgenome.org/working-groups/sequence-variant-interpretation/) on applying population filters.",
"label": "BS1",
"ns": "077",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Grpmax Filtering AF **\\>.01%** in gnomAD v4 dataset",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584509",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584509",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgaa--_"
},
{
"entContent": {
"_uniqueProp": "077_PP4_nuclear_PALB2",
"additionalComments": "Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes.\nFor AR disorder, use PM3 for specific phenotype considerations\n",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "077",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584506",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584506",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgaq--A"
},
{
"entContent": {
"_uniqueProp": "077_PM6_nuclear_PALB2",
"additionalComments": "Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "077",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584502",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584502",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgby---"
},
{
"entContent": {
"_uniqueProp": "077_PM2_nuclear_PALB2",
"additionalComments": "PM2_Supporting is not considered a conflicting piece of evidence to an otherwise benign body of evidence; Coverage must be >30X at the locus.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "* EXCEPTION: under-represented sub-populations with n=1 but frequency >.0003%\n* Is not considered a conflicting piece of evidence for variants that otherwise are likely benign/benign \n* Use as **PM2\\_Supporting** (not moderate)",
"label": "PM2",
"ns": "077",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Frequency ≤ 1/300,000 (**0.000333%**) in gnomAD v4 dataset",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584498",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584498",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgdK---"
},
{
"entContent": {
"_uniqueProp": "077_PM1_nuclear_PALB2",
"additionalComments": "Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "077",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584497",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584497",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgY6---"
},
{
"entContent": {
"_uniqueProp": "077_PS4_nuclear_PALB2",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "PS4_Moderate: Do not use. Proband counting for genes causing a common disorder need to be calibrated in a population-specific way before use. \n",
"label": "PS4",
"ns": "077",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥3 OR lower 95% CI ≥1.5).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584496",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584496",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgYG---"
},
{
"entContent": {
"_uniqueProp": "077_BA1_nuclear_PALB2",
"additionalComments": "FAF is a statistical model that accounts for population size and founder populations.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "Follow all [SVI general guidance](https://clinicalgenome.org/working-groups/sequence-variant-interpretation/) on applying population filters.",
"label": "BA1",
"ns": "077",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Grpmax Filtering AF **\\>.1%** in gnomAD v4 dataset",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584508",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584508",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgXK---"
},
{
"entContent": {
"_uniqueProp": "077_PP1_nuclear_PALB2",
"additionalComments": "Informative pedigrees for segregation in families with AR Ataxia-Telangiectasia are not available. However, this VCEP would consider rules similar to the Glanzman and Hearing Loss VCEP rules if a pedigree becomes available.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "* AD Condition: use as per Co-Segregation Guidelines\n* AR Condition: Affected relatives must have both variants identified in proband.\n* Co-Segregation Guidelines\n * Quantitative co-segregation analysis is mandated for more accurate assessment of causality for PALB2 alterations. It is strongly preferred that biocurators use a quantitative method that accommodates both pathologies of AD PALB2: breast cancer, ovarian cancer and pancreatic cancer. These methods may be conducted by biostatisticians, particularly if they are able to compute LR scores[9](#pmid_29300386) using multiple phenotypes.\n * PP1\\_Strong: LOD ≥1.26 or Bayes Factor (LR) ≥18:1\n * PP1\\_Moderate: LOD ≥.60 or Bayes Factor (LR) ≥4:1\n * PP1: LOD ≥0.3 or Bayes Factor (LR) ≥2:18\n * BS4\\_Supporting: LOD ≤-.32 or Bayes Factor (LR) ≤.48\n * BS4\\_Moderate: LOD ≤ -.64 or Bayes Factor (LR) ≤.23\n * BS4: LOD ≤ -1.28 or Bayes Factor (LR) LR≤.053:1\n* A freely available tool, COOL (COsegregation OnLine) from Bing-Jian Feng’s laboratory can be used to calculate LoD scores for co-segregation analysis \n 1\\. Navigate to COOL (COsegregation OnLine)[7](#url_5e582422-7218-5d1c-9887-88a8dd6ac60f) \n 2\\. Input ‘PALB2’ into the ‘Input a Gene Symbol’ field (the PALB2 defaults are approved by this VCEP) \n 3\\. Upload your Pedigree File (see COOL (COsegregation OnLine) manual[8](#url_5d379a36-2cd8-5961-a6fc-7ce50795ce00) for formatting) \n 4\\. Leave all defaults as is. Select ‘Submit’ to obtain LR based on Full Likelihood Bayes (FLB)",
"label": "PP1",
"ns": "077",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* AD Condition: LOD ≥1.26 or Bayes Factor (LR) ≥18:1\n* AR Condition: Segregation in ≥3 affected relatives",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* AD Condition: LOD ≥.60 or Bayes Factor (LR) ≥4:1\n* AR Condition: Segregation in 2 affected relatives",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* AD Condition: LOD ≥0.3 or Bayes Factor (LR) ≥2:1\n* AR Condition: Segregation in 1 affected relative",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584503",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584503",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgcm--B"
},
{
"entContent": {
"_uniqueProp": "077_PVS1_nuclear_PALB2",
"additionalComments": "Used with PM5_Supporting for non-splice, non-start-loss LoF variants with PTCs upsteram of p.R3047. Per points system, PVS1 + 1 Supporting = LP.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "* Use PALB2 PVS1 Decision Tree Per PALB2 Exon Map and PALB2 PVS1 Guide \n* PVS1: Predicted splice defect \n* PVS1\\_Strength(RNA): Observed splice defect \n* The default RefSeq transcript for nucleotide (c.) annotation is NM\\_024675.3/ENST00000261584.8. Several naturally occurring alternate splicing isoforms have been described[1](#pmid_30890586). Yet, after careful examination, none of them is considered a candidate rescue transcript (very low contribution to overall expression, not coding proteins predicted functional, or both). In keeping with that, we have considered that all presumed LoF events (PVS1 decision tree specifications) occur in biologically relevant transcript(s).\n* WD40 beta propeller and the Coiled-coil domain (CC) are considered indispensable for PALB2 protein function. \n * PVS1 alterations that are predicted to escape NMD, but that adversely affect the WD40 domain can be granted PVS1 (as opposed to PVS1\\_Strong as the recommended baseline[2](#pmid_30192042). The following evidence supports this strength change: \n * The WD40 domain interacts with many different protein partners that are involved in the double strand break repair pathway[3](#pmid_30638972)\n * Two different C-terminal truncating mutations (c.3549C>A and c.3549C>G) resulting in loss of the last 3 amino acids \\[p.(Tyr1183Ter)\\], were identified in trans with PALB2 stop-gain variants in three unrelated FA (FA-N) patients[4](#pmid_17200671)\n * The PALB2 WD40 toroidal structure is “sealed” in the seventh blade by interaction of the C-terminal strand with the incomplete N-terminal blade. The last four residues of PALB2 (Y1183, H1184, Y1185, and S1186) are directly involved in this interaction (molecular Velcro hydrogen bonding)[15](#pmid_28673926). This is the rationale for the clinical relevance of the last 4 amino acids of the protein.\n * Alterations predicted to lead to in frame losses adversely affecting the WD40 structure/function are found in trans with LoF PALB2 alterations in Fanconi Anemia patients[4](#pmid_17200671)\n * Exon 10 donor: c.3113+5G>C (biallelic with c.395delT)\n * Exon 12 donor: c.3350+4A>G (biallelic with c.2393\\_2394insCT)\n * LoF alterations are rare in GnomAD in all exons\n * GnomAD v2.1 accessed 5/30/2019\n * Total Variants (includes splice acceptor/donor-conservative)\n * 1418 variants\n * 336,349 carriers\n * LoF Flag (excludes splice acceptor/donor-conservative)\n * 95 variants (6.7%)\n * 239 carriers (.07%)\n* PVS1 can be applied as per the PVS1 decision tree.\n * PVS1\\_Variable(RNA) shall be used for observed splice defects, whether from canonical +/-1,2 positions or other spliceogenic regions (including mid-exonic missense/synonymous variants that cause splice defects) with baseline weight as per the below decision tree. Weight can be further modified based on the quality of the RNA study including consideration of concepts such as:\n * Starting material (where patient material is preferable to in vitro minigene)\n * Use of NMD inhibitors where translation does occur such as cell lines[5](#pmid_9628884)[6](#pmid_7499432)\n * Primer design (to make sure it’s comprehensive to capture possible multicassette events)\n * Method of quantification \n * where e.g. capillary electrophoresis is preferable to estimation by gel band density\n * where SNP analysis is most preferred (where analysis of exonic SNPs and their relative presence in aberrant and WT transcripts is informative)\n * Quantification (where complete effects should have increased weight over incomplete effects)\n * Specific guidance on the use of RNA evidence in variant assessment is not a gene-specific consideration for PALB2 at this time, therefore discretion is left to assessors until further guidance is provided for this general concept from the Sequence Variant Interpretation group.\n* In the event that RNA data are available and they reflect a substantial variant-specific impact, do not use both PVS1(RNA) and PP3 or BP4. However, in the event that RNA data are available and they reflect no variant-specific impacts, PP3 or BP4 may be applied in conjunction with BP7(RNA).",
"label": "PVS1",
"ns": "077",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use PALB2 PVS1 Decision Tree",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use PALB2 PVS1 Decision Tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use PALB2 PVS1 Decision Tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use PALB2 PVS1 Decision Tree",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584492",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584492",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgd2---"
},
{
"entContent": {
"_uniqueProp": "077_BP7_nuclear_PALB2",
"additionalComments": "BP4 may be used in addition to BP7 for sysnonymous and deep intronic variants to achieve LB; BP7 is not a conflicting piece of evidence against an otherwise pathogenic body of evidence; BP7_O should NOT be used in conjunction with BP4.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "* BP7: Synonymous and deep intronic\n * Can be used for deep intronic variants beyond (but not including) +7 (donor) and -21 (acceptor)\n * May also apply BP4 to achieve Likely Benign\n * Is not considered a conflicting piece of evidence against a body of evidence supporting a pathogenic splice defect\n* BP7\\_Variable(RNA): RNA functional studies\n * Lack of aberrant splice defect: Please see PVS1\\_Variable(RNA) section (above) for guidance on baseline weights and modifications of weight based on quality for RNA assays\n * In the event that RNA data are available and they reflect a substantial variant-specific impact, do not use both PVS1(RNA) and PP3 or BP4. However, in the event that RNA data are available and they reflect no variant-specific impacts, PP3 or BP4 may be applied in conjunction with BP7(RNA).",
"label": "BP7",
"ns": "077",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": "General recommendation",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "BP7\\_Strong(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0220",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "BP7\\_Moderate(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* BP7: Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively.\n* BP7(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584519",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584519",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgYi---"
},
{
"entContent": {
"_uniqueProp": "077_BP4_nuclear_PALB2",
"additionalComments": "●\tProtein: Do not use. So far, published predictors have yet to achieve functional outcome for PALB2 missense variants\n●\tRNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing \no\tNOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects)\no\tNOTE: BP4 for splice predictions may not be applied in conjunction with BP7_Variable(RNA) (a lack of observed RNA defect)\no\tUse caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism. \n",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "* Missense: Do not use. So far, published predictors have yet to achieve functional outcome for PALB2 missense variants \n* NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) \n* NOTE: BP4 for splice predictions may not be applied in conjunction with BP7\\_Variable(RNA) (a lack of observed RNA defect) \n* Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism.\n* The VCEP uses SpliceAI as a sole predictor due to its ability to accurately predict loss of native splice sites and creation of cryptic sites (Jaganathan et al., 2019). This VCEP recommends SpliceAI thresholds set forth by the SVI in applying PP3 and BP4 to non-canonical splice variants: Apply PP3 for SpliceAI scores ≥0.2 and apply BP4 for SpliceAI scores ≤0.1 (Walker et al., 2023).\n* In the event that RNA data are available and they reflect a substantial variant-specific impact, do not use both PVS1(RNA) and PP3 or BP4. However, in the event that RNA data are available and they reflect no variant-specific impacts, PP3 or BP4 may be applied in conjunction with BP7(RNA).",
"label": "BP4",
"ns": "077",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* Missense: Do not use. \n* Splicing: No predicted impact via splicing (SpliceAI **≤0.1**). Do not apply for missense variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584516",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584516",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgeq---"
},
{
"entContent": {
"_uniqueProp": "077_BP2_nuclear_PALB2",
"additionalComments": "Do not use: See Fanconi Anemia BS2 table ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "Use ATM PM3/BP2 table.",
"label": "BP2",
"ns": "077",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": "Gene-specific, Disease-specific, Strength, General recommendation",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": "Gene-specific, Disease-specific, Strength, General recommendation",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": "Gene-specific, Disease-specific, Strength, General recommendation",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584514",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584514",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgf----"
},
{
"entContent": {
"_uniqueProp": "077_PP2_nuclear_PALB2",
"additionalComments": "Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "077",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584504",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584504",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgbW--A"
},
{
"entContent": {
"_uniqueProp": "077_PS3_nuclear_PALB2",
"additionalComments": "●\tProtein: Do not use: Lack of known positive controls \n●\tRNA: Do not use: See code PVS1_Variable(RNA)\n",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "For protein, see detailed notes on ATM-specific assays; For RNA use code PVS1_O and modulate strength based on assay quality and quantity (curator discretion).",
"label": "PS3",
"ns": "077",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": "Gene-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": "Gene-specific, Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": "Gene-specific, Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584495",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584495",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgcK---"
},
{
"entContent": {
"_uniqueProp": "077_BP3_nuclear_PALB2",
"additionalComments": "Do not use: small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity for PALB2. In addition, PALB2 is not considered to have repetitive regions without known function",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "077",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584515",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584515",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgZu---"
},
{
"entContent": {
"_uniqueProp": "077_PP5_nuclear_PALB2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP5",
"ns": "077",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584507",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584507",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgcW---"
},
{
"entContent": {
"_uniqueProp": "077_PP3_nuclear_PALB2",
"additionalComments": "Check splicing scores for all variant types. Do not combine splice prediction weight with other lines of protein evidence.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "* So far, published predictors have yet to achieve functional outcome for PALB2 missense variants \n* NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) \n* NOTE: PP3 for splice predictions may not be applied in addition to PVS1 or PVS1\\_Variable(RNA) codes.\n* Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism.\n* The VCEP uses SpliceAI as a sole predictor due to its ability to accurately predict loss of native splice sites and creation of cryptic sites (Jaganathan et al., 2019). This VCEP recommends SpliceAI thresholds set forth by the SVI in applying PP3 and BP4 to non-canonical splice variants: Apply PP3 for SpliceAI scores ≥0.2 and apply BP4 for SpliceAI scores ≤0.1 (Walker et al., 2023).\n* In the event that RNA data are available and they reflect a substantial variant-specific impact, do not use both PVS1(RNA) and PP3 or BP4. However, in the event that RNA data are available and they reflect no variant-specific impacts, PP3 or BP4 may be applied in conjunction with BP7(RNA).",
"label": "PP3",
"ns": "077",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Missense: Do not use.\n* Splicing: Predicted impact via splicing (SpliceAI **≥0.2**) for silent, missense/in-frame and for intronic variants outside of donor and acceptor 1,2 sites.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584505",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584505",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVga6---"
},
{
"entContent": {
"_uniqueProp": "077_PM5_nuclear_PALB2",
"additionalComments": "No rescue splicing isoforms have been identified in ATM.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "* Based on location of the most C-terminal known pathogenic variant, **p.Tyr1183\\*.**\n* Use as **PM5\\_Supporting** (not moderate)\n* Do not use for missense changes: Missense changes are not yet confirmed as a mechanism of disease for PALB2.",
"label": "PM5",
"ns": "077",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183.\n* Apply to splice variants as with premature termination codons upstream of p.Tyr1183 where PVS1\\_VS(RNA) is applied based on high quality observed splicing impact and must be NMD prone.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584501",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584501",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgcy---"
},
{
"entContent": {
"_uniqueProp": "077_PS2_nuclear_PALB2",
"additionalComments": "Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase\n●\tAutosomal Dominant Disease: Do not use-Informative de novo occurrences have not yet been observed for autosomal dominant disease. As breast cancer is relatively common and occurs frequently as an apparently sporadic event, de novo is unlikely to ever be informative unless specific features of PALB2-related cancer predisposition are identified.\n●\tAutosomal Recessive Disease: Do not use - de novo occurrences are too rare to be informative at this time. In addition, in a biallelic state, de novo occurrences have an exceedingly low probability of being able to be confirmed as in trans because parental testing (and identification of one variant in each parent) is typically required without the use of long-range technologies.\n",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS2",
"ns": "077",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584494",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584494",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgZS--A"
},
{
"entContent": {
"_uniqueProp": "077_PS1_nuclear_PALB2",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "* Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2\n* Splicing: See PALB2 PS1 Table (PMID: 37352859)",
"label": "PS1",
"ns": "077",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use PALB2 PS1 Splicing table",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use PALB2 PS1 Splicing table",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use PALB2 PS1 Splicing table",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584493",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1566584493",
"modified": "2025-07-14T21:29:14.317Z",
"modifier": "mhoenig",
"rev": "_k-pVgdi---"
}
],
"Disease": [
{
"entContent": {
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"id": "http://purl.obolibrary.org/obo/MONDO_0012565",
"lbl": "Fanconi anemia complementation group N",
"meta": {
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"val": "https://www.malacards.org/card/fanconi_anemia_complementation_group_n"
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],
"definition": {
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"xrefs": [
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]
},
"subsets": [
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"synonyms": [
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},
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},
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"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "Fanconi anaemia caused by mutation in PALB2"
},
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"pred": "hasExactSynonym",
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"val": "Fanconi anaemia complementation group type N"
},
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"pred": "hasExactSynonym",
"val": "Fanconi anemia caused by mutation in PALB2",
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},
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"pred": "hasExactSynonym",
"val": "Fanconi anemia complementation group N",
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},
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"val": "Fanconi anemia complementation group type N",
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},
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"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "PALB2 Fanconi anaemia"
},
{
"pred": "hasExactSynonym",
"val": "PALB2 Fanconi anemia",
"xrefs": [
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]
},
{
"pred": "hasRelatedSynonym",
"val": "Fanconi anemia, complementation group N",
"xrefs": [
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}
],
"xrefs": [
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{
"val": "GARD:15500"
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{
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{
"val": "MESH:C563657"
},
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"type": "CLASS"
},
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"name": "Fanconi anemia complementation group N"
},
"entId": "MONDO:0012565",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0012565",
"entType": "Disease",
"ldhId": "467875876",
"ldhIri": "https://cspec.genome.network/cspec/Disease/id/467875876",
"modified": "2025-10-07T16:13:40.840Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7xJwe---"
},
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"id": "http://purl.obolibrary.org/obo/MONDO_0015278",
"lbl": "familial pancreatic carcinoma",
"meta": {
"basicPropertyValues": [
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"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
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{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1385362916"
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"val": "http://purl.obolibrary.org/obo/NCIT_C43298"
},
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"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_1333"
},
{
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"val": "https://omim.org/entry/260350"
}
],
"definition": {
"val": "Familial pancreatic carcinoma is defined by the presence of pancreatic cancer (PC) in two or more first-degree relatives.",
"xrefs": [
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]
},
"subsets": [
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],
"synonyms": [
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"xrefs": [
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},
{
"pred": "hasExactSynonym",
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},
{
"pred": "hasExactSynonym",
"val": "hereditary exocrine pancreatic carcinoma",
"xrefs": [
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]
},
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"pred": "hasExactSynonym",
"val": "hereditary pancreatic cancer",
"xrefs": [
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},
{
"pred": "hasExactSynonym",
"val": "hereditary pancreatic carcinoma",
"xrefs": [
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},
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"val": "pancreatic cancer, somatic"
},
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"val": "pancreatic carcinoma, somatic"
},
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"val": "pancreatic acinar carcinoma"
}
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"xrefs": [
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{
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{
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{
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}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0015278",
"name": "familial pancreatic carcinoma"
},
"entId": "MONDO:0015278",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0015278",
"entType": "Disease",
"ldhId": "467895128",
"ldhIri": "https://cspec.genome.network/cspec/Disease/id/467895128",
"modified": "2025-10-07T16:14:17.854Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7xt9K---"
},
{
"created": "2024-11-20T22:14:03.908Z",
"creator": "cspecAdministrator",
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0700272",
"lbl": "PALB2-related cancer predisposition",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6515"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0002-4142-7153"
}
],
"definition": {
"val": "Hereditary cancer predisposition due to variation(s) in the PALB2 gene. Pathogenic germline variation in PALB2 confers an autosomal dominant predisposition to tumor formation at multiple primary sites, including breast cancer, ovarian cancer, and pancreatic cancer.",
"xrefs": [
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]
},
"subsets": [
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]
},
"type": "CLASS"
},
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"name": "PALB2-related cancer predisposition"
},
"entId": "MONDO:0700272",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0700272",
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},
{
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"label": "Rule28, Condition2",
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}
],
"inference": "Uncertain Significance - Conflicting Evidence",
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},
{
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],
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},
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],
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],
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"condition": "==1",
"getpartitionPath": "",
"label": "Rule19, Condition2",
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],
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},
{
"conditions": [
{
"applicableCriteriaCodes": [
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"condition": "==1",
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}
],
"inference": "Likely Benign",
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}
]
},
"type": "Richards et.al., 2015 - Combining rules"
},
"entType": "RuleSet",
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"ldhIri": "https://cspec.genome.network/cspec/RuleSet/id/1526222369",
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},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Hereditary Breast, Ovarian and Pancreatic Cancer",
"shortBaseName": "HBOP",
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"title": "Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
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"entIri": "http://clinicalgenome.org/affiliation/50039",
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"title": "ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.1.0",
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"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
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"id": "0065",
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"applicability": "Not Applicable",
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"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
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],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "To evaluate splice prediction, use the BP4 code. If BP4 is met for lack of splice effect, BP7 can be applied to silent or intronic variants where the PhyloP score is ≤0.2.",
"type": "EvidenceLineStrength"
}
]
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"creator": "dritter@bcm.edu",
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"geneType": "nuclear",
"instructionsToUse": "The Splice AI score alone can be applied if VarSeak is unable to accept the variant type.",
"label": "BP4",
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"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
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"text": "",
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"specificationType": [
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"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Due to the lack of benign variants, and the drop in classification accuracy for benign VHL variants, missense predictors should not be used to assign the BP4 evidence code. \n\nBP4 can be applied to assess lack of splicing impact, with concordance of Splice AI (≤0.1) and VarSeak (Class 1 or Class 2).",
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}
]
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"modified": "2025-01-10T22:36:51.153Z",
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"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
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"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
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"geneType": "nuclear",
"instructionsToUse": "For BS4, affected members of the pedigree should fulfill the Danish Criteria for VHL. BS4 should not be used if the affected members are only affected with pheochromocytoma (e.g. VHL 2c) and/or Renal Cell Carcinoma. Family members should also be fully characterized for VHL manifestations to be considered unaffected, and be at least 65 years old (age at which full penetrance should be reached).\n\nFor example: two siblings who both have VHL as per the Danish criteria, one has a _VHL_ variant, and the other sibling does not, BS4 could be used. \n\nConversely, two siblings both fully characterized, one sibling has VHL manifestations, the other sibling is >65 yo and does not have VHL manifestations. If both siblings carry the _VHL_ variant, BS4 could be used.\n\nIf the above are fulfilled, BS4 strong could be used if lack of segregation of the variant is seen in affected members of two or more families and BS4\\_supporting be used if one family is observed.\n\nIf a parent fulfills the Danish criteria for VHL disease, but the child is phenotyped and has no manifestations, BS4 cannot be used as the child could develop VHL manifestations at a later age.",
"label": "BS4",
"ns": "078",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0071",
"instructionsToUse": "",
"specificationType": [
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],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation is seen in affected members of ≥2 families",
"type": "EvidenceLineStrength"
},
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"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
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"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation is seen in 1 family.",
"type": "EvidenceLineStrength"
}
]
},
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"ldhId": "1743943303",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943303",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7Hi---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
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"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
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"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "078",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
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"id": "0226",
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"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
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"text": "",
"type": "EvidenceLineStrength"
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"applicability": "Not Applicable",
"id": "0072",
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"specificationType": [
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"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"id": "0100",
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"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
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"id": "0085",
"instructionsToUse": "",
"specificationType": [
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"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "• HIF 1/2a assay replicates WT function and/or\n\n• VBC complex stability is not affected and/or \n\n• ECM formation/fibronectin binding is unaffected \n\nThis rule can be used and weighted as appropriate for functional tests of variants prior to codon 54 (which show the VHL19 product is not impacted). Evidence of benign effect for VHL Type 1 and 2A/B can be seen when HIF1/2a displays degradation (i.e. replicates WT function), and/or the VHL Elongin C, Elongin B, Cullin2 RBX1 (VCB-CR) E3 ubiquitin ligase complex stability is not affected and/or ECM formation/fibronectin binding is unaffected. Note: VHL Type 2C variants typically do not affect HIF1/2a; absence of HIF1/2a alone when testing a suspected VHL Type 2C variant should not be used for BS3. Functional studies of fibronectin and ECM formation are needed for VHL Type 2C. Follow modified SVI guidance for functional assays, general controls and benign controls. For splicing variants (and intronic/synonymous), RNA assays must demonstrate no impact on splicing.",
"type": "EvidenceLineStrength"
}
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},
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"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
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"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
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"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "078",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
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],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "VHL is not highly penetrant _at an early age._ BS2 can be applied if: There are at least 3 individuals, all >=65yo, unaffected, harboring the same variant, _**with full phenotyping and screening**_ for the absence of VHL-related cancers.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "VHL is not highly penetrant _at an early age._ BS2\\_Supporting can be applied if: At least 3 individuals, all >=65yo, unaffected, harboring the same variant, _**lacking full phenotyping and screening**_, with no noted VHL-related cancers",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943301",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943301",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7bO---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_BA1_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "Follow all [SVI general guidance](https://clinicalgenome.org/working-groups/sequence-variant-interpretation/) on applying population filters.",
"label": "BA1",
"ns": "078",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Use a BA1 cut off of >=0.000156 (0.0156%) GroupMax Filtering Allele Frequency in gnomAD (based on gnomAD v4 release).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943299",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943299",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7I6---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PP2_nuclear_VHL",
"additionalComments": "Do not use. While there are known pathogenic missense in VHL, there is also evidence of benign or common missense in VHL. gnomAD shows VHL is not intolerant to missense (Z score = -0.39). Missense variants in VHL will need to achieve pathogenic interpretation via other evidence codes.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "**Do not use.** While there are known pathogenic missense in VHL, there is also evidence of benign or common missense in VHL. gnomAD shows VHL is not intolerant to missense (Z score = -0.39). Missense variants in VHL will need to achieve pathogenic interpretation via other evidence codes.",
"label": "PP2",
"ns": "078",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943295",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943295",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7WG---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PM2_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "Follow all [SVI general guidance](https://clinicalgenome.org/working-groups/sequence-variant-interpretation/) on applying population filters.",
"label": "PM2",
"ns": "078",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "PM2\\_Supporting can be applied for variants either absent from gnomAD or with \\<= 0.00000156 (0.000156%) GroupMax Filtering Allele Frequency in gnomAD (based on gnomAD v4 release). If no GroupMax Filtering Allele Frequency is calculated (ex. due to a single variant present), PM2\\_Supporting may also be applied.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943289",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943289",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7Jy---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_BP3_nuclear_VHL",
"additionalComments": "Not applicable at this time.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "078",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "BP3 can be applied to the 8x GXEEX AA repeat motif in the 5’ end of VHL p30 (AA14-AA48). Otherwise, the rest of the coding regions in VHL do not contain repeats (and none contain LINE/SINE, low complexity or other repeat types as identified by RepeatMasker) and BP3 is not applicable.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943306",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943306",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7Ua---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_BP1_nuclear_VHL",
"additionalComments": "This rule code does not apply to this gene, as truncating variants account for only a portion of disease-causing variants.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "078",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943304",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943304",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7G2---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PP4_nuclear_VHL",
"additionalComments": "Combine with PS4 to avoid double counting probands. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "078",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943297",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943297",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7cq---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PP1_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "Meioses can be counted additively across multiple families. This code may only be applied when the phenotype is highly consistent with VHL (Danish Criteria in a family with history of disease).",
"label": "PP1",
"ns": "078",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "\\>7 meioses across >=2 families",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "5 – 6 meioses across ≥1 family.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "3 – 4 meioses across ≥1 family.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943294",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943294",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7d6---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PS3_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS3",
"ns": "078",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Acceptable assays that display functional effect in VHL are the following: \n\n• HIF 1/2a degradation assays -- HIF1/2a is not degraded and/or \n\n• VBC complex stability is affected and/or\n\n• Pathogenicity supported by abnormal ECM formation and impaired fibronectin binding [1](#pmid_9651579) , [2](#pmid_11331613) , [3](#pmid_11358843) , [17](#pmid_14706840)\n\nMultiple studies and publications confirm the role of VHL in HIF1/2a regulation and VBC complex stability for VHL Type 1, and 2A/B, as well as fibronectin binding/deposition and assays evaluating extra-cellular matrix composition. In-vitro assays should display total loss of HIF1/2a degradation (i.e. HIF1/2a presence) for VHL Type 1, and 2A/B. VHL Type 2C should display presence of HIF1/2a (with VBC complex stability variably affected and fibronectin deposition/extra cellular matrix composition affected). These assays are typically performed in Renal Cell Carcinoma (RCC) cells lacking VHL, introducing normal pVHL as a control in addition to a variant-VHL, then comparing HIF1/2a levels to WT pVHL. Brnich et al proposed 10 controls to achieve PS3\\_Supporting and 11 for PS3\\_Moderate [10](#pmid_31892348). We propose to _follow the workflow outlined in Brnich et al._ Type 2C VHL variants are typically missense variants in the alpha domain of VHL, and do not usually affect HIF1/2a. If HIF1/2a maintains presence and VHL Type 2C is suspected, assays evaluating fibronectin deposition or extracellular matrix assembly should be used. \n\n**SPLICING:** **PS3:** RNA transcripts carrying splicing mutation display splicing defects in patient cells. **PS3\\_Moderate**: RNA transcripts carrying splicing mutation display splicing defects in in-vivo or in-vitro assays. **Functional Assay Documentation** : [https://drive.google.com/file/d/1w8P8zs1fHUolaAYmBL1jw-vcjsX3N_yh/view?usp=sharing](https://drive.google.com/file/d/1w8P8zs1fHUolaAYmBL1jw-vcjsX3N_yh/view?usp=sharing)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943286",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943286",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7K2---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_BP6_nuclear_VHL",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP6",
"ns": "078",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943309",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943309",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7Fe---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_BS1_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "Follow all [SVI general guidance](https://clinicalgenome.org/working-groups/sequence-variant-interpretation/) on applying population filters.",
"label": "BS1",
"ns": "078",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Use BS1 cut off of >=0.0000156 (0.00156%) GroupMax Filtering Allele Frequency in gnomAD (based on gnomAD v4).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943300",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943300",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7b2---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PP5_nuclear_VHL",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP5",
"ns": "078",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943298",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943298",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7NG---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_BP5_nuclear_VHL",
"additionalComments": "Given the broad spectrum of DICER1-related neoplasms and the General recommendation lack of evidence of other high-penetrance germline variants that could account for such neoplasms (except perhaps for some already low-specificity phenotypes such as Wilms tumor), this rule should not be used at this time.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "078",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "BP5 can be applied for two or more co-occurrences with pathogenic variants in a different gene that fully explained the patient's phenotype, but specific circumstances would need to be met in order for a case to be considered for inclusion. First, the variant in the other gene must be considered highly penetrant, with both the individual's age, tumour type and gender taken into consideration. Additionally, the patient's personal and family history (including up to 2nd degree relatives) should not overlap with features seen in VHL and VHL tumour histologies. As an example, an individual with a personal and family history of pheochromocytoma who harbored a _VHL_ variant in addition to a pathogenic SDHB variant BP5 would not apply, because pheochromocytoma is a known risk in VHL and the _VHL_ variant might have contributed to this individual's pheochromocytoma cancer risk. However, an individual with a personal and family history of chromophobic RCC who was positive for a _VHL_ variant as well as a pathogenic FLCN variant would be considered for BP5 application, as non-clear cell RCC is not associated with VHL disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943308",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943308",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7Sm---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_BP2_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "BP2 should not be used in the presence of any clinical or molecular findings of congenital polycythemia",
"label": "BP2",
"ns": "078",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "i) -variant observed in trans with a known pathogenic variant (phase confirmed), in the absence of congenital polycythemia (clinical manifestations or molecular)\n\nii) -OR observed in the homozygous state in an individual without personal &/or family history of Von Hippel-Lindau disease or congenital polycythemia\n\niii) -OR observed _in cis_ or with unknown phase with three or more different pathogenic _VHL_ variants",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "\\-variant is observed _in cis_ (or phase is unknown) w/ a pathogenic _VHL_ variant",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943305",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943305",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7L6---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PM5_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PM5",
"ns": "078",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Pathogenicity of prior variant is established by interpretation of the VHL VCEP or variants with pathogenicity established using VHL VCEP specifications. The Grantham distance should be used to compare variants. The variant under consideration must be equal or a larger distance than the classified pathogenic variant (Grantham, 1974, Table 2 [16](#pmid_4843792) ). Splice metapredictors should be used to ensure the variant is not predicted to have an effect on splicing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943292",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943292",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7f----"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PM4_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "078",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "In-frame insertion / deletions in the B and alpha domains and stop-loss variants adding significant additional amino acids to VHL [15](#pmid_20560986) cites multiple pathogenic cases and experimental evidence of stop loss extensions in VHL that are associated with Type 2A VHL disease). The functional domains are: Beta (β) domain (AA 63 - 155, Nuclear Export), Alpha (ɑ) domain (AA 156-192, Elongin C binding), and Second Beta (β) domain (AA 193-204). \n\nPM4 does not apply to in-frame indels prior to codon 54 that do not alter the Met54 VHL p19 codon and beyond.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943291",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943291",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7N2---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PM1_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "_**See germline and somatic hotspot residue table.**_ PM1 can be used for (1) known germline mutational hotspots, and for (2) currently 11 somatic hotspots (cancerhotspots.org) where there is not already a germline mutational hotspot (see Walsh et al 2018 [11](#pmid_30311369) and cancer hotspots.org(v2) [12](#pmid_29247016) ): Following PM1 somatic hotspot recommendations through the ClinGen Germline/Somatic Subcommittee where: AA with >= 10 somatic occurrences in the same AA can receive PM1, while AA with \\<10 can receive PM1\\_Supporting. It can also be used for (3) location in a key functional domain if a residue is not a germline or somatic hotspot.",
"label": "PM1",
"ns": "078",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Putative missense variants that are known germline hotspots AND/OR in key functional domains AND/OR somatic variants that have ≥10 instances for the same AA in cancerhotspots.org. See the table of Germline and Somatic Hotspots.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Putative missense variants seen in somatic databases, having \\<10 instances for the same AA in cancerhotspots.org. See the table of Germline and Somatic Hotspots.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943288",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943288",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7aa---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PS4_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "**See phenotype and points tables.** When the phenotype meets Danish Criteria (panel is not required, unless only RCC+Pheo. If a case with RCC+Pheo does not have a panel, they are scored as \"Nonspecific\" (0.25 points)), count 1 point per proband. When the phenotype is consistent with VHL but is not highly specific (such as RCC+Pheo) count 0.5 and when not specific and no panel, count as 0.25. Unrelated probands are to be used, and may be aggregated across all three categories (highly specific Danish Criteria, Consistent and Nonspecific). If there is a pedigree with a choice of probands with VHL disease, choose the proband that most closely matches Danish Criteria. When the phenotype is not available (e.g. from a published article on a VHL cohort that does not detail the phenotype), count 0.25 points per proband. For example, for variant A, 2 probands meet Danish Criteria, 2 probands display Pheochromocytoma only and 4 probands were defined as VHL probands in a published manuscript but lack any further specific criteria or phenotypic details. This would be calculated as (2, 1 pt each per Danish Criteria proband) + (1, 0.5 pt each per Consistent proband) + (1, 0.25 pt each per Nonspecific proband) = 4. PS4 would be downgraded to moderate (PS4\\_Moderate).",
"label": "PS4",
"ns": "078",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "**16+ points the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.**",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**5-15 points the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.**",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**2 – 4 points the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.**",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**1 point the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.**",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943287",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943287",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7PC---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PVS1_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PVS1",
"ns": "078",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "**LINK TO PVS1 DECISION TREE DOCUMENT:** [**https://drive.google.com/file/d/1mGfChgxbGVbzYn6Ggmb9rYvoGGah25ll/view?usp=sharing**](https://drive.google.com/file/d/1mGfChgxbGVbzYn6Ggmb9rYvoGGah25ll/view?usp=sharing)\n\n**Do not apply PVS1 for truncations that occur prior to Codon 54 (including frameshift events that start and end prior to Codon 54 but the truncation extends beyond Codon 54.)**\n\n**Note1: Exon presence in biologically relevant transcripts:** In some transcripts exon 2 of _VHL_ is skipped and expressed at low levels. The function of this transcript is not fully known. Exon 2 comprises almost the entirety of the nuclear export function region of the Beta domain and is critical for known VHL function. Exon 1 contains the only initiator codons in _VHL_. Exon 3 contains the elongin binding function. _**All exons should be considered as \"present in biologically relevant transcripts\" in the PVS1 decision tree.**_\n\n**Note 2: The 10% PVS1 downgrade to Moderate cannot apply to VHL** because of the small size.\n\n**Nonsense Mediated Decay** [5](#pmid_22825683) [4](#pmid_20145706) **NMD experimental evidence in 1st exon after codon 54 and to 5' region of 2nd exon (codon 138)**.\\*\\*\n\n**Critical Domains:**\n\n1st Beta (β) domain (63-154), especially Nuclear Export (114-155)\n\nAlpha (ɑ) domain (155-192), especially Elongin C binding (157 - 172)\n\nSecond Beta domain (193-204) \n\n_Truncating variants after Met54 and predicted to undergo NMD (from AA55-AA136/c.408) or in the beta or alpha domains can receive PVS1, and those outside the second Beta domain (205-213) can receive PVS1\\_Moderate downgrade to account for minimal loss of VHL protein. Notably a frame shift deletion at 205 is pathogenic in ClinVar (ID 18971) as are stop loss extension variants in the last codons (see PM4)._\n\n**SPLICE: If any canonical exon is skipped, the variant receives PVS1.** If a cryptic splice disrupts the reading frame, and is in a critical domain (AA63-AA204) or is predicted to undergo NMD (AA55-AA136) it receives PVS1. If it is outside a critical domain and predicted to undergo NMD (AA55-62), it receives PVS1\\_Strong (the second site outside of critical domains AA205-213 is not predicted to undergo NMD). If a cryptic splice does not alter the reading frame, and is in a critical domain (AA 63-204), it can receive PVS1\\_Strong, and if it is outside the critical domain (AA 205-213) or in an NMD prediction (AA 55-62), it receives PVS1\\_Moderate. Note: There is a cryptic exon (E1) in intron 1 [7](#pmid_31996412) [6](#pmid_29891534), and silent variants in exon 2 that are reported to cause skipping of exon 1. If there is functional evidence of exon skipping (RNA splice assay) then PVS1 can apply. Do not double count evidence. Ex. PVS1 should be used in place of PS3 functional evidence confirming splice alteration, but PS3 evidence code could still apply to other relevant assays confirming effect on HIF1/2a presence etc. \n\n**EXON DELETION:** SVI PVS1 decision tree modified for whole exon deletions. There are only 3 exons in _VHL_ and each has an important functional domain. Any exon deletion of _VHL_ receives PVS1. \n\n**EXON DUPLICATION:** Follow PVS1 decision tree. Note: few pathogenic exon duplications are reported in ClinVar. (ID:417571, ID:584137). These have no literature cited. \n\n**INITIATION CODON:** VHL Met 1 (in VHL p30) truncation or missense would not affect VHL p19, as VHL has a second start at codon 54 (VHL p19), it cannot be scored in the PVS1 decision tree. After that, no other viable alternative starts are known. Start loss at codon 54 would presumably result in an impact, as VHL p30 and p19 would be truncated prior to any known functional domains (PVS1). Ong 2007 has 1 family (2 subjects) with Met54X and reports cerebellar hemangioblastomas. There is no functional study in the paper for this variant. Olschwang et al 1998 VHL Type 2A, one subject with 161insT (FS result). There is no functional study in the paper. Missense at Met 54 (VHL p19 initiation codon) would presumably not result in as strong an impact as the full length VHL p30 would still be produced (PVS1 decision tree = N/A). ClinVar has M54T (ID:819688) and M54L (ID:843990). M54T is uncertain, with no other evidence provided. M54L references M54I which segregates in homozygous state with erythrocytosis in individuals of Moroccan descent [9](#pmid_26224408) [8](#pmid_27578599), and those heterozygous for M54I did not present VHL phenotype [9](#pmid_26224408).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943283",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943283",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7gq---"
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{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PP3_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "The Splice AI score alone can be applied if VarSeak is unable to accept the variant type. Note: for canonical splice variants do not use PP3 if PVS1 is applied.",
"label": "PP3",
"ns": "078",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For missense variants, use REVEL score >=0.664. \n\nFor splice variants, concordance of Splice AI (>0.5) and VarSeak (class 4 or class 5).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943296",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943296",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7Vi---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PM6_nuclear_VHL",
"additionalComments": "Combined with PS2. Use PS2 instead of PM6.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "See PS2 evidence code for scoring and phenotypes.",
"label": "PM6",
"ns": "078",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See PS2 evidence code for scoring and phenotypes. Assumed _de novo_ receives half the points as compared to maternity and paternity confirmed _de novo_. If paternity and maternity are not confirmed, score as the PM6 code. PM6 can receive “VeryStrong” strength. For example, if there are >4 de novo probands with Danish Criteria and none have paternity confirmed, this can receive PM6\\_VeryStrong. Note: the VCI as of Nov 2022 does not allow PM6\\_VeryStrong. Instead apply the PS2 evidence code and increase the strength to “VeryStrong” with a note that paternity and/or maternity is not confirmed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943293",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943293",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7XC---"
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{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PM3_nuclear_VHL",
"additionalComments": "Autosomal dominant.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "078",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943290",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943290",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
"rev": "_jDHa7ZW---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PS2_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "Use the SVI-recommended scoring system ( 0.5 supporting, 1 moderate, 2 strong, 4 very strong) with disease-specific phenotype detailed as follows: Danish Criteria (see recently updated Danish Criteria [18](#pmid_35709961) ), Consistent Phenotype (1 phenotype of VHL disease without family history or strong indication of VHL phenotype) or Nonspecific Phenotype (specific information on tumor types is not provided). Negative panel testing is required as follows: For Renal Cell Carcinoma, tumor histopathologies should be clear cell and a negative panel should include at least SDHB/C/D and for Pheochromocytoma only negative panels should include at least SDHB/C/D and RET. If paper states Danish or International Criteria but does not provide case-specific details, count these cases as \"Phenotype consistent.\" If there is no family history of VHL disease, Renal Cell Carcinoma and Pheochromocytoma only will count as \"Phenotype consistent\" (with negative panel testing).",
"label": "PS2",
"ns": "078",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "A single proband cannot be very strong evidence, but multiple probands can be combined to reach very strong (4+ points).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Phenotype highly specific for the gene (Danish Criteria) (≥2 but less than 4 _de novo_ points).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Phenotype consistent but not highly specific. Ex. VHL spectrum cancer without family history or strong indication of VHL phenotype. (≥1 but less than 2 _de novo_ points)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype consistent but not highly specific (≥0.5 but less than 1 _de novo_ points) Ex. subject included in a VHL cohort, but specific information on tumor types is not provided.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943285",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943285",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
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"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PS1_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "078",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applied only to variants with interpretation by the VHL VCEP or by a variant with pathogenicity established using VHL VCEP specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943284",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1743943284",
"modified": "2025-01-10T22:36:51.153Z",
"modifier": "dritter@bcm.edu",
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"label": "Rule11, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule11"
},
{
"conditions": [
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"applicableCriteriaCodes": [
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"PS2",
"PS4",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule12, Condition1",
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},
{
"applicableCriteriaCodes": [
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"PS3_Supporting",
"PS4_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule12, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule12"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
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"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=3",
"label": "Rule13, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule13"
},
{
"conditions": [
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"applicableCriteriaCodes": [
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"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule14, Condition1",
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},
{
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"PM1_Supporting",
"PM2_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule14, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
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"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
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"PS4_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PP1",
"PP3"
],
"condition": ">=4",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS4",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule20, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
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"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule20, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule20"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
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"BS2",
"BS4",
"BP2_Strong"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
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"condition": "==1",
"label": "Rule17, Condition1",
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"rule": "Rule17"
},
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"conditions": [
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"applicableCriteriaCodes": [
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"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
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"applicableCriteriaCodes": [
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"BS3_Supporting",
"BS4_Supporting",
"BP2",
"BP3",
"BP4",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
}
]
}
},
"entType": "RuleSet",
"ldhId": "1527855768",
"ldhIri": "https://cspec.genome.network/cspec/RuleSet/id/1527855768",
"modified": "2025-01-10T22:36:50.775Z",
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},
"step4": {
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}
},
"curationActivity": "Variant Pathogenicity",
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"shortBaseName": "VHL",
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},
"entId": "50036",
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{
"entContent": {
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"description": "Rule specifications for Bernard-Soulier syndrome associated with the GP1BA gene.\n ",
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"shortTitle": "Platelet Disorders Specification",
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"states": [
{
"current": false,
"event": {
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"name": "cspec-created",
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"timeStamp": "2022-09-28T19:45:18.591Z"
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},
{
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{
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{
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{
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{
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},
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},
{
"current": false,
"event": {
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},
{
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{
"current": true,
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{
"current": false,
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}
],
"tagNameSpaces": [
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],
"title": "ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GP1BA Version 1.1.0",
"type": "Richards et.al., 2015 - Combining rules",
"version": "1.1.0",
"versioned": true
},
"entId": "GN079",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
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"baseStrength": "Pathogenic",
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"gene": [
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"geneType": "nuclear",
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"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
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"completed": true
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"Pilot Rules In Prep": {
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"applicability": "Not applicable",
"id": "0240",
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
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{
"applicability": "Not applicable",
"id": "0021",
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"strengthSepioID": "SEPIO:0000220",
"text": "",
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"specificationType": [
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],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use as originally specified, but the comparison variant must reach a pathogenic classification using these rule specifications in order to apply code.",
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{
"applicability": "Applicable",
"id": "0046",
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],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
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},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
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]
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{
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"creator": "justyne",
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"applicability": "Applicable",
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"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BP2",
"ns": "079",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
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"status": {
"Classification Rules In Prep": {
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"Pilot Rules In Prep": {
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"strengthSepioID": "SEPIO:0000325",
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{
"applicability": "Not applicable",
"id": "0207",
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"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"id": "0068",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
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"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
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"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use as written for recessive variants (i.e. - variant must be observed in cis with a pathogenic variant).",
"type": "EvidenceLineStrength"
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]
},
"entType": "CriteriaCode",
"ldhId": "116281432",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281432",
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"sepioID": "SEPIO-CG:99038",
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"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "gnomAD MAF of greater than or equal to 0.001 (or 0.1%).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0202",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
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"entType": "CriteriaCode",
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"modifier": "leekristy",
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"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BS2",
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"sepioID": "SEPIO-CG:99040",
"specificationType": [],
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"completed": true
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"Pilot Rules In Prep": {
"completed": true
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},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Use this rule with 1 or more homozygotes who are unaffected (proven with aggregometry OR flow cytometry AND normal platelet count AND normal platelet size).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
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"entType": "CriteriaCode",
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281435",
"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
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"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
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"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
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"geneType": "nuclear",
"label": "BS4",
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"sepioID": "SEPIO-CG:99042",
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"status": {
"Classification Rules In Prep": {
"completed": true
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"Pilot Rules In Prep": {
"completed": true
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"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant not tracking in an affected family member.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
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"entType": "CriteriaCode",
"ldhId": "116281434",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281434",
"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
"rev": "_kXXnXYS---"
},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "079_PS3_nuclear_GP1BA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "079",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "In a transgenic animal model, must demonstrate minimal to no function.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Functional assays measuring quantity of GP1ba expression on cell surface measured by flow cytometry analysis of GPIb and GPIX when there is absent or near absent expression, >75% reduction (see spreadsheet for more detail).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116281431",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281431",
"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
"rev": "_kXXnXXe---"
},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "079_BP4_nuclear_GP1BA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"instructionsToUse": "Determine REVEL and Splice AI cutoff before applying this code. Do not use if PP3 is met.",
"label": "BP4",
"ns": "079",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "For a missense variant apply when REVEL score is less than or equal to 0.290, based on recommendations of Pejaver et al., 2022 (PMID: 36413997) AND SpliceAI score is zero.\n\nOR for a synonymous or intronic variant apply when SpliceAI score is zero.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116281427",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281427",
"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
"rev": "_kXXnXSm---"
},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "079_PVS1_nuclear_GP1BA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"instructionsToUse": "See _GP1BA_ modified decision tree below.",
"label": "PVS1",
"ns": "079",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use _GP1BA_ modified decision tree as per SVI WG.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use _GP1BA_ modified decision tree as per SVI WG.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use _GP1BA_ modified decision tree as per SVI WG.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use _GP1BA_ modified decision tree as per SVI WG.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116281424",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281424",
"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
"rev": "_kXXnXSW---"
},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "079_BP5_nuclear_GP1BA",
"additionalComments": "Do not use this rule as an individual can be a carrier of an unrelated pathogenic variant for a recessive disorder.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "079",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116281423",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281423",
"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
"rev": "_kXXnXRy---"
},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "079_PP4_nuclear_GP1BA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "079",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Must meet both criteria:\n\n1)Proband with platelet aggregation study absent for ristocetin and present for all other agonists OR flow cytometry or Western blot less than 10% expression of GPIba.\n\n2)Proband must have full sequencing of all three BSS genes (_GP1BA, GP1BB_ and _GP9_) and deletion/duplication analysis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Proband with platelet aggregation study absent for ristocetin and present for all other agonists, OR \n* Flow cytometry or Western blot less than 10% expression of GPIba.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116281422",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281422",
"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
"rev": "_kXXnXRi---"
},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "079_BP3_nuclear_GP1BA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "079",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use with no specification",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116281406",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281406",
"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
"rev": "_kXXnXU----"
},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "079_PS2_nuclear_GP1BA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"instructionsToUse": "Only applicable when proband has a known pathogenic or likely pathogenic variant according to the BSS rule specifications along with the de novo variant. Only use “highly specific phenotype” scoring if all three BSS genes were sequenced. Otherwise use the “consistent but not highly specific” scoring. See further instructions below.",
"label": "PS2",
"ns": "079",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use proposed SVI point recommendations. See further instruction below. Total of 4 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use proposed SVI point recommendations. See further instruction below. Total of 2 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use proposed SVI point recommendations. See further instruction below. Total of 1 point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use proposed SVI point recommendations. See further instruction below. Total of 0.5 point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116281428",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281428",
"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
"rev": "_kXXnXS6---"
},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "079_PM2_nuclear_GP1BA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "079",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "gnomAD MAF of less than or equal to 0.0001114.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116281420",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281420",
"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
"rev": "_kXXnXQu---"
},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "079_BP1_nuclear_GP1BA",
"additionalComments": "Rule does not apply as truncating variants do not predominate and missense variants are a known cause of disease.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "079",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116281414",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281414",
"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
"rev": "_kXXnXV----"
},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "079_PP3_nuclear_GP1BA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "079",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "REVEL score of ≥0.773 based on recommendations of Pejaver et al., 2022 (PMID: 36413997).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "REVEL score of ≥0.644 (to \\<0.773), based on recommendations of Pejaver et al., 2022 (PMID: 36413997).\n\nOR suggested splicing effect using SpliceAI greater than or equal to 0.5.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116281413",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281413",
"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
"rev": "_kXXnXUy---"
},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "079_BP7_nuclear_GP1BA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"instructionsToUse": "Can be used for intronic variants. Also, can be used in combination with BP4.",
"label": "BP7",
"ns": "079",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use SpliceAI to rule out possible splicing defect (score = 0.2 or less) and reference PhyloP (score = 1.5 or less) to assess conservation.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116281411",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281411",
"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
"rev": "_kXXnXUi---"
},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "079_PM5_nuclear_GP1BA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "079",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use as originally specified, but the comparison variant must reach a pathogenic classification using the these rule specifications in order to apply code.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use as originally specified, but the comparison variant must reach a likely pathogenic classification using the these rule specifications in order to apply code.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116281410",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281410",
"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
"rev": "_kXXnXWa---"
},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "079_PM3_nuclear_GP1BA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"instructionsToUse": "_In trans_ variants classified as a variant of uncertain significance, as per the _GP1BA_ rule specifications, must meet PM2\\_supporting to be scored. Conversely, _in trans_ variants that meet a pathogenic or likely pathogenic classification using the _GP1BA_ rule specifications do not have to meet PM2\\_supporting criteria; however, they cannot meet BS1 or BA1 criteria. See PM3 instructions below for further detail.",
"label": "PM3",
"ns": "079",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use proposed SVI point recommendations. Both variants must be classified using these rule specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use proposed SVI point recommendations. Both variants must be classified using these rule specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use proposed SVI point recommendations. Both variants must be classified using these rule specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use proposed SVI point recommendations. Both variants must be classified using these rule specifications.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116281407",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281407",
"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
"rev": "_kXXnXUO---"
},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "079_BS1_nuclear_GP1BA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "079",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "gnomAD MAF greater than or equal to 0.0005 but less than 0.001.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116281436",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281436",
"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
"rev": "_kXXnXYu---"
},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "079_PM1_nuclear_GP1BA",
"additionalComments": "Rule does not apply due to gene being polymorphic.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "079",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Disulfide bonds in GPIb are well-established as critical to function, both for interaction with GPIX (PMID: 12036872) and receptor binding to von Willebrand factor (PMID: 18647229). PM1 can be applied when the following cysteine residues (at which there are no known benign variants) are altered: 20, 33, 225, 227, 264, 280, 526, 527.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116281421",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281421",
"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
"rev": "_kXXnXRO---"
},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "079_BS3_nuclear_GP1BA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "079",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Must demonstrate normal aggregometry in a transgenic mouse model",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In a heterologous cell line, must demonstrate BOTH normal expression and normal protein function as compared to wildtype.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116281417",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281417",
"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
"rev": "_kXXnXVS---"
},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "079_PP1_nuclear_GP1BA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"instructionsToUse": "For Bernard-Soulier syndrome (BSS), segregation of the variant in a pedigree is considered informative in the case of both additional relatives with BSS and in heterozygous relatives with measurable, quantitative abnormalities relevant to the disease. Caveat, there must be a biallelic BSS patient, meeting PP4, before segregation points are awarded. Additionally, heterozygotes used for PP1 cannot be applied to PS4.\n\nSegregation scoring: \n(1) Proband – 0pt (proband should be accounted for in PP4 or PS4) \n(2) BSS affected relative with the same biallelic variant(s) identified in the proband – 1pt \n(3) Relative heterozygous for the variant under assessment with a relevant measurable, quantitative abnormality. Caveat, only score one parent of a homozygous proband in a consanguineous pedigree. \n3a. significantly reduced surface expression of GP1b measured by flow cytometry – 0.5pt \nOR \n3b. giant platelets (MPD >7 microns) or macrothrombocytopenia (MPV >12 fL and platelet count \\<150x10^9/L) – 0.25pt",
"label": "PP1",
"ns": "079",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "See instructions below for scoring system. Total segregation score 3+ points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See instructions below for scoring system. Total segregation score 2-2.75 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "See instructions below for scoring system. Total segregation score 1-1.75 points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116281405",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281405",
"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
"rev": "_kXXnXTm---"
},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "079_PS4_nuclear_GP1BA",
"additionalComments": "Rule does not apply due to rarity of disorder and lack of appropriate studies.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"instructionsToUse": "According to Bragadottir, et al, individuals heterozygous for Bernard-Soulier syndrome variants are considered informative due to measurable, quantitative abnormalities relevant to the disease (PMID: 25370924). Caveats, (1) The variant must be sufficiently rare, meeting PM2\\_supporting (2) There must be an assumed unrelated biallelic BSS patient, meeting PP4, before heterozygotes are considered (3) A single proband of a family can be included in either PM3 (biallelic proband) or PS4 (monoallelic proband), not both (4) Any additional family members are not included in PS4, they may be considered for segregation in PP1.\n\nScoring: \nsignificantly reduced surface expression of GP1b measured by flow cytometry – 0.5pt \nOR \ngiant platelets (MPD >7 microns) or macrothrombocytopenia (MPV >12 fL and platelet count \\<150x10^9/L) – 0.25pt",
"label": "PS4",
"ns": "079",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
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"status": {
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"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"text": "",
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{
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"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See instructions below for scoring heterozygous individuals only. Moderate strength applicable for score of 2+ points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "See instructions below for scoring heterozygous individuals only. Supporting strength applicable for scores ranging from 1-1.75",
"type": "EvidenceLineStrength"
}
]
},
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"ldhId": "116281404",
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{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
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"applicability": "Not applicable",
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"evidenceCategory": "Functional Data",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "079",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
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"completed": true
},
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}
},
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{
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"status": "not approved",
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
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"status": "approved",
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"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
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"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
"rev": "_kXXnXXG---"
},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "079_BP6_nuclear_GP1BA",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "079",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116281429",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116281429",
"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
"rev": "_kXXnXW2---"
},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "079_PP5_nuclear_GP1BA",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "079",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
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"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
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"strength": "Supporting",
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"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
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"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
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}
]
},
"entType": "CriteriaCode",
"ldhId": "116281419",
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"modified": "2025-09-29T16:58:33.605Z",
"modifier": "leekristy",
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},
{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
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"applicability": "Applicable",
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP1BA"
],
"geneType": "nuclear",
"label": "PM4",
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}
},
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0012",
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"status": "not approved",
"strength": "Very Strong",
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
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"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Moderate",
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"text": "Use with no specification.",
"type": "EvidenceLineStrength"
},
{
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"id": "0059",
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"status": "not approved",
"strength": "Supporting",
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"type": "EvidenceLineStrength"
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]
},
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{
"created": "2025-02-12T13:36:04.680Z",
"creator": "justyne",
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"applicability": "Not applicable",
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"evidenceCategory": "De novo Data",
"gene": [
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],
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"text": "",
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{
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{
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"id": "0022",
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"text": "",
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]
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],
"Disease": [
{
"entContent": {
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"lbl": "Bernard-Soulier syndrome",
"meta": {
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},
{
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"val": "https://www.malacards.org/card/bernard_soulier_syndrome"
},
{
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"val": "http://identifiers.org/meddra/10057473"
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},
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"val": "http://identifiers.org/medgen/2212"
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{
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}
],
"definition": {
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"xrefs": [
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},
"subsets": [
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{
"pred": "hasExactSynonym",
"val": "Bernard - Soulier thrombopathy",
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{
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},
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"pred": "hasExactSynonym",
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{
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]
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},
{
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},
{
"pred": "hasRelatedSynonym",
"val": "Bernard-Soulier syndrome, type C"
},
{
"pred": "hasRelatedSynonym",
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},
{
"pred": "hasRelatedSynonym",
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},
{
"pred": "hasRelatedSynonym",
"val": "Von Willebrand Factor receptor deficiency"
},
{
"pred": "hasRelatedSynonym",
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},
{
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"val": "deficiency of platelet glycoprotein 1b",
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},
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},
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},
{
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},
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},
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},
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"name": "Bernard-Soulier syndrome"
},
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{
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{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BP7_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "This code can also be used for non-canonical intronic variants. The use of BP7 with BP4 is allowed, as appropriate, to classify variants meeting both criteria as likely benign.",
"label": "BP7",
"ns": "080",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0065",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applicable for variants that have no observable splicing impact with RNA sequencing and/or minigene assay and a SpliceAI score of less than or equal to 0.1.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Splicing prediction score of less than or equal to 0.1 is required. Conservation should be assess using PhyloP (cutoff less than 0.1) and PhastCons (cutoff less than 0.5).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363712",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363712",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY95-C---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PP3_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "Do not apply PP3 for variants that meet criteria for a PVS1\\_RNA rule code.",
"label": "PP3",
"ns": "080",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Code can be applied for variants where the REVEL score is greater than or equal to 0.6 or a SpliceAI score of greater than or equal to 0.2.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363711",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363711",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY95-q---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BA1_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "99.99% CI; subpopulation must have a minimum of five variant alleles present. Males and females are included for this code.",
"label": "BA1",
"ns": "080",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"defaultPoint": "Not Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "MAF cutoff of greater than or equal to 0.0000556 (or 0.00556%).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363709",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363709",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY94yK---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PVS1_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "Apply the ClinGen Coagulation Factor Deficiency VCEP/SVI decision tree to determine use and strength of the PVS1 rule. PVS1 (RNA): assays demonstrating a variant leads to aberrant splicing profile that can be used in the PVS1 decision tree as described in Walker et al. (PMID: 36865205) that was added to the v1 CFD-VCEP PVS1 flowchart. If using PVS1(RNA), do not apply PP3.",
"label": "PVS1",
"ns": "080",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 8,
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363707",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363707",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY942a---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PP1_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "Base strength of rule code on number of meioses across one or more families.",
"label": "PP1",
"ns": "080",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This code is applicable when there ≥4 meioses across ≥2 families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This code is applicable when there are at least 3 meioses across one or more families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This code is applicable when there 2 meioses in one family **OR** 1 meiosis between 2 affected siblings.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363705",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363705",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY95AW---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BP4_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "none",
"label": "BP4",
"ns": "080",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -4,
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This code can be applied for variants reaching a REVEL score of 0.3 or below AND a Splice AI score of less than or equal to 0.1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363704",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363704",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY94y6---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BP3_nuclear_F9",
"additionalComments": "Not applicable for F9 gene.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "080",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363702",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363702",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY9436---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PM5_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "The combined weight of codes PM1 and PM5 applied for a single variant can only equal strong.",
"label": "PM5",
"ns": "080",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This evidence code can be applied when there is 1 pathogenic variant or 2 likely pathogenic variants at the same residue based on _F9_ rule specification from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This evidence code can be applied when there is 1 likely pathogenic variant at the same residue based on _F9_ rule specifications Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect. A “highly suspicious” VUS is defined as a variant that is 1 supporting code away from reaching a likely pathogenic classification.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363695",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363695",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY946C---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BS2_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "none",
"label": "BS2",
"ns": "080",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This evidence code can be used when a _F9_ variant is observed in a male with a normal factor IX activity level (at least >40% IU or as defined by laboratory cut off).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -1,
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363692",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363692",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY947i---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PM3_nuclear_F9",
"additionalComments": "Not applicable for the F9 gene.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "080",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 8,
"id": "0038",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 4,
"id": "0058",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 2,
"id": "007",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0027",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363691",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363691",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY948G---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BP6_nuclear_F9",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "080",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363716",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363716",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY9412---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PS4_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "**Hemophilia B phenotype requirements:** \n\\-Abnormal factor IX activity levels in the severe, moderate or mild range (\\< 40% factor IX activity level) are sufficient to confer a diagnosis. \n\\- It is reasonable to expect that genomic data from individuals with hemophilia B could be used in population databases. Therefore, we decided to implement use of a ratio of hemizygotes found to harbor a variant of interest by the total number of alleles in XY individuals in that population database (# of hemizygotes with variant of interest/total # of alleles from XY individuals sequenced in the database) as a criteria for using the PS4 code. The PS4 code is only applicable to variants with a ratio lower than or equal to 1.26 x 10-5. This ratio was set by using the most frequently seen pathogenic variant, F9 c.316G>A, p.Gly106Ser, in gnomAD that was studied in the Coagulation Factor Deficiency VCEP pilot _F9_ study.",
"label": "PS4",
"ns": "080",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 8,
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥8 probands meet criteria described below",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "4-7 probands meet criteria described below",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "2-3 probands meet criteria described below",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1 proband meets criteria described below",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363706",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363706",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY95Ci---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BP2_nuclear_F9",
"additionalComments": "Not being used at this time. There are reports of males with hemophilia having two suspicious pathogenic variants.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "Evidence code is dependent on the strength of data. Take consideration of the quality of sequencing data when applying code.",
"label": "BP2",
"ns": "080",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0084",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363700",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363700",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY944W---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PS1_nuclear_F9",
"additionalComments": "Not applicable for CDH1.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "080",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This evidence code can be applied when there is 1 pathogenic variant or 2 likely pathogenic variants at the same residue based on _F9_ gene rule specifications from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect.\n\n**OR**\n\nWhen two or more variants are share the same predicted splicing effect and one comparison splicing variant reaches a pathogenic classification or 2 comparison variants reach a likely pathogenic classification using the Coagulation Factor Deficiency VCEP specifications modified from Walker, et al 2023 (PMID: 37352859).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This evidence code can be applied when there is 1 likely pathogenic variants at the same residue based on _F9_ gene rule specifications from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect.\n\n**OR**\n\nWhen the comparison variant shares the same predicted splicing effect and the comparison splicing variant reaches a likely pathogenic classification using the Coagulation Factor Deficiency VCEP specifications based on Walker, et al 2023 (PMID: 37352859).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363699",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363699",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY9442---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BP1_nuclear_F9",
"additionalComments": "Not applicable for F9 gene.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "080",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363696",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363696",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY945W---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PM4_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": ".",
"label": "PM4",
"ns": "080",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "009",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use code with no specification.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363693",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363693",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY95B----"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PM2_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "none",
"label": "PM2",
"ns": "080",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Variant must be absent in males in population databases, such as gnomAD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363715",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363715",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY947C---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PP4_nuclear_F9",
"additionalComments": "Use PS4 to count probands with hemophilia B diagnosis.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "**Hemophilia B phenotype requirements:** \n\\-Abnormal factor IX activity levels in the severe, moderate or mild range (\\< 40% factor IX activity level) are sufficient to confer a diagnosis. \n\\-A proband must have had full gene sequencing and deletion/duplication analysis to apply this code.\n\n\\-A proband used for this code cannot be applied towards the PS4 count.",
"label": "PP4",
"ns": "080",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Proband must meet hemophilia B phenotype criteria AND have full gene sequencing and deletion/duplication analysis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "0063",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363713",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363713",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY949W---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BP5_nuclear_F9",
"additionalComments": "This rule code is not recommended for use at this time. There is no known alternate cause of isolated factor IX deficiency.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "This applies if a P/LP variant is identified in an alternate gene known to cause HDGC (currently only CTNNA1).",
"label": "BP5",
"ns": "080",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363708",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363708",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY95_u---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PS3_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "See functional study spreadsheet.",
"label": "PS3",
"ns": "080",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 8,
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Abnormal factor IX activity level (\\<40 IU/dL or 40%) in a cell line and/or mouse model.\n\n\\--OR--\n\nAbnormal factor IX activity level (\\<40 IU/dL or 40%) studied in an animal model setting other than mouse (i.e. – bovine factor IX activity levels compared to factor X levels).\n\n\\--OR--\n\nAbsent or significantly reduced factor IX antigen level compared to wildtype using conformation-specific reporter assay in cell lines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363703",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363703",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY9426---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BS4_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "none",
"label": "BS4",
"ns": "080",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This evidence code can be used when a _F9_ variant is observed in a male with a family history of hemophilia B and has a normal factor IX activity level.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -1,
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363697",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363697",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY940m---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BS3_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "none",
"label": "BS3",
"ns": "080",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This code can be used for _F9_ gene variants studied in a cell line or mouse model setting that confer a normal factor IX activity AND normal factor IX antigen levels **OR** normal Western Blot.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -1,
"id": "0085",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363694",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363694",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY946a---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PP2_nuclear_F9",
"additionalComments": "Not applicable for F9.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "080",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363710",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363710",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY95B6---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PM6_nuclear_F9",
"additionalComments": "This rule code is combined with PS2. Please combined assumed de novo cases with confirmed de novo cases and apply PS2 at the appropriate weight.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "Use ClinGen’s de novo point system for a highly specific phenotype.",
"label": "PM6",
"ns": "080",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 8,
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 4,
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 2,
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363698",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363698",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY940----"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BS1_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "99.99% CI; subpopulation must have a minimum of five variant alleles present. Males and females are included for this code.",
"label": "BS1",
"ns": "080",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "MAF cutoff of greater than or equal to 0.00000556 (or 0.000556%).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -1,
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363690",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363690",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY948u---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PS2_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "Use ClinGen’s de novo modified point system for a highly specific phenotype (see guidance below). Combine all assumed and confirmed de novo cases for this code and use at the appropriate strength based on amount of points for all probands. Probands must meet the PS4 phenotype criteria to apply this code.",
"label": "PS2",
"ns": "080",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 8,
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use the SVI recommendations for de novo cases; 4 points. Use de novo guidance below to determine point value.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use the SVI recommendations for de novo cases; 2 points. Use de novo guidance below to determine point value.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use the SVI recommendations for de novo cases; 1 point. Use de novo guidance below to determine point value.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use the SVI recommendations for de novo cases; 0.5 point. Use de novo guidance below to determine point value.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363701",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1620363701",
"modified": "2026-04-16T14:44:13.209Z",
"modifier": "leekristy",
"rev": "_lXY95D----"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0010604",
"lbl": "hemophilia B",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/9097"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0010604"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/hemophilia_b"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/8732/hemophilia-b"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10016077"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1901375668"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/945"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D002836"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/41788008"
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{
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}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987691",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987691",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Atq--T"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_BP4_nuclear_VWF",
"additionalComments": "Not using at this time but will note CADD and SpliceAI scores and consider use during pilot testing. ",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "081",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use for missense variants that have a REVEL score of less than or equal to 0.290 AND SpliceAI cutoff of \\<0.1. Use SpliceAI cutoff of \\<0.1 for other variant types.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987685",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987685",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Ate-_-"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_PS3_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "081",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Either \n\n(1) In a transgenic animal model, must demonstrate minimal to no function.\n\nOR\n\n(2) The following types of assays using recombinant vWF are approved for each subtype:\n\nSubtype 2A = A multimerization assay in which the variant is expressed in a recombinant system (either independently or coexpressed with WT) resulting in abnormal multimers, with a reported loss of HMWM, AND, to confirm this is consistent with the variant's mechanism of disease, there must be a patient harboring the variant with a clinical assay also showing loss of HMWMs. This evidence must be published in a peer reviewed journal and a picture of the gel must be visible for evaluation.\n\nSubtype 2B = A GP1b or platelet binding assay indicating gain of function by increased binding at low doses of ristocetin\n\nSubtype 2M = Either (1) A GP1b or platelet binding assay OR (2) Collagen binding assay, indicating loss of function by decreased binding \n\nSee attached spreadsheet for examples of approved assay instances to use for this rule code. There are no universal thresholds for these assays; however, the relevant results should be described as clinically significant if assays were performed in a clinical laboratory or statistically significant if pertaining to research findings.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Subtype 2A = Either (1) a multimerization assay in which the variant is expressed in a recombinant system (either independently or coexpressed with WT) resulting in abnormal multimers, with a reported loss of HMWM. This evidence must be published in a peer reviewed journal and a picture of the gel must be visible for evaluation. (2) a ADAMTS susceptibility assay indicating increased susceptibility relative to WT.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987684",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987684",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Ati--6"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_PM2_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "081",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use code for variants with a popmax MAF of \\<0.0001 in gnomAD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987696",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987696",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Ate-_J"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_BA1_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "081",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Appropriate to use for variants with a Popmax MAF of >0.1 in gnomAD.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987690",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987690",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Ate-_E"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_PVS1_nuclear_VWF",
"additionalComments": "VWD type 2 is defined by qualitative defects in the VWF protein and not caused by null variants.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "081",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987688",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987688",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Ate-_C"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_PS4_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"instructionsToUse": "Do not apply this code for variants that meet BS1 or BA1 criteria. Do not count proband used for PP4 in this code's proband count.",
"label": "PS4",
"ns": "081",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Appropriate to use code when there are 8 or more probands that meet the laboratory phenotype of the PP4 definition for a specific VWD type 2 phenotype (i.e. – all probands must qualify for a clinical diagnosis of the same VWD type 2 phenotype based on laboratory criteria stated under PP4).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Appropriate to use code when there are 4-7 probands that meet the laboratory phenotype of the PP4 definition for a specific VWD type 2 phenotype (i.e. – all probands must qualify for a clinical diagnosis of the same VWD type 2 phenotype based on laboratory criteria stated under PP4).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Appropriate to use code when there are 2-3 probands that meet the laboratory phenotype of the PP4 definition for a specific VWD type 2 phenotype (i.e. – all probands must qualify for a clinical diagnosis of the same VWD type 2 phenotype based on laboratory criteria stated under PP4).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Appropriate to use code when there is 1 proband that meets the laboratory phenotype of the PP4 definition for a specific VWD type 2 phenotype.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987687",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987687",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Atm--L"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_PS2_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "081",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use proposed SVI point recommendations for **“Phenotype consistent with gene but not highly specific”** if the proband meets **PP4 criteria**. Use **“Phenotype highly specific for gene”** phenotype consistency if the proband meets **PP4\\_Moderate criteria**. See Table 1 attached. Required 4 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use proposed SVI point recommendations for **“Phenotype consistent with gene but not highly specific”** if the proband meets **PP4 criteria**. Use **“Phenotype highly specific for gene”** phenotype consistency if the proband meets **PP4\\_Moderate criteria**. See Table 1 attached. Required 2 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use proposed SVI point recommendations for **“Phenotype consistent with gene but not highly specific”** if the proband meets **PP4 criteria**. Use **“Phenotype highly specific for gene”** phenotype consistency if the proband meets **PP4\\_Moderate criteria**. See Table 1 attached. Required 1 point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use proposed SVI point recommendations for **“Phenotype consistent with gene but not highly specific”** if the proband meets **PP4 criteria**. If the proband meets PP4\\_Moderate criteria, use a moderate or higher evidence weight (see above). See Table 1 attached. Required 0.5 point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987682",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987682",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Atq--R"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_BP1_nuclear_VWF",
"additionalComments": "The VWF gene is not constrained for missense variation (gnomAD). ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "081",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987677",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987677",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Atm--J"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_BS3_nuclear_VWF",
"additionalComments": "There are no available assays that can clearly and dependably show no damaging protein effects. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "081",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987675",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987675",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Ate--8"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_BP5_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "081",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A second variant in VWF may be considered an alternate molecular basis for disease when that variant is LP/P (as evaluated by the VWD VCEP) and fully explains the phenotype of the patient's reported VWD subtype.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987689",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987689",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Atm--M"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_PP1_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "081",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0023",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Appropriate to use when there are multiple families each reported to have two or more meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Appropriate to use when there are 2 or more meioses within a single family.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987686",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987686",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Ate-_A"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_BP3_nuclear_VWF",
"additionalComments": "There are no known repetitive regions in the VWF gene without a known function. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "081",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987683",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987683",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Atq--S"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_PM4_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "081",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use with no specification for type 2A and 2M. This rule code is not applicable to variants associated with type 2B disease, since type 2B is only associated with gain of function variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987674",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987674",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Ati--z"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_BS2_nuclear_VWF",
"additionalComments": "Not applicable due to the incomplete penetrance seen in VWD. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "081",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0069",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0076",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987673",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987673",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Ate--6"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_BS4_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "081",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Appropriate to use when two or more relatives have the phenotype consistent with VWD type 2 without harboring the variant identified in other affected family members. Additionally, there is not another established cause of type 2 VWD (e.g. - there are not multiple type 2 VWD diagnoses) segregating in the family.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Appropriate to use when only one relative has the phenotype consistent with VWD type 2 without harboring the variant identified in other affected family members. Additionally, there is not another established cause of type 2 VWD (e.g. - there are not multiple type 2 VWD diagnoses) segregating in the family.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987678",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987678",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Ati--1"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_PM3_nuclear_VWF",
"additionalComments": "These are dominant conditions, so this rule code does not apply.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "081",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987672",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987672",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Ata--s"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_BS1_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "081",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Appropriate to use for variants with a Popmax MAF of >0.01 in gnomAD.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987671",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987671",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Ati--x"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_BP6_nuclear_VWF",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"VWF"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "081",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987697",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987697",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Ate-_L"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_PM1_nuclear_VWF",
"additionalComments": "Rule does not apply due to benign variation being present throughout the gene.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "081",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
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"completed": true
},
"Pilot Rules In Prep": {
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},
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"applicability": "Not applicable",
"id": "0230",
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"status": "not approved",
"strength": "Stand Alone",
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987695",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987695",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Ate-_H"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
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"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
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"VWF"
],
"geneType": "nuclear",
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"ns": "081",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
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"completed": true
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"Pilot Rules In Prep": {
"completed": true
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"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The patient must have a clinical phenotype of excessive mucocutaneous bleeding and required laboratory values to use the PP4 rule code at the moderate strength. See Table 2A for required and consistent laboratory values.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The patient must have a clinical phenotype of excessive mucocutaneous bleeding and required laboratory values to use the PP4 rule code at the supporting strength. See Table 2B for required and consistent laboratory values.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987694",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Atm--N"
},
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"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
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"applicability": "Applicable",
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"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
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"ns": "081",
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"Pilot Rules In Prep": {
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"instructionsToUse": "",
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"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Appropriate to use for missense variants that have a REVEL score of greater or equal to 0.644 OR a SpliceAI score suggestive of a splicing defect (greater or equal to 0.5).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987692",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987692",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Ate-_F"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_BP2_nuclear_VWF",
"additionalComments": "Do not use due to potential of variant being associated with VWD 2N (recessive disease).",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "081",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0084",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987681",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987681",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Atm--K"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_PS1_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PS1",
"ns": "081",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use with no specification except comparison variant must be classified as pathogenic using rules from the VWD VCEP.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
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],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use with no specification except comparison variant must be classified as likely pathogenic using rules from the VWD VCEP.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987680",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
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},
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"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_PM6_nuclear_VWF",
"additionalComments": "Use the PS2 code in lieu of using this code for de novo variants.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
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],
"geneType": "nuclear",
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"ns": "081",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
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"completed": true
},
"Pilot Rules In Prep": {
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"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987679",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987679",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Ati--3"
},
{
"created": "2024-07-09T13:42:12.201Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "081_PM5_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "081",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
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"status": {
"Classification Rules In Prep": {
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},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use code when previously reported variant reaches a pathogenic classification using the VWD Type 2 rule specifications. Previously reported variant can be associated with a different type of VWD.\n\nCode may also be applied when two previously reported variants reach a likely pathogenic classification using the VWD Type 2 rule specifications. Previously reported variants can be associated with a different type of VWD.",
"type": "EvidenceLineStrength"
},
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"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use code when previously reported variant reaches a likely pathogenic classification using the VWD Type 2 rule specifications. Previously reported variant can be associated with a different type of VWD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807987676",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807987676",
"modified": "2024-07-09T13:42:12.201Z",
"modifier": "leekristy",
"rev": "_inf5Atq--Q"
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"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use as originally specified, but the comparison variant must reach a pathogenic classification using the these rule specifications in order to apply code.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use as originally specified, but the comparison variant must reach a likely pathogenic classification using the these rule specifications in order to apply code.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280469",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280469",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXn0_C---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_PM2_nuclear_GP1BB",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "082",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "gnomAD MAF of less than or equal to 0.00006517.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280463",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280463",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXnz9a---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_PS2_nuclear_GP1BB",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"instructionsToUse": "Only applicable when proband has a known pathogenic or likely pathogenic variant according to the BSS rule specifications along with the de novo variant. Only use “highly specific phenotype” scoring if all three BSS genes were sequenced. Otherwise use the “consistent but not highly specific” scoring. See further instructions below.",
"label": "PS2",
"ns": "082",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use proposed SVI point recommendations. See further instruction below. Total of 4 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use proposed SVI point recommendations. See further instruction below. Total of 2 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use proposed SVI point recommendations. See further instruction below. Total of 1 point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280461",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280461",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXn0Ay---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_PS4_nuclear_GP1BB",
"additionalComments": "Rule does not apply due to rarity of disorder and lack of appropriate studies.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"instructionsToUse": "According to Bragadottir, et al, individuals heterozygous for Bernard-Soulier syndrome variants are considered informative due to measurable, quantitative abnormalities relevant to the disease (PMID: 25370924). Caveats, (1) The variant must be sufficiently rare, meeting PM2\\_supporting (2) There must be an assumed unrelated biallelic BSS patient, meeting PP4, before heterozygotes are considered (3) A single proband of a family can be included in either PM3 (biallelic proband) or PS4 (monoallelic proband), not both (4) Any additional family members are not included in PS4, they may be considered for segregation in PP1.\n\nScoring: \nsignificantly reduced surface expression of GP1b measured by flow cytometry – 0.5pt \nOR \ngiant platelets (MPD >7 microns) or macrothrombocytopenia (MPV >12 fL and platelet count \\<150x10^9/L) – 0.25pt",
"label": "PS4",
"ns": "082",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0053",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See instructions below for scoring heterozygous individuals only. Moderate strength applicable for score of 2+ points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "See instructions below for scoring heterozygous individuals only. Supporting strength applicable for scores ranging from 1-1.75",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280460",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280460",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXn0Ai---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_BA1_nuclear_GP1BB",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "082",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "gnomAD MAF greater than or equal to 0.001 (or 0.1%) in gnomAD.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280458",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280458",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXn0A----"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_PP5_nuclear_GP1BB",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "082",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280457",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280457",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXn0_q---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_PP3_nuclear_GP1BB",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "082",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "REVEL score of ≥0.773 based on recommendations of Pejaver et al., 2022 (PMID: 36413997).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "REVEL score of ≥0.644 (to \\<0.773), based on recommendations of Pejaver et al., 2022 (PMID: 36413997).\n\nOR suggested splicing effect using SpliceAI greater than or equal to 0.5.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280487",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280487",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXn0BW---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_PM5_nuclear_GP1BB",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "082",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use as originally specified, but the comparison variant must reach a pathogenic classification using these rule specifications in order to apply code.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use as originally specified, but the comparison variant must reach a likely pathogenic classification using these rule specifications in order to apply code.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280481",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280481",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXnz7K---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_BP4_nuclear_GP1BB",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"instructionsToUse": "Determine REVEL and Splice AI cutoff before applying this code. Do not use if PP3 is applicable.",
"label": "BP4",
"ns": "082",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "For a missense variant apply when REVEL score is less than or equal to 0.290, based on recommendations of Pejaver et al., 2022 (PMID: 36413997) AND SpliceAI score is zero.\n\nOR for a synonymous or intronic variant apply when SpliceAI score is zero.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280477",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280477",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXnz5y---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_BP2_nuclear_GP1BB",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "082",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use as written for recessive variants (i.e. - variant must be observed in cis with a pathogenic variant)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280473",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280473",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXnz82---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_PVS1_nuclear_GP1BB",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"instructionsToUse": "Use _GP1BB_ modified decision tree below.",
"label": "PVS1",
"ns": "082",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use _GP1BB_ modified decision tree as per SVI WG.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use _GP1BB_ modified decision tree as per SVI WG.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use _GP1BB_ modified decision tree as per SVI WG.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use _GP1BB_ modified decision tree as per SVI WG.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280459",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280459",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXn0AO---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_BS2_nuclear_GP1BB",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "082",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Use this rule with 1 or more homozygotes who are unaffected (proven with aggregometry OR flow cytometry AND normal platelet count AND normal platelet size).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280482",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280482",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXnz7a---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_BP3_nuclear_GP1BB",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "082",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use with no specification",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280478",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280478",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXnz6K---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_PS3_nuclear_GP1BB",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "082",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "In a transgenic animal model, must demonstrate minimal to no function.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Functional assays measuring quantity of GP1ba and/or GPIX expression on cell surface measured by flow cytometry (see spreadsheet for more detail).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280472",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280472",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXnz8q---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_BP7_nuclear_GP1BB",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"instructionsToUse": "Can be used for intronic variants. Can be used in combination with BP4.",
"label": "BP7",
"ns": "082",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use SpliceAI to rule out possible splicing defect (score = 0.2 or less) and reference PhyloP (score = 1.5 or less) to assess conservation.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280465",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280465",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXnz92---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_PM1_nuclear_GP1BB",
"additionalComments": "Rule does not apply due to gene being polymorphic.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "082",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Disulfide bonds in GPIb are well-established as critical to function, both for interaction with GPIX (PMID: 12036872) and receptor binding to von Willebrand factor (PMID: 18647229). PM1 can be applied when the following cysteine residues (at which there are no known benign variants) are altered: 93, 95, 118, 141, and 147.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280464",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280464",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXnz9q---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_BS1_nuclear_GP1BB",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "082",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "gnomAD MAF greater than or equal to 0.0005 but less than 0.001.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280484",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280484",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXnz8----"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_PM3_nuclear_GP1BB",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"instructionsToUse": "_In trans_ variants classified as a variants of uncertain significance, as per the _GP1BB_ rule specifications, must meet PM2\\_supporting to be scored. Conversely, _in trans_ variants that meet a pathogenic or likely pathogenic classification using the _GP1BB_ rule specifications do not have to meet PM2\\_supporting criteria; however, they cannot meet BS1 or BA1 criteria. See PM3 instructions below for further detail.",
"label": "PM3",
"ns": "082",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use proposed SVI point recommendations. Both variants must be classified using these rule specifications, with the exception that a 22q11.2 deletion in trans ([https://www.ncbi.nlm.nih.gov/books/NBK1523/](https://www.ncbi.nlm.nih.gov/books/NBK1523/)) may be automatically scored 1pt with confirmation that deletion includes the _GP1BB_ gene.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use proposed SVI point recommendations. Both variants must be classified using these rule specifications, with the exception that a 22q11.2 deletion in trans ([https://www.ncbi.nlm.nih.gov/books/NBK1523/](https://www.ncbi.nlm.nih.gov/books/NBK1523/)) may be automatically scored 1pt with confirmation that deletion includes the _GP1BB_ gene.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use proposed SVI point recommendations. Both variants must be classified using these rule specifications, with the exception that a 22q11.2 deletion in trans ([https://www.ncbi.nlm.nih.gov/books/NBK1523/](https://www.ncbi.nlm.nih.gov/books/NBK1523/)) may be automatically scored 1pt with confirmation that deletion includes the _GP1BB_ gene.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use proposed SVI point recommendations. Both variants must be classified using these rule specifications.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280483",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280483",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXnz7u---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_BP1_nuclear_GP1BB",
"additionalComments": "Rule does not apply as truncating variants do not predominate and missense variants are a known cause of disease.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "082",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280480",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280480",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXnz66---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_PM4_nuclear_GP1BB",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "082",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use with no specification.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280474",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280474",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXnz9G---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_PP1_nuclear_GP1BB",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"instructionsToUse": "For Bernard-Soulier syndrome (BSS), segregation of the variant in a pedigree is considered informative in the case of both additional relatives with BSS and in heterozygous relatives with measurable, quantitative abnormalities relevant to the disease. Caveat, there must be a biallelic BSS patient, meeting PP4, before segregation points are awarded. Additionally, heterozygotes used for PP1 cannot be applied to PS4.\n\nSegregation scoring: \n(1) Proband – 0pt (proband should be accounted for in PP4 or PS4) \n(2) BSS affected relative with the same biallelic variant(s) identified in the proband – 1pt \n(3) Relative heterozygous for the variant under assessment with a relevant measurable, quantitative abnormality. Caveat, only score one parent of a homozygous proband in a consanguineous pedigree. \n3a. significantly reduced surface expression of GP1b measured by flow cytometry – 0.5pt \nOR \n3b. giant platelets (MPD >7 microns) or macrothrombocytopenia (MPV >12 fL and platelet count \\<150x10^9/L) – 0.25pt",
"label": "PP1",
"ns": "082",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "See instructions below for scoring system. Total segregation score 3+ points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See instructions below for scoring system. Total segregation score 2-2.75 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "See instructions below for scoring system. Total segregation score 1-1.75 points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280468",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280468",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXn0-q---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_BP5_nuclear_GP1BB",
"additionalComments": "Do not use this rule as an individual can be a carrier of an unrelated pathogenic variant for a recessive disorder.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "082",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280467",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280467",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXn0-a---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_PP2_nuclear_GP1BB",
"additionalComments": "This rule does not apply because BSS is a rare disease and this gene is not constrained for missense variation (gnomAD). ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "082",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280466",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280466",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXn0-K---"
},
{
"created": "2025-02-12T13:35:42.320Z",
"creator": "justyne",
"entContent": {
"_uniqueProp": "082_BS3_nuclear_GP1BB",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"GP1BB"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "082",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Must demonstrate normal aggregometry in a transgenic mouse model",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In a heterologous cell line, must demonstrate BOTH normal expression and normal protein function as compared to wildtype.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "116280462",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/116280462",
"modified": "2025-09-29T16:59:02.938Z",
"modifier": "leekristy",
"rev": "_kXXn0BG---"
}
],
"Disease": [
{
"entContent": {
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"lbl": "Bernard-Soulier syndrome",
"meta": {
"basicPropertyValues": [
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{
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},
{
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},
{
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"xrefs": [
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},
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},
{
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},
{
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},
{
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},
{
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},
{
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{
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},
{
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},
{
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]
},
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{
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},
{
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},
{
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]
},
{
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},
{
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},
{
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},
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},
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},
{
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},
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"entIri": "http://purl.obolibrary.org/obo/MONDO_0009276",
"entType": "Disease",
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"modified": "2025-10-07T16:12:55.289Z",
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],
"Gene": [
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"strengthSepioID": "SEPIO:0000220",
"text": "Use _GP9_ modified decision tree as per SVI WG.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use _GP9_ modified decision tree as per SVI WG.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use _GP9_ modified decision tree as per SVI WG.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use _GP9_ modified decision tree as per SVI WG.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438212",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438212",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRdS---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_BP6_nuclear_GP9",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"GP9"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "083",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438202",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438202",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRX----"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_PM5_nuclear_GP9",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "083",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use as originally specified, but the comparison variant must reach a pathogenic classification using these rule specifications in order to apply code.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use as originally specified, but the comparison variant must reach a likely pathogenic classification using these rule specifications in order to apply code.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438200",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438200",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRca---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_BS1_nuclear_GP9",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "083",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "gnomAD MAF of greater than or equal to 0.0007 but less than 0.001.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438196",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438196",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRbG---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_PS1_nuclear_GP9",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "083",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use as originally specified, but the comparison variant must reach a pathogenic classification using the these rule specifications in order to apply code.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use as originally specified, but the comparison variant must reach a likely pathogenic classification using the these rule specifications in order to apply code.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438193",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438193",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRaS---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_PS4_nuclear_GP9",
"additionalComments": "Rule does not apply due to rarity of disorder and lack of appropriate studies.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"instructionsToUse": "According to Bragadottir, et al, individuals heterozygous for Bernard-Soulier syndrome variants are considered informative due to measurable, quantitative abnormalities relevant to the disease (PMID: 25370924). Caveats, (1) The variant must be sufficiently rare, meeting PM2\\_supporting (2) There must be an assumed unrelated biallelic BSS patient, meeting PP4, before heterozygotes are considered (3) A single proband of a family can be included in either PM3 (biallelic proband) or PS4 (monoallelic proband), not both (4) Any additional family members are not included in PS4, they may be considered for segregation in PP1.\n\nScoring: \nsignificantly reduced surface expression of GP1b measured by flow cytometry – 0.5pt \nOR \ngiant platelets (MPD >7 microns) or macrothrombocytopenia (MPV >12 fL and platelet count \\<150x10^9/L) – 0.25pt",
"label": "PS4",
"ns": "083",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0053",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See instructions below for scoring heterozygous individuals only. Moderate strength applicable for score of 2+ points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "See instructions below for scoring heterozygous individuals only. Supporting strength applicable for scores ranging from 1-1.75",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438192",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438192",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRaC---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_BP4_nuclear_GP9",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"instructionsToUse": "Determine REVEL and Splice AI cutoff before applying this code. Do not use if PP3 is applicable.",
"label": "BP4",
"ns": "083",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "For a missense variant apply when REVEL score is less than or = to 0.290, based on recommendations of Pejaver et al., 2022 (PMID: 36413997) AND SpliceAI score is zero.\n\nOR for a synonymous or intronic variant apply when SpliceAI score is zero.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438216",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438216",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRd2---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_PP2_nuclear_GP9",
"additionalComments": "This rule does not apply because BSS is a rare disease and this gene is not constrained for missense variation (gnomAD). ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "083",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438205",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438205",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRY----"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_BP5_nuclear_GP9",
"additionalComments": "Do not use this rule as an individual can be a carrier of an unrelated pathogenic variant for a recessive disorder.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "083",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438191",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438191",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRZm---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_PM1_nuclear_GP9",
"additionalComments": "Rule does not apply due to gene being polymorphic.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "083",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438219",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438219",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRWG---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_PP1_nuclear_GP9",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"instructionsToUse": "For Bernard-Soulier syndrome (BSS), segregation of the variant in a pedigree is considered informative in the case of both additional relatives with BSS and in heterozygous relatives with measurable, quantitative abnormalities relevant to the disease. Caveat, there must be a biallelic BSS patient, meeting PP4, before segregation points are awarded. Additionally, heterozygous relatives counted for PP1 must not be counted for PS4. \n\nSegregation scoring: \n(1) Proband – 0 points (proband should be accounted for in PP4 or PS4) \n(2) BSS affected relative with the same biallelic variant(s) identified in the proband – 1 pt \n(3) Relative heterozygous for the variant under assessment with a relevant measurable, quantitative abnormality. Caveat, only score one parent of a homozygous proband in a consanguineous pedigree. \n3a. significantly reduced surface expression of GP1b measured by flow cytometry – 0.5 pt \nOR \n3b. giant platelets (MPD >7 microns) or macrothrombocytopenia (MPV >12 fL and platelet count \\<150x10^9/L) – 0.25pt",
"label": "PP1",
"ns": "083",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "See instructions below for scoring system. Total segregation score 3+ points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See instructions below for scoring system. Total segregation score 2-2.75 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "See instructions below for scoring system. Total segregation score 1-1.75 points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438213",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438213",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRdm---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_BS2_nuclear_GP9",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "083",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Use this rule with 1 or more homozygotes who are unaffected (proven with aggregometry OR flow cytometry AND normal platelet count AND normal platelet size).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438210",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438210",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRZO---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_BA1_nuclear_GP9",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "083",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "gnomAD MAF of greater than or equal to 0.001 (or 0.1%).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438207",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438207",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRYO---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_PM2_nuclear_GP9",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "083",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "gnomAD MAF of less than or equal to 0.0000329.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438203",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438203",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRXS---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_BS3_nuclear_GP9",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "083",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Must demonstrate normal aggregometry in a transgenic mouse model",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In a heterologous cell line, must demonstrate BOTH normal expression and normal protein function as compared to wildtype.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438201",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438201",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRcq---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_BP7_nuclear_GP9",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"instructionsToUse": "Can be used for intronic variants. Can be used along with BP4.",
"label": "BP7",
"ns": "083",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use SpliceAI to rule out possible splicing defect (score = 0.2 or less) and reference PhyloP (score = 1.5 or less) to assess conservation.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438198",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438198",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRbu---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_PM3_nuclear_GP9",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"instructionsToUse": "_In trans_ variants classified as a variants of uncertain significance, as per the _GP9_ rule specifications, must meet PM2\\_supporting to be scored. Conversely, _in trans_ variants that meet a pathogenic or likely pathogenic classification using the _GP9_ rule specifications do not have to meet PM2\\_supporting criteria; however, they cannot meet BS1 or BA1 criteria. See PM3 instructions below for further detail.",
"label": "PM3",
"ns": "083",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use proposed SVI point recommendations (see below). Both variants must be classified using these rule specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use proposed SVI point recommendations (see below). Both variants must be classified using these rule specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use proposed SVI point recommendations (see below). Both variants must be classified using these rule specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use proposed SVI point recommendations (see below). Both variants must be classified using these rule specifications.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438218",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438218",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRee---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_BP2_nuclear_GP9",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "083",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use as written for recessive variants (i.e. - variant must be observed in cis with a pathogenic variant)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438217",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438217",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoReK---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_PM6_nuclear_GP9",
"additionalComments": "Use PS2 for de novo cases in lieu of this rule code.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "083",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438209",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438209",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRY2---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_PP3_nuclear_GP9",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "083",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "REVEL score of ≥0.773 based on recommendations of Pejaver et al., 2022 (PMID: 36413997).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "REVEL score of ≥0.644 (to \\<0.773), based on recommendations of Pejaver et al., 2022 (PMID: 36413997),\n\nOR suggested splicing affect using SpliceAI greater than or equal to 0.5.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438204",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438204",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRXu---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_PP4_nuclear_GP9",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "083",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Must meet both criteria: \n\n1. Proband with platelet aggregation study absent for ristocetin and present for all other agonists OR flow cytometry or Western blot less than 10% expression of GPIba \n2. Proband must have full sequencing of all three BSS genes (_GP1BA, GP1BB_ and _GP9_) and deletion/duplication analysis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Proband with platelet aggregation study absent for ristocetin and present for all other agonists, OR \n* Flow cytometry or Western blot less than 10% expression of GPIba.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438197",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438197",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRbW---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_BS4_nuclear_GP9",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "083",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant not tracking in an affected family member.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438194",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438194",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRai---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_BP3_nuclear_GP9",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "083",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use with no specification",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438220",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438220",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRWe---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_PP5_nuclear_GP9",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"GP9"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "083",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438211",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438211",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRd----"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_PS2_nuclear_GP9",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"instructionsToUse": "Only applicable when proband has a known pathogenic or likely pathogenic variant according to the BSS rule specifications along with the de novo variant. Only use “highly specific phenotype” scoring if all three BSS genes were sequenced. Otherwise use the “consistent but not highly specific” scoring. More detailed instructions are below if needed.",
"label": "PS2",
"ns": "083",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use proposed SVI point recommendations. See further instruction below. Total of 4 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use proposed SVI point recommendations. See further instruction below. Total of 2 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use proposed SVI point recommendations. See further instruction below. Total of 1 point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use proposed SVI point recommendations. See further instruction below. Total of 0.5 point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438208",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438208",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRYm---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_PS3_nuclear_GP9",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "083",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "In a transgenic animal model, must demonstrate minimal to no function.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Functional assays measuring quantity of GP9 expression on cell surface measured by flow cytometry analysis of GPIb and GPIX when there is absent or near absent expression, >75% reduction (see spreadsheet for more detail).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438199",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438199",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRcC---"
},
{
"created": "2025-02-11T19:17:36.997Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "083_BP1_nuclear_GP9",
"additionalComments": "Rule does not apply as truncating variants do not predominate and missense variants are a known cause of disease.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GP9"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "083",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "115438195",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/115438195",
"modified": "2025-09-29T16:59:33.093Z",
"modifier": "leekristy",
"rev": "_kXXoRay---"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0009276",
"lbl": "Bernard-Soulier syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0009276"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/bernard_soulier_syndrome"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10057473"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/507309898"
},
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"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-01-30T22:24:12.728Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2025-01-24T15:41:27.199Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2025-02-07T20:15:32.135Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2025-02-21T16:25:01.206Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2025-03-06T19:07:13.751Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"084"
],
"title": "ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.1.0",
"version": "1.1.0",
"versioned": true
},
"entId": "GN084",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "084_PS1_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "Use caution not to compare variants being curated to variants that are potential cryptic slice sites.",
"label": "PS1",
"ns": "084",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use with no specification except comparison variant must be classified as pathogenic using _SERPINC1_ rule specifications from the Thrombosis VCEP.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use with no specification except comparison variant must be classified as likely pathogenic using _SERPINC1_ rule specifications from the Thrombosis VCEP.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900904",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900904",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpNO---"
},
{
"entContent": {
"_uniqueProp": "084_BP1_nuclear_SERPINC1",
"additionalComments": "This rule code does not apply to the SERPINC1 gene, as missense and truncating variants account for disease.\n",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "084",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900901",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900901",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpIO---"
},
{
"entContent": {
"_uniqueProp": "084_PP4_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "Please see attached guidance regarding the use of PP4/PS4 rule codes to properly assess eligibility. Do not apply this code for variants that meet BS1 or BA1 criteria. Do not count the proband used for the PP4 code for the PS4 code's proband count.",
"label": "PP4",
"ns": "084",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0018",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Proband must have an antithrombin activity level of \\< 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range). confirmed on repeated independent samples. An abnormal crossed immunoelectrophoresis assay demonstrating decreased antithrombin function may be used in lieu of low activity levels, which is typically caused by type II variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900918",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900918",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpVO---"
},
{
"entContent": {
"_uniqueProp": "084_BA1_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BA1",
"ns": "084",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Appropriate to use for variants with a popmax MAF of greater than or equal to 0.002 in gnomAD.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900914",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900914",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpFu---"
},
{
"entContent": {
"_uniqueProp": "084_BP5_nuclear_SERPINC1",
"additionalComments": "This rule code is not recommended for use at this time. There are other genes that can be associated with decreased antithrombin activity levels, such as genes associated with the congenital disorders of glycosylation.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "084",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900913",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900913",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpGi---"
},
{
"entContent": {
"_uniqueProp": "084_BS4_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "084",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Appropriate to use when the variant is found not to segregate in a minimum of four relatives with abnormal antithrombin activity levels \\[\\< 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range)\\] within the same family, **OR** the variant does not segregate in 2 or more families. Non-segregation defined by having abnormal antithrombin activity levels without _SERPINC1_ variant of interest.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Appropriate to use when the variant is found not to segregate in a minimum of two relatives with abnormal antithrombin activity levels \\[\\< 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range)\\] within the same family.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900902",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900902",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpbS---"
},
{
"entContent": {
"_uniqueProp": "084_BP6_nuclear_SERPINC1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "084",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900921",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900921",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpUa---"
},
{
"entContent": {
"_uniqueProp": "084_PP3_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP3",
"ns": "084",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Appropriate to use for missense variants that have a REVEL score of greater or equal to 0.6. For potential splicing variants, SpliceAI must predict a damaging impact with a score greater or equal to 0.5.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900916",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900916",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpN6---"
},
{
"entContent": {
"_uniqueProp": "084_PP2_nuclear_SERPINC1",
"additionalComments": "Not applicable due to presence of benign variation throughout the SERPINC1 gene. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "084",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900915",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900915",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpFG---"
},
{
"entContent": {
"_uniqueProp": "084_PVS1_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "084",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use decision tree as per SVI WG with specified “regions critical to protein function”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use decision tree as per SVI WG with specified “regions critical to protein function”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use decision tree as per SVI WG with specified “regions critical to protein function”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use decision tree as per SVI WG with specified “regions critical to protein function”.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900912",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900912",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpO6---"
},
{
"entContent": {
"_uniqueProp": "084_PP1_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "084",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Appropriate to use there are 7 or more meioses across more than one family.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Appropriate to use there are 4-6 meioses across one or more families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Appropriate to use when there are 2-3 meioses across one or more families.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900910",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900910",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpWG---"
},
{
"entContent": {
"_uniqueProp": "084_BP4_nuclear_SERPINC1",
"additionalComments": "Not using at this time but will note CADD and SpliceAI scores and consider use during pilot testing. ",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "084",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use this code for missense variants with a REVEL score of \\< or equal to 0.30 and no evidence of a potential splicing effect using the Splice AI prediction tool (less than or equal to 0.1), or for non-canonical intronic variants with no evidence of a potential splicing effect using the Splice AI prediction tool.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900909",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900909",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpQq---"
},
{
"entContent": {
"_uniqueProp": "084_PS2_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "Any proband must meet the PP4 defined antithrombin deficiency laboratory phenotype (see PP4/PS4 description below).",
"label": "PS2",
"ns": "084",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 4 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 2 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 1 point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 0.5 point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900906",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900906",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpRe---"
},
{
"entContent": {
"_uniqueProp": "084_PM6_nuclear_SERPINC1",
"additionalComments": "Use the PS2 code in lieu of using this code for de novo variants.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "084",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900903",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900903",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpau---"
},
{
"entContent": {
"_uniqueProp": "084_BS1_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "Common founder SERPINC1 variants are excluded from eligibility of the BS1 code. The list of variants will likely grow over time, but currently consists of the SERPINC1 c.218C>T; p.Pro73Leu (PMID:23910795), SERPINC1 c.236G>A; p.Arg79His (AT Padua), SERPINC1 c.439A>G; p.Thr147Ala (PMID:32920809) and SERPINC1 c.1246G>T ; SERPINC1 p.Ala416Ser (AT Cambridge II); SERPINC1 p.Leu131Phe (PMID:26748602); SERPINC1 c.89T>A; p.Val30Glu (AT Dublin; PMID:27098529) variants.",
"label": "BS1",
"ns": "084",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Appropriate to use for variants with a Popmax MAF of >0.0002 in gnomAD.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900895",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900895",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpTa---"
},
{
"entContent": {
"_uniqueProp": "084_PP5_nuclear_SERPINC1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "084",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900922",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900922",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpLW---"
},
{
"entContent": {
"_uniqueProp": "084_PM2_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "084",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use code for variants with a popmax MAF of \\<0.00002 in gnomAD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900920",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900920",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpCq---"
},
{
"entContent": {
"_uniqueProp": "084_BP3_nuclear_SERPINC1",
"additionalComments": "There are no known repetitive regions in the SERPINC1 gene without a known function. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "084",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900907",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900907",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpMK---"
},
{
"entContent": {
"_uniqueProp": "084_PM5_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "Use caution not to compare variants being curated to variants that are potential cryptic slice sites.",
"label": "PM5",
"ns": "084",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use code when previously reported variant reaches a pathogenic classification using the _SERPINC1_ rule specifications from the Thrombosis VCEP.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use code when previously reported variant reaches a likely pathogenic classification using the _SERPINC1_ rule specifications from the Thrombosis VCEP.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900900",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900900",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpJW---"
},
{
"entContent": {
"_uniqueProp": "084_PM4_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "084",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "No specification",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900898",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900898",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpXq---"
},
{
"entContent": {
"_uniqueProp": "084_BS2_nuclear_SERPINC1",
"additionalComments": "Not applicable due to the incomplete penetrance seen in VWD. ",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "084",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This evidence code is available when the variant is identified in 2 or more heterozygotes or 1 or more homozygotes with normal antithrombin levels \\[> 0.8 IU/mL (or above the lower limit of a laboratory’s assays reference range)\\].",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This evidence code is available when the variant is identified in 1 heterozygote with normal antithrombin levels \\[> 0.8 IU/mL (or above the lower limit of a laboratory’s assays reference range)\\].",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900897",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900897",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpKW---"
},
{
"entContent": {
"_uniqueProp": "084_PM3_nuclear_SERPINC1",
"additionalComments": "Variants in this gene are being curated as a dominant condition, so this rule code does not apply.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "084",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900896",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900896",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpYm---"
},
{
"entContent": {
"_uniqueProp": "084_PM1_nuclear_SERPINC1",
"additionalComments": "Rule does not apply due to benign variation being present throughout the gene and no known hotspots.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "084",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This code is applicable for variants disrupting cystine residues involved in disulfide bridges (Cys40, Cys53, Cys127, Cys160, Cys279, Cys462)1, variants that would impact heparin binding site residues (Ile39, Arg56, Pro73, Arg79), variants involving reactive site residues (Ala414 and Ala416)2, and variants involving the N-glycosylation site (Asn224)3.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900919",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900919",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpZy---"
},
{
"entContent": {
"_uniqueProp": "084_BP7_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "084",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use Splice AI to rule out a predicted splicing effect (less than or equal to 0.1). Evolutionary conservation is defined as a PhyloP > 0.1 **OR** the reference nucleotide is present in 3 mammals or 1 primate.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900917",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900917",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpDm---"
},
{
"entContent": {
"_uniqueProp": "084_PS4_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "This code requires the use of proband points. Please see attached guidance on tallying proband points for this phenotype. Do not apply this code for variants that meet BS1 or BA1 criteria. Do not count proband used for PP4 in this code's proband count.",
"label": "PS4",
"ns": "084",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Appropriate to use code when there 8 or more proband points that meet the defined antithrombin deficiency laboratory phenotype.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Appropriate to use code when there 4-7 proband points that meet the defined antithrombin deficiency laboratory phenotype.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Appropriate to use code when there 2-3 proband points that meet the defined antithrombin deficiency laboratory phenotype.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Appropriate to use code when there is 1 proband point that meets the defined antithrombin deficiency laboratory phenotype.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900911",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900911",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpPq---"
},
{
"entContent": {
"_uniqueProp": "084_PS3_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "Model organism do not tend to recapitulate the phenotype of interest and are not used for curation.",
"label": "PS3",
"ns": "084",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "See attached spreadsheet for list of approved assays to use for this rule code. Below is a general description of assays that can be used:\n\n - _In vitro_ functional studies in COS-1, HEK293T, HEK-EBNA cells demonstrating abnormal activity levels:\n\n* Antithrombin activity levels measured by FXa inhibition activity assay\n* Antithrombin activity levels measured by thrombin inhibition activity assay\n\nOR\n\n\\- _In vitro_ functional studies in COS-1, HEK293T, HEK-EBNA cells demonstrating abnormal antigen levels:\n\n* Antithrombin antigen levels measured by ELISA\n * Immunofluorescence assay – intracellular retention and secretion defects\n\nOR\n\n\\- _In vivo_ studies demonstrating rescue of antithrombin levels would be considered, but no studies are known to be available at this time.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900908",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1611900908",
"modified": "2025-02-07T20:15:34.428Z",
"modifier": "leekristy",
"rev": "_jMGLpHe---"
},
{
"entContent": {
"_uniqueProp": "084_BP2_nuclear_SERPINC1",
"additionalComments": "Do not use as individuals can be homozygous for SERPINC1 variants.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "084",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
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"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Apply to normoglycemic individuals age 70 or older (i.e., genotype positive, phenotype negative)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887509",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887509",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7Vi---"
},
{
"entContent": {
"_uniqueProp": "085_PP2_nuclear_HNF4A",
"additionalComments": "While missense variants in HNF4A are a common mechanism of monogenic diabetes, and the constraint score for HNF4A (gene) is 1.81, the MDEP does not support using this criterion at this time. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "085",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887504",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887504",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7dS---"
},
{
"entContent": {
"_uniqueProp": "085_PS2_nuclear_HNF4A",
"additionalComments": "To obtain maximum points (“phenotype highly specific for gene”) patient must meet criteria for PP4 (result of ≥50% chance or higher of testing positive for MODY on the MODY Probability calculator (https://www.diabetesgenes.org/mody-probability-calculator/) AND have negative HNF4A testing). If patient does not meet PP4 but is noted to have diabetes, use points corresponding to “phenotype consistent with gene but not highly specific”. If patient shows evidence of an autoimmune etiology for their diabetes and/or absolute or near-absolute insulin deficiency (see above), do not apply PS2. ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "To obtain maximum points (“phenotype highly specific for gene”) patient must meet criteria for PP4 (result of ≥50% chance or higher of testing positive for MODY on the MODY Probability calculator ([https://www.diabetesgenes.org/mody-probability-calculator/](https://www.diabetesgenes.org/mody-probability-calculator/)) and negative HNF1A testing). To obtain standard points (“phenotype consistent with gene but not highly specific”), the phenotype of the patient must include diabetes. Probands (and/or family members when assessing segregation for PP1) with evidence of an autoimmune etiology of diabetes and/or absolute or near-absolute insulin deficiency will be excluded when assessing criteria that includes phenotype information. Such evidence includes the following:One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD) (Ref 7,8,9,10). Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (\\<200pmol/L or 0.6ng/mL)(Ref 11,12) or urinary C-peptide/creatinine ratio \\<0.2 nmol/mmol (Ref 8,9)\n\nDo not apply PS2 if the proband has an affected parent with any of the following:\n\n* Affected parent meets PP4 specifications\n* Parent is described as having similarly atypical diabetes to the proband\n* Parent was diagnosed with non-autoimmune diabetes before age 30",
"label": "PS2",
"ns": "085",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887494",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887494",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7WW---"
},
{
"entContent": {
"_uniqueProp": "085_PVS1_nuclear_HNF4A",
"additionalComments": "Per guidance from ClinGen/SVI, PM2_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",
"label": "PVS1",
"ns": "085",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use _HNF4A_ PVS1 decision tree.\n\n* Variants generating PTCs in exon 10 and last 55 nucleotides of exon 9 (c.1162-1216) are not expected to cause NMD[1](#pmid_24274751)\n * The most 3’ nonsense or frameshift variant is c.1256C>G, p.S419X in the last exon. This variant has been classified as Pathogenic by the MDEP. There are six other nonsense and frameshift variants in exon 10, none of which have case information and are all currently classified as VUS. The collective evidence supports applying PVS1 for variants at codon 419 (c.1257) and 5’ and PVS1\\_Supporting for variants at c.1258 (G)/p.Gly420 and 3’.\n* “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”\n * Exons 1, 2 (LRG 4), 3 (LRG 5), 4 (LRG 6), 6 (LRG 8): deletion or skipping causes frameshift: PVS1 \n * Exons 5 (LRG 7), 7 (LRG 9), 8 (LRG 10), 9 (LRG 11) - deletion or skipping causes in-frame deletion, 52/52/79/51-79 AA deleted, that is >10 % of the protein in each case - PVS1\\_Strong \n * Exon 10 (LRG 12) - 46 AA, contains the transactivation domain, includes stop loss - PVS1\\_Strong",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use _HNF4A_ PVS1 decision tree.\n\n* “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” \n * Exons 5 (LRG 7), 7 (LRG 9), 8 (LRG 10), 9 (LRG 11) - deletion or skipping causes in-frame deletion, 52/52/79/51-79 AA deleted, that is >10 % of the protein in each case - PVS1\\_Strong \n * Exon 10 (LRG 12) - 46 AA, contains the transactivation domain, includes stop loss - PVS1\\_Strong\n* Apply PVS1\\_Strong to initiation codon variants. MDEP has classified two start codon variants as likely pathogenic (c.3G>A: PM2\\_Supporting + PP4\\_Moderate + PP1\\_Strong + PVS1\\_Moderate (c.1delA); c.1delA: PM2\\_Supporting + PP1 + PP4\\_Moderate + PVS1\\_Moderate) and there are multiple P/LP variants before the next methionine, p.Met71.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use _HNF4A_ PVS1 decision tree.\n\nApply PVS1\\_Supporting to nonsense or frameshift variants at c.1258 (G)/p.Gly420 and 3’.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887492",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887492",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7du---"
},
{
"entContent": {
"_uniqueProp": "085_BP7_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "085",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way \\< 2.0.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887517",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887517",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7b----"
},
{
"entContent": {
"_uniqueProp": "085_BP2_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "085",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Also applicable when in cis or trans with a likely pathogenic variant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887513",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887513",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7XC---"
},
{
"entContent": {
"_uniqueProp": "085_BS1_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "If there is a Grpmax Filtering AF for both exomes and genomes, use the one with the larger denominator.",
"label": "BS1",
"ns": "085",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "gnomAD Grpmax FAF ≥ 1:30,000 (≥0.0033% or 0.000033)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887508",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887508",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7ZG---"
},
{
"entContent": {
"_uniqueProp": "085_PP4_nuclear_HNF4A",
"additionalComments": "Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see rules).\nCertain assumptions can be made in order to use the MODY probability calculator: \n* Specific clinical information about parents not given but lab/literature states “Family history of diabetes”: Click “Parent with diabetes” in calculator. \n* No information about family history of diabetes is provided: Attempt to use the calculator using both possibilities (yes/no). If this makes a difference in the ability to meet the PP4 cutoff (>50%), PP4 cannot be used. \n* Weight/Height/BMI not given but lab/literature states patient is “lean”: Enter BMI of 30. \n* HbA1c is not provided: Attempt to use the calculator using values of 6% and 10%. If this makes a difference in the ability to meet the PP4 cutoff (>50%), PP4 cannot be used. \n* Treatment information is not provided: Cannot use calculator. ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "MODY probability calculator result of ≥50% chance of testing positive (https://www.diabetesgenes.org/mody-probability-calculator/) AND negative HNF1A genetic analysis, given the similarities in phenotypes between HNF1A-MODY and HNF4A-MODY. Clinical judgement may need to be used when applying this criterion, as the MODY Probability Calculator is not as reliable for non-European ancestry individuals or people diagnosed >35. For example, use of PP4 is acceptable in the absence of HNF1A analysis when the MPC is >50% and the phenotype is specific to HNF4A, for example someone in the family with neonatal hypoglycemia that is responsive to diazoxide or hyperinsulinemic hypoglycemia. If individual was tested due to neonatal hypoglycemia, PP4 can be used if ABCC8 and KCNJ11 testing are negative (no MODY Probability Calculator result required). Certain assumptions can be made in order to use the MODY probability calculator. Specific clinical info about parents not given but lab/literature states “Family history of diabetes”, click “Parent with diabetes” in calculator. If no information about family history of diabetes is provided, run the calculator in both conditions (yes/no) and document whether this makes a difference in overall probability score. Weight/Height/BMI not given but lab/literature states patient is “lean”, enter BMI of 30. HbA1c is not provided, enter 6% and 10% and document whether this makes a difference in overall probability score. Treatment information is not provided, cannot use calculator. ",
"label": "PP4",
"ns": "085",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Phenotype: MODY Probability Calculator result ≥50% chance of testing positive[6](#url_187f5e4a-1941-5c2d-9c9f-1dc999cc5454) AND negative _HNF1A_ testing AND presence of at least one additional feature characteristic of \\__HNF4A_\\_-MODY: \n\n* Antibody negative and/or persistent C-peptide after five years following T1DM diagnosis \n* Personal or family history of persistent neonatal hypoglycemia \n* Personal or family history of large for gestational age (LGA) infants or macrosomia in the absence of sufficient maternal hyperglycemia \n* Response to low-dose SU (extreme response- hypoglycemia) \n* Biochemical/Molecular phenotypic evidence from patient cell lines \n* Fanconi phenotype in conjunction with c.187C>T p.R63W",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "MODY Probability Calculator (MPC)6 result ≥50% chance of testing positive AND negative _HNF1A_ testing",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887506",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887506",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7dC---"
},
{
"entContent": {
"_uniqueProp": "085_PM6_nuclear_HNF4A",
"additionalComments": "Subsumed by PS2.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "085",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887502",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887502",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7XW---"
},
{
"entContent": {
"_uniqueProp": "085_PM2_nuclear_HNF4A",
"additionalComments": "Per guidance from ClinGen/SVI, PM2_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "Recommend using as supporting level of evidence (PM2_Supporting) per ClinGen guidance. Per guidance from ClinGen/SVI, PM2_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic. We recommend investigating the genotype metrics in gnomAD for variants that have been flagged for having failed one or more quality parameters, as it is possible that some of these filtered variants are actually real. The number of filtered alleles can be counted to determine whether PM2_Supporting would be met even if they were genuine calls. If the filtered calls are sufficient in number to not meet PM2_Supporting, then we would not use it. Because it is also possible that these calls are false positives, we would not use filtered variants to support BA1 or BS1. ",
"label": "PM2",
"ns": "085",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "gnomAD Grpmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887498",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887498",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7aK---"
},
{
"entContent": {
"_uniqueProp": "085_PS3_nuclear_HNF4A",
"additionalComments": "Studies performed on a cell line generated from a patient sample (which will be heterozygous and also contain other variants in the patient’s genome which could modify function) will not count as PS3 but instead will count toward PP4_Moderate. \nNote that although occurrence in the transactivation domain (codons 281-631, NM_000545.8 has been cited in older publications as evidence for causality, it is known that the transactivation domain is more tolerant to benign missense variation and therefore we will not apply PM1 at any level to variants within this region at this time (PMID: 11272211, 18003757, 23348805).",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "See list of approved functional studies and guidelines for interpretation of data.",
"label": "PS3",
"ns": "085",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "List of approved functional studies and guidelines for interpretation:\n\n* EMSA for DNA binding\n * “Decreased function” is defined as activity less than 60% of wildtype \n * Note: the effect of the variant on DNA binding will be highly dependent on whether the variant is located within the DNA binding domain.\n* Luciferase assays for transactivation \n * “Decreased function” is defined as activity less than 60% of wildtype \n * Note: this threshold is not 100% specific for transactivation (TA) activity and is complicated by the fact that TA activity will vary depend on many factors, for instance cell line that is used (HeLa, INS, MIN6 etc).\n* Western blotting and indirect immunofluorescence for protein expression (specifically levels and nuclear and cytoplasmic localization, respectively).\n * Determining appropriate thresholds for protein expression is more difficult due to variability in results due to the complexity of the technique. Sample preparations, gel loading, transfer efficiency, specificity of the antibody, choice of internal control and inaccurate detection and quantification are some of the factors that can contribute to varying and inconsistent results. If a reduction in protein expression is seen by immunoblotting, then further testing by quantitative PCR (qPCR) is recommended in order to measure the mRNA level and assess whether a reduction in amount of protein is due to a reduced mRNA level.\n* To use PS3\\_Supporting, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus wild-type allele) does not count as PS3\\_Supporting.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887495",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887495",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7Xq---"
},
{
"entContent": {
"_uniqueProp": "085_BS4_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "085",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applicable to family members without variant who have MPC6 score ≥50% (i.e., genotype negative, phenotype positive).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887511",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887511",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7cC---"
},
{
"entContent": {
"_uniqueProp": "085_PM4_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "085",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "For deletions/insertions of more than one amino acid in a non-repeat region, use as moderate level of evidence.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For single amino acid deletions/insertions, use as supporting level of evidence",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887500",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887500",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7Z6---"
},
{
"entContent": {
"_uniqueProp": "085_PM1_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "085",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable to amino acids that directly bind DNA and are necessary for Zinc-finger or homodimer formation[2](#pmid_18829458) \n\n* Directly bind DNA: Asp43, His49, Tyr 50, Gly51, Asp56, Gly57, Lys59, Arg63, Arg64, Arg67, His70, Tyr72, Arg87, Asn88, Arg91, Arg94, Gln109, Arg112 \n* Homodimer: Arg75, Gln89, Glu111, Asp113 \n* Zinc finger: Cys38, Cys41, Cys55, Cys58, Cys74, Cys80, Cys90, Cys93\n\nApplicable to variants within the promoter region that are direct HNF1A/HNF1B binding sites [15](#pmid_23332764), [16](#pmid_38909044):\n\n* c.-170 to c.-173 and c.-178 to c.-181 (NM\\_175914.4)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion can be used for missense variants in well-conserved regions within the DNA and ligand-binding domains. It can also be used for variants within certain conserved transcription factor binding sites in the promoter (see below for details).\n\n* Promoter region: \n * c.-132 to c.-141 (HNF6/OC2 binding site)\n * c.-143 to c.-149, c.-151 (PDX1 (formerly IPF1) binding site) \n * c.-169, c.-174, c.-176, and c.-177 (HNF1A/HNF1B binding site)\n* DNA binding: \n * codons 37-113 (NM\\_175914.4:c.175C-339C p.Leu37-Asp113) (While the paper describing the crystal structure of _HNF4A_[2](#pmid_18829458) shows the sequence as amino acids 33-113, amino acids 33-36 do not bind DNA and the conserved sequence starts as Leu37.)\n* Ligand binding: \n * codons 180-220 and 300-350 \n * (NM\\_175914.4:c.538G-658G p.Ala180-Val220) \n * (NM\\_175914.4:c.898T-1048G p.Tyr300-Glu350)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887497",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887497",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7aa---"
},
{
"entContent": {
"_uniqueProp": "085_PS1_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "085",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applicable for a same amino acid change if the previously established variant is classified as pathogenic by ClinGen MDEP specifications.\n\nPS1 can also be applied for canonical and non-canoncial splicing variants that have a SpliceAI score within 10% of the original variant, or a greater predicted deleterious impact than the comparision (likely) pathogenic variant. See Table 2 from [PMID: 37352859](https://pmc.ncbi.nlm.nih.gov/articles/PMC10357475/table/tbl2/) for determining when PS1 should be applied at the Strong, Moderate, or Supporting level in these instances.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable for a same amino acid change if the previously established variant is classified as likely pathogenic by ClinGen MDEP specifications.\n\nPS1 can also be applied for canonical and non-canoncial splicing variants that have a SpliceAI score within 10% of the original variant, or a greater predicted deleterious impact than the comparision (likely) pathogenic variant. See Table 2 from [PMID: 37352859](https://pmc.ncbi.nlm.nih.gov/articles/PMC10357475/table/tbl2/) for determining when PS1 should be applied at the Strong, Moderate, or Supporting level in these instances.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "PS1 can also be applied for canonical and non-canoncial splicing variants that have a SpliceAI score within 10% of the original variant, or a greater predicted deleterious impact than the comparision (likely) pathogenic variant. See Table 2 from [PMID: 37352859](https://pmc.ncbi.nlm.nih.gov/articles/PMC10357475/table/tbl2/) for determining when PS1 should be applied at the Strong, Moderate, or Supporting level in these instances.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887493",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887493",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7YC---"
},
{
"entContent": {
"_uniqueProp": "085_BP6_nuclear_HNF4A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "085",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887518",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887518",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7YW---"
},
{
"entContent": {
"_uniqueProp": "085_BP5_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "085",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A variant in another monogenic diabetes gene is Pathogenic/Likely Pathogenic.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887516",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887516",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7Wy---"
},
{
"entContent": {
"_uniqueProp": "085_BP3_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "085",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887514",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887514",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7bS---"
},
{
"entContent": {
"_uniqueProp": "085_BS3_nuclear_HNF4A",
"additionalComments": "To use BS3, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus wild-type allele and other variants in the patient’s genome) it cannot count as BS3. ",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "To use BS3, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus wild-type allele) it cannot count as BS3. ",
"label": "BS3",
"ns": "085",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "List of approved functional studies and guidelines for interpretation of data.\n\n* EMSA for DNA binding \n * “No functional impact” is defined as ≥75% activity of wildtype \n * Note: the effect of the variant on DNA binding will be highly dependent on whether the variant is located within the DNA binding domain.\n* Luciferase assays for transactivation \n * “No functional impact” is defined as ≥75% activity of wildtype \n * Note: this threshold is not 100% specific for transactivation (TA) activity and is complicated by the fact that TA activity will vary depend on many factors, for instance cell line that is used (HeLa, INS, MIN6 etc). Assays should include controls for WT, T2DM and known MODY variants.\n* Western blotting and indirect immunofluorescence for protein expression (specifically levels and nuclear and cytoplasmic localization, respectively). \n * Determining appropriate thresholds for protein expression is more difficult due to variability in results due to the complexity of the technique. Sample preparations, gel loading, transfer efficiency, specificity of the antibody, choice of internal control and inaccurate detection and quantification are some of the factors that can contribute to varying and inconsistent results. If a difference in protein expression compared to WT is seen by immunoblotting, then further testing by quantitative PCR (qPCR) is recommended in order to measure the mRNA level and assess whether the difference in amount of protein is due to a reduced mRNA level.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887510",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887510",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7ci---"
},
{
"entContent": {
"_uniqueProp": "085_PP1_nuclear_HNF4A",
"additionalComments": "Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see rules).",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "Variable penetrance and phenocopies complicate co-segregation studies. The presence of type 1 and type 2 diabetes phenocopies and significance of variants in unaffected individuals as defined above will need to be considered. If a family member(s) shows evidence of an autoimmune etiology for their diabetes and/or absolute or near-absolute insulin deficiency (see below), do not include them in PP1 calculation.One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD) (Ref 7,8,9,10). Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (<200pmol/L or 0.6ng/mL) (Ref 11,12) or urinary C-peptide/creatinine ratio <0.2 nmol/mmol (Ref 8,9). Unaffected family members without the variant under assessment can also be used in segregation analysis(Ref 5). An individual is considered “unaffected” if over age 70 and non-diabetic (based on Exeter work (Ref 13) which shows penetrance of HNF4A-MODY at 98% by age 70).",
"label": "PP1",
"ns": "085",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use thresholds suggested by Jarvik and Browning[5](#pmid_27236918)\n\n* Single Family : ≤ 1/32 (5 meioses)\n* \\> 1 Family : ≤ 1/16 (4 meioses)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use thresholds suggested by Jarvik and Browning[5](#pmid_27236918)\n\n* Single Family : ≤ 1/16 (4 meioses)\n* \\> 1 Family : ≤ 1/8 (3 meioses)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use thresholds suggested by Jarvik and Browning[5](#pmid_27236918)\n\n* Single Family : ≤ 1/8 (3 meioses)\n* \\> 1 Family : ≤ ¼ (2 meioses)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887503",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887503",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7Y6---"
},
{
"entContent": {
"_uniqueProp": "085_PM5_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM5",
"ns": "085",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance than the novel variant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887501",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887501",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7Vu---"
},
{
"entContent": {
"_uniqueProp": "085_PS4_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "The phenotype of the patient must include diabetes, with evidence of an autoimmune etiology and/or absolute or near-absolute insulin deficiency (see above) considered as exclusionary. Variant should meet PM2_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region). ",
"label": "PS4",
"ns": "085",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "7 (seven) or more unrelated occurrences = Strong. Variant should meet PM2\\_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region). Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology.\n\n* One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD)[7](#pmid_21395678),[8](#pmid_28701371),[9](#pmid_30409810),[10](#pmid_31704690) \n* Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (\\<200pmol/L or 0.6ng/mL)[11](#pmid_30225972),[12](#pmid_23771925) or urinary C-peptide/creatinine ratio \\<0.2 nmol/mmol[8](#pmid_28701371),[9](#pmid_30409810)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "4-6 unrelated occurrences = Moderate. Variant should meet PM2\\_Supporting in order to use PS4 at any level. Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology.\n\n* One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD)[7](#pmid_21395678),[8](#pmid_28701371),[9](#pmid_30409810),[10](#pmid_31704690)\n* Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (\\<200pmol/L or 0.6ng/mL)[11](#pmid_30225972),[12](#pmid_23771925) or urinary C-peptide/creatinine ratio \\<0.2 nmol/mmol[8](#pmid_28701371),[9](#pmid_30409810)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887496",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533887496",
"modified": "2025-10-10T18:20:03.281Z",
"modifier": "cjodarski",
"rev": "_ka7X7au---"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0015967",
"lbl": "monogenic diabetes",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/254"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/8319"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0015967"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/rare_genetic_diabetes_mellitus"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1392102"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C3888631"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C129739"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_1001511"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_183625"
}
],
"definition": {
"val": "Diabetes mellitus that is caused by mutations in a single gene.",
"xrefs": [
"https://doi.org/10.2337/dci20-0065"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#inferred_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "monogenic diabetes",
"xrefs": [
"NCIT:C129739"
]
},
{
"pred": "hasExactSynonym",
"val": "rare genetic diabetes mellitus",
"xrefs": [
"Orphanet:183625"
]
}
],
"xrefs": [
{
"val": "EFO:1001511"
},
{
"val": "MEDGEN:1392102"
},
{
"val": "NCIT:C129739"
},
{
"val": "Orphanet:183625"
},
{
"val": "UMLS:C3888631"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0015967",
"name": "monogenic diabetes"
},
"entId": "MONDO:0015967",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0015967",
"entType": "Disease",
"ldhId": "467884025",
"ldhIri": "https://cspec.genome.network/cspec/Disease/id/467884025",
"modified": "2025-10-07T16:14:27.279Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7x3Hu---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056949438414800,
"agr": "HGNC:5024",
"alias_symbol": [
"NR2A1",
"HNF4"
],
"ccds_id": [
"CCDS13330",
"CCDS42876",
"CCDS68131",
"CCDS46605",
"CCDS13331",
"CCDS46604",
"CCDS74728"
],
"date_approved_reserved": "1998-04-20",
"date_modified": "2021-05-26",
"date_name_changed": "2016-01-18",
"ena": [
"X76930"
],
"ensembl_gene_id": "ENSG00000101076",
"entrez_id": "3172",
"gene_group": [
"MicroRNA protein coding host genes",
"Hepatocyte nuclear factor 4 family"
],
"gene_group_id": [
1691,
2085
],
"hgnc_id": "HGNC:5024",
"iuphar": "objectId:608",
"location": "20q13.12",
"location_sortable": "20q13.12",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
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},
"name": "Released"
},
{
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"event": {
"modifiedBy": "cjodarski",
"name": "cspec-reopened",
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},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "mrichardson",
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"prevState": "Pilot Rules Submitted",
"timeStamp": "2025-07-03T14:59:44.059Z"
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{
"current": false,
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],
"tagNameSpaces": [
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"title": "ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 3.1.0",
"type": "Richards et.al., 2015 - Combining rules",
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},
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"entType": "SequenceVariantInterpretation",
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"CriteriaCode": [
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"entContent": {
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"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "086",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
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"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888306",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888306",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
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{
"entContent": {
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"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "086",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888299",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888299",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
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},
{
"entContent": {
"_uniqueProp": "086_BS2_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "086",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "We expect to see hyperglycemia at birth in an individual with \\_GCK\\_-MODY and therefore consider an individual unaffected if euglycemic in childhood or adulthood. Since individuals typically do not present with symptoms of diabetes, evidence that someone is “nondiabetic” is insufficient; fasting glucose must be tested and found to be within normal limits (\\<100 mg/dl / 5.5 mmol/L).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888296",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888296",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
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{
"entContent": {
"_uniqueProp": "086_BS1_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BS1",
"ns": "086",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "gnomAD Grpmax FAF ≥ 1:25,000 (0.004% or 0.00004)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888295",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888295",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6Xa---"
},
{
"entContent": {
"_uniqueProp": "086_PM4_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "086",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "For deletions/insertions of more than one amino acid in a non-repeat region, use as moderate level of evidence.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Apply at the Supporting level when there is an insertion or deletion of a single amino acid in a non-repeat region.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888287",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888287",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6Zy---"
},
{
"entContent": {
"_uniqueProp": "086_PM3_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable for variants found in neonatal diabetes. Criterion can also be used to interpret the pathogenicity of a heterozygous variant (i.e., GCK-MODY) if the variant under assessment has also been identified in a patient with neonatal diabetes in the homozygous state or in trans (or phase unknown per the point system) with a P/LP variant or VUS).",
"label": "PM3",
"ns": "086",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use SVI-recommended point-based system.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use SVI-recommended point-based system.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use SVI-recommended point-based system.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use SVI-recommended point-based system.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888286",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888286",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6aC---"
},
{
"entContent": {
"_uniqueProp": "086_PS4_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "Variant should meet PM2_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region). Phenotype of the patient must include diabetes, with evidence of an autoimmune etiology and/or absolute or near-absolute insulin deficiency considered as exclusionary: One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD) (Ref 15,16, 17, 18). Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (<200pmol/L or 0.6ng/mL) (Ref 13, 14) or urinary C-peptide/creatinine ratio <0.2 nmol/mmol (Ref 16, 17)",
"label": "PS4",
"ns": "086",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "7 or more occurrences in unrelated individuals = Strong.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "4-6 occurrences in unrelated individuals = Moderate.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888283",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888283",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6Ue---"
},
{
"entContent": {
"_uniqueProp": "086_BS3_nuclear_GCK",
"additionalComments": "To use BS3, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus wild-type allele and other variants in the patient’s genome) it cannot count as BS3. ",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "To use BS3, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus any other genomic variants the patient has) it cannot count as BS3. ",
"label": "BS3",
"ns": "086",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing (see BP4).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use GCK PS3 decision tree, which incorporates the relative activity index (RAI), relative stability index (RSI) and assays that measure the impact of variants on binding with GKRP and GKA.\n\nEvidence of no impact on function:\n\n* Normal RAI (>0.5) + normal RSI (>0.5) + normal inhibition/activation with GKRP/GKA = BS3\\_Supporting \n* Normal RAI (>0.5) + normal RSI (>0.5) but no studies investigating GKRP/GKA = Cannot use PS3 or BS3\n\nGloyn, et al. 2005 [5](#pmid_15677479); Beer, et al. 2012 [6](#pmid_22611063); Raimondo, et al. 2014 [7](#pmid_25015100); Gloyn, et al. (2004)12.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888297",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888297",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6WC---"
},
{
"entContent": {
"_uniqueProp": "086_PP4_nuclear_GCK",
"additionalComments": "Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see rules).\nCertain assumptions can be made in order to use the MODY probability calculator: \n* Specific clinical information about parents not given but lab/literature states “Family history of diabetes”: Click “Parent with diabetes” in calculator. \n* No information about family history of diabetes is provided: Attempt to use the calculator using both possibilities (yes/no). If this makes a difference in the ability to meet the PP4 cutoff (>50%), PP4 cannot be used. \n* Weight/Height/BMI not given but lab/literature states patient is “lean”: Enter BMI of 30. \n* HbA1c is not provided: Attempt to use the calculator using values of 6% and 10%. If this makes a difference in the ability to meet the PP4 cutoff (>50%), PP4 cannot be used. \n* Treatment information is not provided: Cannot use calculator. ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "Negative testing of other genes not necessary because phenotype is very specific. Sixty percent of patients with GCK-MODY phenotype will test positive. There is a small chance that patient has HNF1A- or HNF4A-MODY in the early stages of disease (can get info about likelihood from family history). Non-glycemic factors including hemoglobinopathies can affect HbA1c levels. This should be considered in cases where the HbA1c is outside the typical GCK range but fasting glucose and other features are consistent with GCK-hyperglycemia. About 1% of patients with GCK-MODY will have deletions or other variants (e.g., promoter) that are not identified via Sanger sequencing- consider testing via NGS or other technology. For patients tested because of neonatal diabetes, PP4 can be applied if there has been negative testing for three most common monogenic causes for neonatal diabetes. These include ABCC8, KCNJ11, and INS. In consanguineous cases, EIF2AK3 should be tested as well, as it generally accounts for a negligible proportion of neonatal diabetes but becomes more likely with consanguinity.",
"label": "PP4",
"ns": "086",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND fasting plasma glucose always (FPG) 5.5-8 mmol/L (100-144 mg/dL) AND presence of any of the following additional features:\n\n* Pediatric patient (prepubertal or \\<10 years) (picked up in the absence of symptoms, either incidentally during workup for an unrelated indication or during routine screening)\n* Multiple values (=persistent) of mild fasting hyperglycemia in PP4 range\n * Either (≥ 1 HbA1c + ≥ 2 FPG) OR (≥ 2 HbA1c + ≥ 1 FPG)\n * Only 1 HbA1c and 1 FPG in range but they are at least 6 months apart\n * Patient in literature is described as having a multi-year history of impaired fasting glucose (IFG)\n* OGTT (oral glucose tolerance test) with 2-hour increment \\<3 mmol/L (54 mg/dl) \n* Antibody negative \n* Macrosomia in normoglycemic offspring of hyperglycemic gestational parent\n* Low birthweight in hyperglycemic offspring of hyperglycemic gestational parent. \n* Three-generation, dominant family history of diabetes or hyperglycemia (in a family not used for PP1)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND fasting plasma glucose always (FPG) 5.5-8 mmol/L (100-144 mg/dL)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888293",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888293",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6Q2---"
},
{
"entContent": {
"_uniqueProp": "086_PM2_nuclear_GCK",
"additionalComments": "Per guidance from ClinGen/SVI, PM2_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "Recommend using as supporting level of evidence (PM2\\_Supporting) per ClinGen guidance. Per guidance from ClinGen/SVI, PM2\\_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic. We recommend investigating the genotype metrics in gnomAD for variants that have been flagged for having failed one or more quality parameters, as it is possible that some of these filtered variants are actually real. The number of filtered alleles can be counted to determine whether PM2\\_Supporting would be met even if they were genuine calls. If the filtered calls are sufficient in number to not meet PM2\\_Supporting, then we would not use it. Because it is also possible that these calls are false positives, we would not use filtered variants to support BA1 or BS1. Grpmax FAF cutoffs using combined frequencies or dataset (exomes or genomes) with highest denominator if combined not available in gnomAD v4.1.",
"label": "PM2",
"ns": "086",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "gnomAD Grpmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888285",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888285",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6Ru---"
},
{
"entContent": {
"_uniqueProp": "086_PS2_nuclear_GCK",
"additionalComments": "To obtain maximum points (“phenotype highly specific for gene”) patient must meet criteria for PP4 (result of ≥50% chance or higher of testing positive for MODY on the MODY Probability calculator (https://www.diabetesgenes.org/mody-probability-calculator/) AND have negative HNF4A testing). If patient does not meet PP4 but is noted to have diabetes, use points corresponding to “phenotype consistent with gene but not highly specific”. If patient shows evidence of an autoimmune etiology for their diabetes and/or absolute or near-absolute insulin deficiency (see above), do not apply PS2. ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "To obtain maximum points (“phenotype highly specific for gene”), patient must meet criteria for PP4. To obtain standard points (“phenotype consistent with gene but not highly specific”), the phenotype of the patient must include hyperglycemia or impaired fasting glucose, with no evidence of an autoimmune etiology of diabetes and/or absolute or near-absolute insulin deficiency. Exclusionary evidence of an autoimmune etiology of diabetes and/or absolute or near-absolute insulin deficiency includes the following: One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD) (Ref 15, 16, 17, 18). Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (\\<200pmol/L or 0.6ng/mL) (Ref 13, 14) or urinary C-peptide/creatinine ratio \\<0.2 nmol/mmol (Ref 16, 17). We expect to see hyperglycemia at birth in an individual with GCK-MODY and therefore consider an individual unaffected if euglycemic in childhood or adulthood. Since individuals typically do not present with symptoms of diabetes, a statement that someone is “nondiabetic” is insufficient to consider a parent unaffected; fasting glucose must be tested and found to be within normal limits (\\<100 mg/dl = 5.5 mmol/L) or HbA1c \\<=5.5% (37 mmol/mol) since the GCK range was 5.6 - 7.6% (38 – 60 mmol/mol)(Ref 19). Presence of clinically significant diabetes complications in anyone with the variant is an exclusion.\n\nDo not apply PS2 if the proband has an affected parent with any of the following:\n\n* Affected parent meets PP4 specifications\n* Parent is described as having similarly atypical diabetes to the proband\n* Parent was diagnosed with non-autoimmune diabetes before age 30",
"label": "PS2",
"ns": "086",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888281",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888281",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6Uu---"
},
{
"entContent": {
"_uniqueProp": "086_BP5_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "086",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A variant in another monogenic diabetes gene is P/LP.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888303",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888303",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6S2---"
},
{
"entContent": {
"_uniqueProp": "086_BP3_nuclear_GCK",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "086",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888301",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888301",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6XC---"
},
{
"entContent": {
"_uniqueProp": "086_PP2_nuclear_GCK",
"additionalComments": "Missense variants account for 55% of all published pathogenic variants in this gene (Colclough et al 2013), however the constraint score for HNF1A (gene) is 1.07, which is not significant; therefore, we do not support using this criterion at this time. The low constraint score is most likely due to high tolerance for missense variants in the transactivation domain (see PM1 section). There are significantly more pathogenic missense variants in the DNA binding and dimerization domains, which are much less tolerant to missense variation. We may update this in the future if we can generate domain-specific scores.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "086",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Apply to all missense variants in GCK. gnomAD missense constraint score for _GCK_ is 3.07 (observed/expected= 0.5), which is significant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888291",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888291",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6Tu---"
},
{
"entContent": {
"_uniqueProp": "086_PVS1_nuclear_GCK",
"additionalComments": "Per guidance from ClinGen/SVI, PM2_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "Use GCK PVS1 decision tree.",
"label": "PVS1",
"ns": "086",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": " Use _GCK_ PVS1 decision tree created based on PVS1 decision tree from ClinGen SVI group[1](#pmid_30096381)\n\n* Variants generating PTCs 3’ of c.1198 (p.Asp400) of NM\\_000162.3, which includes the last 55 nucleotides of exon 9 and exon 10, are not expected to cause NMD[2](#pmid_24274751). The α13 helix (p.444-456), located at the C-end of the protein, has a critical role in GCK conformational change upon glucose binding. Individuals with PTCs in exon 10 have a MODY phenotype. Therefore, a “very strong” level of evidence will be applied for PTCs in exon 10.\n* “Exon skipping or “use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” \n * single exon deletions \n * deletion of exon 1 is in-frame but over 20 families with GCK-MODY phenotype and exon 1 deletion (some also have promoter deletions) --> PVS1 \n * deletions of single **exons 2,3,6 and 7** cause frameshift --> **PVS1** \n * deletions or skipping of **exons 8 and 9** are in-frame and the proportion is >10 % (52 AA and 78 AA, respectively) --> **PVS1** \n * deletions or skipping of **exons 4 and 5** are in-frame and the proportion is \\<10 % (40 AA and 32 AA, respectively). Exon 4 (p.122-161) and exon 5 (p.162-193) contain each a part of the active site that binds glucose /p.151-180[3](#pmid_23957911) according to Beck et al., Biochemistry 2013/ --> **PVS1** \n * deletion of exon 10 (47 AA) – There are a number of patients with a GCK-MODY phenotype with reported with missense, frameshift, PTC, splice acceptor, and stop loss variants in exon 10 --> **PVS1**\n* Apply PVS1\\_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1\\_Supporting + PM2\\_Supporting; one case submitted, dx.53 and no other info provided to lab). The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. \n* Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use _GCK_ PVS1 decision tree.\n\nPer the SVI standard PVS1 decision tree, apply PVS1\\_Strong to duplications ≥ 1 exon in size, contained completely within gene, presumed in tandem, reading frame presumed disrupted, and NMD predicted to occur.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use _GCK_ PVS1 decision tree.\n\n* Apply PVS1\\_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1\\_Supporting + PM2\\_Supporting; one case submitted, dx.53 and no other info provided to lab). The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. \n* Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888279",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888279",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6SO---"
},
{
"entContent": {
"_uniqueProp": "086_BP7_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "086",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way \\< 2.0.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888304",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888304",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6Sq---"
},
{
"entContent": {
"_uniqueProp": "086_BP4_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "086",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2[9](#pmid_32123317),[10](#pmid_30661751).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888302",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888302",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6Wu---"
},
{
"entContent": {
"_uniqueProp": "086_BP2_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "086",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Also applicable when in cis or trans with a likely pathogenic variant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888300",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888300",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6Vy---"
},
{
"entContent": {
"_uniqueProp": "086_BS4_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "086",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applicable to family members without variant who meet PP4 criteria (HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL))",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888298",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888298",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6Ti---"
},
{
"entContent": {
"_uniqueProp": "086_PM6_nuclear_GCK",
"additionalComments": "Subsumed in PS2.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "086",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888289",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888289",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6UK---"
},
{
"entContent": {
"_uniqueProp": "086_PM5_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM5",
"ns": "086",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888288",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888288",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6Xy--A"
},
{
"entContent": {
"_uniqueProp": "086_PM1_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "See attached chart.",
"label": "PM1",
"ns": "086",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable for glucose- and ATP-binding sites (see attached chart for details).\n\nGlucose-binding sites: Ser151 - Pro153; Thr168 - Lys169; Asn204 - Thr206; Ile225 - Asn231; Asn254 - Gly258; Gln287; Glu290\n\nATP-binding sites: Asp78 - Arg85; Ser151; Lys169; Asp205; Ile225 - Gly229; Gly295 - Lys296; Glu331 - Arg333; Ser336; Gly410 - His416",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": "Gene-specific, Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888284",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888284",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6YS---"
},
{
"entContent": {
"_uniqueProp": "086_PS3_nuclear_GCK",
"additionalComments": "Studies performed on a cell line generated from a patient sample (which will be heterozygous and also contain other variants in the patient’s genome which could modify function) will not count as PS3 but instead will count toward PP4_Moderate. \nNote that although occurrence in the transactivation domain (codons 281-631, NM_000545.8 has been cited in older publications as evidence for causality, it is known that the transactivation domain is more tolerant to benign missense variation and therefore we will not apply PM1 at any level to variants within this region at this time (PMID: 11272211, 18003757, 23348805).",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "Use GCK PS3 decision tree, which incorporates the relative activity index (RAI), relative stability index (RSI), and assays that measure the impact of variants on binding with GKRP and GKA. (Ref 5,6,7,12). For canonical splice site variants, do not use PS3 for RNA studies demonstrating abnormal splicing, since PVS1 will already be used at some level. To use PS3, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus any other genomic variation the patient has) does not count as PS3.",
"label": "PS3",
"ns": "086",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See list of approved functional studies and guidelines for interpretation of data.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "See list of approved functional studies and guidelines for interpretation of data (below).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888282",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888282",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6Ym---"
},
{
"entContent": {
"_uniqueProp": "086_PS1_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "086",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applicable for a same amino acid change if the previously established variant is classified as pathogenic by ClinGen MDEP specifications.\n\nPS1 can also be applied for canonical and non-canoncial splicing variants that have a SpliceAI score within 10% of the original variant, or a greater predicted deleterious impact than the comparision (likely) pathogenic variant. See Table 2 from [PMID: 37352859](https://pmc.ncbi.nlm.nih.gov/articles/PMC10357475/table/tbl2/) for determining when PS1 should be applied at the Strong, Moderate, or Supporting level in these instances.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable for a same amino acid change if the previously established variant is classified as likely pathogenic by ClinGen MDEP specifications.\n\nPS1 can also be applied for canonical and non-canoncial splicing variants that have a SpliceAI score within 10% of the original variant, or a greater predicted deleterious impact than the comparision (likely) pathogenic variant. See Table 2 from [PMID: 37352859](https://pmc.ncbi.nlm.nih.gov/articles/PMC10357475/table/tbl2/) for determining when PS1 should be applied at the Strong, Moderate, or Supporting level in these instances.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "PS1 can also be applied for canonical and non-canoncial splicing variants that have a SpliceAI score within 10% of the original variant, or a greater predicted deleterious impact than the comparision (likely) pathogenic variant. See Table 2 from [PMID: 37352859](https://pmc.ncbi.nlm.nih.gov/articles/PMC10357475/table/tbl2/) for determining when PS1 should be applied at the Strong, Moderate, or Supporting level in these instances.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888280",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888280",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6VC---"
},
{
"entContent": {
"_uniqueProp": "086_BP6_nuclear_GCK",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "086",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888305",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888305",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6Va---"
},
{
"entContent": {
"_uniqueProp": "086_BA1_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BA1",
"ns": "086",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "gnomAD Grpmax FAF ≥ 1:10,000 (≥ 0.01% or 0.0001)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888294",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888294",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6ZW---"
},
{
"entContent": {
"_uniqueProp": "086_PP3_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "086",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is at least 0.2[9](#pmid_32123317),[10](#pmid_30661751)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888292",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888292",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6We---"
},
{
"entContent": {
"_uniqueProp": "086_PP1_nuclear_GCK",
"additionalComments": "Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see rules).",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "Variable penetrance and phenocopies complicate co-segregation studies. The presence of type 1 and type 2 diabetes phenocopies and significance of variants in unaffected individuals as defined above will need to be considered. We expect to see hyperglycemia at birth in an individual with GCK-MODY and therefore consider an individual unaffected if euglycemic in childhood or adulthood. Since individuals typically do not present with symptoms of diabetes, a statement that someone is “nondiabetic” is insufficient to classify a family member as unaffected; fasting glucose must be tested and found to be within normal limits (<100 mg/dl = 5.5 mmol/L) or HbA1c test <=5.5% since the GCK range was 5.6 - 7.6% (Ref13).
Presence of clinically significant diabetes complications in anyone with the variant is an exclusion.",
"label": "PP1",
"ns": "086",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use thresholds suggested by Jarvik and Browning[8](#pmid_27236918)\n\n* Single Family : ≤ 1/32 (5 meioses)\n* \\>1 Family : ≤ 1/16 (4 meioses)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use thresholds suggested by Jarvik and Browning[8](#pmid_27236918)\n\n* Single Family : ≤ 1/16 (4 meioses)\n* \\>1 Family : ≤ 1/8 (3 meioses)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use thresholds suggested by Jarvik and Browning[8](#pmid_27236918)\n\n* Single Family : ≤ 1/8 (3 meioses)\n* \\>1 Family : ≤ ¼ (2 meioses)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888290",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1533888290",
"modified": "2025-10-10T18:22:13.254Z",
"modifier": "cjodarski",
"rev": "_ka7Z6RS---"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0015967",
"lbl": "monogenic diabetes",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/254"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/8319"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0015967"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/rare_genetic_diabetes_mellitus"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1392102"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C3888631"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C129739"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_1001511"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_183625"
}
],
"definition": {
"val": "Diabetes mellitus that is caused by mutations in a single gene.",
"xrefs": [
"https://doi.org/10.2337/dci20-0065"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#inferred_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "monogenic diabetes",
"xrefs": [
"NCIT:C129739"
]
},
{
"pred": "hasExactSynonym",
"val": "rare genetic diabetes mellitus",
"xrefs": [
"Orphanet:183625"
]
}
],
"xrefs": [
{
"val": "EFO:1001511"
},
{
"val": "MEDGEN:1392102"
},
{
"val": "NCIT:C129739"
},
{
"val": "Orphanet:183625"
},
{
"val": "UMLS:C3888631"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0015967",
"name": "monogenic diabetes"
},
"entId": "MONDO:0015967",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0015967",
"entType": "Disease",
"ldhId": "467884025",
"ldhIri": "https://cspec.genome.network/cspec/Disease/id/467884025",
"modified": "2025-10-07T16:14:27.279Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7x3Hu---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056948280787000,
"agr": "HGNC:4195",
"alias_name": [
"hexokinase 4"
],
"alias_symbol": [
"HK4"
],
"ccds_id": [
"CCDS5479",
"CCDS5480"
],
"date_approved_reserved": "1991-06-05",
"date_modified": "2021-05-26",
"date_name_changed": "2016-01-22",
"ena": [
"AF041014"
],
"ensembl_gene_id": "ENSG00000106633",
"entrez_id": "2645",
"enzyme_id": [
"2.7.1.2",
"2.7.1.1"
],
"hgnc_id": "HGNC:4195",
"iuphar": "objectId:2798",
"location": "7p13",
"location_sortable": "07p13",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/GCK",
"LRG_1074|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_1074.xml"
],
"mane_select": [
"ENST00000403799.8",
"NM_000162.5"
],
"mgd_id": [
"MGI:1270854"
],
"name": "glucokinase",
"omim_id": [
"138079"
],
"orphanet": 122053,
"prev_name": [
"maturity onset diabetes of the young 2",
"glucokinase (hexokinase 4)"
],
"prev_symbol": [
"MODY2"
],
"pubmed_id": [
1740341,
1502186
],
"refseq_accession": [
"NM_000162"
],
"rgd_id": [
"RGD:2670"
],
"status": "Approved",
"symbol": "GCK",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc003tkl.3",
"uniprot_ids": [
"P35557"
],
"uuid": "ea8a5be4-e0f0-4dd4-8d5b-a40844aeb9ff",
"vega_id": "OTTHUMG00000022903"
}
},
"entId": "GCK",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:4195",
"entType": "Gene",
"ldhId": "467827496",
"ldhIri": "https://cspec.genome.network/cspec/Gene/id/467827496",
"modified": "2021-10-14T11:36:39.977Z",
"modifier": "genbadmin",
"rev": "_inf5BNC--l"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "086_nuclear_GCK",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Semidominant inheritance",
"preferredMondoId": "MONDO:0015967",
"preferredTitle": "monogenic diabetes"
}
],
"gene": "GCK",
"preferredTranscript": "NM_000162.5"
}
],
"ns": "086",
"references": [
{
"auths": [
"DiStefano MT",
"Hemphill SE",
"et al."
],
"doiStr": "10.1016/j.jmoldx.2018.06.005",
"id": "30096381",
"iss": "(6)",
"namespace": "pmid",
"pages": "p. 789-801.",
"source": "J Mol Diagn",
"title": "Curating Clinically Relevant Transcripts for the Interpretation of Sequence Variants.",
"vol": "20",
"year": "2018"
},
{
"auths": [
"Popp MW",
"Maquat LE"
],
"doiStr": "10.1146/annurev-genet-111212-133424",
"id": "24274751",
"iss": "",
"namespace": "pmid",
"pages": "p. 139-65.",
"source": "Annu Rev Genet",
"title": "Organizing principles of mammalian nonsense-mediated mRNA decay.",
"vol": "47",
"year": "2013"
},
{
"auths": [
"Beck T",
"Miller BG"
],
"doiStr": "10.1021/bi400838t",
"id": "23957911",
"iss": "(36)",
"namespace": "pmid",
"pages": "p. 6232-9.",
"source": "Biochemistry",
"title": "Structural basis for regulation of human glucokinase by glucokinase regulatory protein.",
"vol": "52",
"year": "2013"
},
{
"auths": [
"Brnich SE",
"Abou Tayoun AN",
"et al."
],
"doiStr": "10.1186/s13073-019-0690-2",
"id": "31892348",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 3.",
"source": "Genome Med",
"title": "Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework.",
"vol": "12",
"year": "2019"
},
{
"auths": [
"Gloyn AL",
"Odili S",
"et al."
],
"doiStr": "10.1074/jbc.M413146200",
"id": "15677479",
"iss": "(14)",
"namespace": "pmid",
"pages": "p. 14105-13.",
"source": "J Biol Chem",
"title": "Insights into the structure and regulation of glucokinase from a novel mutation (V62M), which causes maturity-onset diabetes of the young.",
"vol": "280",
"year": "2005"
},
{
"auths": [
"Beer NL",
"Osbak KK",
"et al."
],
"doiStr": "10.2337/dc11-2420",
"id": "22611063",
"iss": "(7)",
"namespace": "pmid",
"pages": "p. 1482-4.",
"source": "Diabetes Care",
"title": "Insights into the pathogenicity of rare missense GCK variants from the identification and functional characterization of compound heterozygous and double mutations inherited in cis.",
"vol": "35",
"year": "2012"
},
{
"auths": [
"Raimondo A",
"Chakera AJ",
"et al."
],
"doiStr": "10.1093/hmg/ddu360",
"id": "25015100",
"iss": "(24)",
"namespace": "pmid",
"pages": "p. 6432-40.",
"source": "Hum Mol Genet",
"title": "Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability.",
"vol": "23",
"year": "2014"
},
{
"auths": [
"Jarvik GP",
"Browning BL"
],
"doiStr": "10.1016/j.ajhg.2016.04.003",
"id": "27236918",
"iss": "(6)",
"namespace": "pmid",
"pages": "p. 1077-1081.",
"source": "Am J Hum Genet",
"title": "Consideration of Cosegregation in the Pathogenicity Classification of Genomic Variants.",
"vol": "98",
"year": "2016"
},
{
"auths": [
"Wai HA",
"Lord J",
"et al."
],
"doiStr": "10.1038/s41436-020-0766-9",
"id": "32123317",
"iss": "(6)",
"namespace": "pmid",
"pages": "p. 1005-1014.",
"source": "Genet Med",
"title": "Blood RNA analysis can increase clinical diagnostic rate and resolve variants of uncertain significance.",
"vol": "22",
"year": "2020"
},
{
"auths": [
"Jaganathan K",
"Kyriazopoulou Panagiotopoulou S",
"et al."
],
"doiStr": "10.1016/j.cell.2018.12.015",
"id": "30661751",
"iss": "(3)",
"namespace": "pmid",
"pages": "p. 535-548.e24.",
"source": "Cell",
"title": "Predicting Splicing from Primary Sequence with Deep Learning.",
"vol": "176",
"year": "2019"
},
{
"id": "187f5e4a-1941-5c2d-9c9f-1dc999cc5454",
"namespace": "url",
"value": "https://www.diabetesgenes.org/mody-probability-calculator/"
},
{
"id": "7b8ee3e0-95c7-50ca-a251-415116c1a95b",
"namespace": "footnote",
"value": "Gloyn, et al. (2004). Glucokinase and the Regulation of Blood Sugar In Matschinsky FM & Magnuson MA (Eds), Glucokinase and Glycemic Disease: From Basics to Novel Therapeutics. (pp. 92-109). Karger. DOI:10.1159/000079009"
},
{
"auths": [
"Hattersley AT",
"Greeley SAW",
"et al."
],
"doiStr": "10.1111/pedi.12772",
"id": "30225972",
"iss": "",
"namespace": "pmid",
"pages": "p. 47-63.",
"source": "Pediatr Diabetes",
"title": "ISPAD Clinical Practice Consensus Guidelines 2018: The diagnosis and management of monogenic diabetes in children and adolescents.",
"vol": "19 Suppl 27",
"year": "2018"
},
{
"auths": [
"Pihoker C",
"Gilliam LK",
"et al."
],
"doiStr": "10.1210/jc.2013-1279",
"id": "23771925",
"iss": "(10)",
"namespace": "pmid",
"pages": "p. 4055-62.",
"source": "J Clin Endocrinol Metab",
"title": "Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth.",
"vol": "98",
"year": "2013"
},
{
"auths": [
"McDonald TJ",
"Colclough K",
"et al."
],
"doiStr": "10.1111/j.1464-5491.2011.03287.x",
"id": "21395678",
"iss": "(9)",
"namespace": "pmid",
"pages": "p. 1028-33.",
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"rev": "_i2oD0B----"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_PM1_nuclear_MRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
"label": "PM1",
"ns": "087",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable only to critical and well-established functional domains available in the supplementary table (P-loop \\[AA 20-27\\], SW1 \\[AA 35-50\\], SW2 \\[AA 67-74\\], no SAK). Not applicable to specific amino acid residues (see PM5).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324486",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324486",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oDz3K---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_PM3_nuclear_MRAS",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "087",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"This requires testing of parents (or offspring) to determine phase."
]
},
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324485",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324485",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oDz32---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_BS4_nuclear_MRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Lack of segregation in affected members of a family.",
"label": "BS4",
"ns": "087",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Requires only one informative meiosis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324480",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324480",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oDz4q---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_PM5_nuclear_MRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable for observed analogous residue positions in HRAS, KRAS, MRAS, NRAS, RIT1, and RRAS2. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
"label": "PM5",
"ns": "087",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥2 different \\[likely\\] pathogenic residues changes at the same codon observed in ≥5 probands.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 \\[likely\\] pathogenic residue change at the same codon.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324478",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324478",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oD0Dm---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_PS3_nuclear_MRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Approved assays are available in the supplemental materials.",
"label": "PS3",
"ns": "087",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Not Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Two or more different approved assays.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One approved assay.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324492",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324492",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oD0CG---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_BP7_nuclear_MRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"label": "BP7",
"ns": "087",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324490",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324490",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oDz06---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_PM6_nuclear_MRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PS2 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PM6",
"ns": "087",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 Points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324489",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324489",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oDz9a---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_PP2_nuclear_MRAS",
"additionalComments": "Not applicable because missense z score is <3.09 in gnomAD.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "087",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324482",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324482",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oDztS---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_BP4_nuclear_MRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≤0.3. For splicing variants: predicted outcome is negligible or does not match disease mechanism.",
"label": "BP4",
"ns": "087",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "For missense variants: REVEL ≤0.3.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324501",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324501",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oD0AG---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_BS1_nuclear_MRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "GnomAD filtering allele frequency ≥0.025%.",
"label": "BS1",
"ns": "087",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "GnomAD filtering allele frequency ≥0.025%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324493",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324493",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oDz8e---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_PP3_nuclear_MRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"label": "PP3",
"ns": "087",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324491",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324491",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oDzqm---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_PVS1_nuclear_MRAS",
"additionalComments": "Not applicable.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "087",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Not applicable",
"id": "0017",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324487",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324487",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oDzrm---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_PM2_nuclear_MRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "The variant must be absent from controls (gnomAD).",
"label": "PM2",
"ns": "087",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Population data for insertions/deletions may be poorly called by next-generation sequencing."
]
},
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The variant must be absent from controls (gnomAD).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324475",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324475",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oDzuG---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_PM4_nuclear_MRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"label": "PM4",
"ns": "087",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "No known repetitive areas in gene. Use as described.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324474",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324474",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oDzve---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_PS2_nuclear_MRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PM6 (see Reference 1) and phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS2",
"ns": "087",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 Points.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324498",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324498",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oDz6e---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_PP1_nuclear_MRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Segregation in more than one family is recommended.",
"label": "PP1",
"ns": "087",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥7 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥5 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"May be used as stronger evidence with increasing segregation data"
]
},
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥3 informative meioses.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324495",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324495",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oDzpe---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_BA1_nuclear_MRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "GnomAD filtering allele frequency ≥0.05%.",
"label": "BA1",
"ns": "087",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "GnomAD filtering allele frequency ≥0.05%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324488",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324488",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oDz2----"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_PP5_nuclear_MRAS",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "087",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324484",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324484",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oD0Cu---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_BP1_nuclear_MRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Truncating, LOF variant in a gene for which primarily missense, GOF variants are known to cause disease.",
"label": "BP1",
"ns": "087",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0075",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0205",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324481",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324481",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oDzxy---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_PS4_nuclear_MRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring for autosomal dominant cases with phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS4",
"ns": "087",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥5 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥3 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥1 points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324476",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324476",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oD0Ee---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_BP6_nuclear_MRAS",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "087",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324500",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324500",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oDzzG---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_PS1_nuclear_MRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"label": "PS1",
"ns": "087",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in _HRAS, KRAS, MRAS, NRAS, RIT1,_ and _RRAS2._",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324499",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324499",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oDzzu---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_PP4_nuclear_MRAS",
"additionalComments": "Not applicable, see PS4.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "087",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324497",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324497",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oDzwO---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_BS2_nuclear_MRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Strength adjustment using point-based scoring based on phenotypic specifications. Phenotypic specifications: based on healthy homozygote or heterozygote individuals, reduced points for apparently unaffected heterozygous individuals, applicable to parent or sibling samples during clinical family evaluations.",
"label": "BS2",
"ns": "087",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "\\-4 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "\\-1 Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324483",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324483",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oD0-u---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_BS3_nuclear_MRAS",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"label": "BS3",
"ns": "087",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324479",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324479",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oD0_O---"
},
{
"created": "2024-08-03T01:09:15.742Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "087_BP2_nuclear_MRAS",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"MRAS"
],
"geneType": "nuclear",
"instructionsToUse": "Points are awarded for an alternative molecular cause of a RASopathy in the same gene (and/or in conjunction with BP5) and the phenotype is consistent with expected severity of the RASopathy.",
"label": "BP2",
"ns": "087",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828324477",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828324477",
"modified": "2024-12-03T03:17:27.299Z",
"modifier": "RFWebb",
"rev": "_i2oDz52---"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0021060",
"lbl": "RASopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0021060"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/basis_in_disruption_of_process.yaml"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/disrupts_process.yaml"
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"modifier": "monicacsulit",
"rev": "_k7u31L6---"
},
{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
"_uniqueProp": "088_BP2_nuclear_RMRP",
"additionalComments": "Does not apply.\n",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "088",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0084",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407196",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407196",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
"rev": "_k7u31Pi---"
},
{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
"_uniqueProp": "088_BS4_nuclear_RMRP",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "088",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Can be applied without additional specifications. To apply the BS4 criteria, it is sufficient to have one affected family member without the segregation of the variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407195",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407195",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
"rev": "_k7u31PG---"
},
{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
"_uniqueProp": "088_BP7_nuclear_RMRP",
"additionalComments": "Does not apply.\n",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "088",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0079",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407194",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407194",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
"rev": "_k7u31Oe---"
},
{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
"_uniqueProp": "088_BP6_nuclear_RMRP",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "088",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407192",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407192",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
"rev": "_k7u31Na---"
},
{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
"_uniqueProp": "088_PVS1_nuclear_RMRP",
"additionalComments": "Does not apply.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "088",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Not applicable",
"id": "0017",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407217",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407217",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
"rev": "_k7u31WO---"
},
{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
"_uniqueProp": "088_BS3_nuclear_RMRP",
"additionalComments": "Does not apply.\n",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "088",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407213",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407213",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
"rev": "_k7u31US---"
},
{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
"_uniqueProp": "088_PM6_nuclear_RMRP",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"instructionsToUse": "The following guidelines should be used when determining the phenotypic consistency of each proband:\n\n* “Phenotype highly specific for gene” proband must meet PP4\\_Moderate criteria;\n* “Phenotype consistent with gene but not highly specific” proband must meet PP4 criteria;\n* “Phenotype consistent with gene but not highly specific and high genetic heterogeneity”: proband has been asserted to have a Cartilage-hair hypoplasia (CHH) phenotype but does not meet PP4 criteria;\n* Reduce points per proband by half if the phase is unconfirmed.",
"label": "PM6",
"ns": "088",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407210",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407210",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
"rev": "_k7u31TW---"
},
{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
"_uniqueProp": "088_PP5_nuclear_RMRP",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "088",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407206",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407206",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
"rev": "_k7u31Mu---"
},
{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
"_uniqueProp": "088_PS3_nuclear_RMRP",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"instructionsToUse": "PS3 may be applied when RT/PCR or RNA evidence indicates variant results in absent expression.",
"label": "PS3",
"ns": "088",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "PS3 may potentially be applied at the default strength level of strong for evidence from an animal model expressing the variant of interest and recapitulating the Cartilage-hair hypoplasia (CHH) phenotype. Animal models will be reviewed on a case-by-case basis by the VCEP to determine the appropriate strength level.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "PS3\\_Supporting can be applied based on an abnormal result in **at least** one approved _in vitro_ assay.\n\nApproved assay instances:\n\n* Endonucleolytic cleavage activity assay (mRNA cleavage activity smaller than 0.9) \n * Thiel et al., 2005 (PMID: 16252239)\n * Thiel et al., 2007 (PMID: 17701897)) **OR**\n* Luciferase reporter assay \n * Hermanns et al., 2005 (PMID: 16254002)) (luciferase activity higher than 7)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407203",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407203",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
"rev": "_k7u31KG---"
},
{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
"_uniqueProp": "088_PP3_nuclear_RMRP",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "088",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or\n\ngene product (conservation, evolutionary, splicing impact, etc).\n\n* Use RNAsnp to access SNP effects on local RNA secondary structure ([https://rth.dk/resources/rnasnp/](https://rth.dk/resources/rnasnp/))\n* Use only for Single Nucleotide Polymorphism inside the gene (do not use for promoter sequence)\n * Parameters utilized:\n * Input sequence: FASTA (Ensembl NR\\_\\_003051.3)\n * Insert SNP details\n * Mode: 1\n * Folding window: 100 nt\n * Measure: “Distance” option\n * Minimum length of the sequence interval: 50 \n * Cut-off the base pair probabilities: 0.01\n\nThe p-value threshold significance should be considered 0.1 according to Sabarinathan et al., 2013. PMID: 23315997. If the value is less than 0.1, apply PP3 as a supporting level of evidence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407199",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407199",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
"rev": "_k7u31Qy---"
},
{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
"_uniqueProp": "088_BP1_nuclear_RMRP",
"additionalComments": "Does not apply.\n",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "088",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407220",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407220",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
"rev": "_k7u31Xm---"
},
{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
"_uniqueProp": "088_PP2_nuclear_RMRP",
"additionalComments": "Does not apply.\n",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "088",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407219",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407219",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
"rev": "_k7u31XG---"
},
{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
"_uniqueProp": "088_PS2_nuclear_RMRP",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"instructionsToUse": "The following guidelines should be used when determining the phenotypic consistency of each proband:\n\n* “Phenotype highly specific for gene” proband must meet PP4\\_Moderate criteria;\n* “Phenotype consistent with gene but not highly specific” proband must meet PP4 criteria;\n* “Phenotype consistent with gene but not highly specific and high genetic heterogeneity”: proband has been asserted to have a Cartilage-hair hypoplasia (CHH) phenotype but does not meet PP4 criteria;\n* Reduce points per proband by half if the phase is unconfirmed.",
"label": "PS2",
"ns": "088",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below).",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407208",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407208",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
"rev": "_k7u31SW---"
},
{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
"_uniqueProp": "088_PM2_nuclear_RMRP",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "088",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Population data for insertions/deletions may be poorly called by next-generation sequencing."
]
},
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent in population databases (or at extremely low frequency if recessive).\n\n* Downgraded to PM2\\_Supporting.\n* gnomAD popmax filtering allele frequency \\<0.0000447\n\nThe applicability of PM2 to suspected founder variants with allele frequencies exceeding the PM2 threshold will be evaluated on a case-by-case basis by the VCEP.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407198",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407198",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
"rev": "_k7u31Qa---"
},
{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
"_uniqueProp": "088_BP4_nuclear_RMRP",
"additionalComments": "Does not apply.\n",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "088",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant."
]
},
"applicability": "Not applicable",
"id": "0080",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407215",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407215",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
"rev": "_k7u31VG---"
},
{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
"_uniqueProp": "088_PM4_nuclear_RMRP",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "088",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Defined to include insertions/duplications of 6 or more nucleotides increasing the distance between the TATA box (spanning n.-32 to n.-24) and the transcription start site (n.4).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407214",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407214",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
"rev": "_k7u31Uu---"
},
{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
"_uniqueProp": "088_BP5_nuclear_RMRP",
"additionalComments": "Does not apply.\n",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "088",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407202",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407202",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
"rev": "_k7u31JC---"
},
{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
"_uniqueProp": "088_PM5_nuclear_RMRP",
"additionalComments": "Does not apply.\n",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "088",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0056",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Not applicable",
"id": "008",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407200",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407200",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
"rev": "_k7u31RS---"
},
{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
"_uniqueProp": "088_PS4_nuclear_RMRP",
"additionalComments": "Does not apply.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "088",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
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"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
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},
"applicability": "Not applicable",
"id": "0053",
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"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0057",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0032",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
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},
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"ldhId": "295407197",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407197",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
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{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
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"_uniqueProp": "088_PP1_nuclear_RMRP",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"instructionsToUse": "Use ClinGen SVI recommendations for co-segregation criterion (PMID: 30311386) with the additional specification that unaffected individuals contributing to the calculated LOD score **(Attached document: PP1 specifications)** must be heterozygous carriers of one of the variants observed in the affected individuals (i.e. do not count wild-type/wild-type, individuals).",
"label": "PP1",
"ns": "088",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"May be used as stronger evidence with increasing segregation data"
]
},
"applicability": "Applicable",
"id": "0060",
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"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407216",
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"modified": "2026-01-20T16:25:38.168Z",
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"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PS1",
"ns": "088",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
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"completed": true
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"completed": true
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"id": "0240",
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"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
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"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Not Applicable",
"id": "0050",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
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"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\n\n* Downgraded to PS1\\_Supporting.\n* Applicable if a different nucleotide change at the same nucleotide position has been previously classified as pathogenic or likely pathogenic.\n* Cannot be applied if a different nucleotide change at the same position has been previously classified as benign or likely benign.\n* Previously established variants must be classified by SCID VCEP specifications for _RMRP_.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407207",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407207",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
"rev": "_k7u31R6---"
},
{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
"_uniqueProp": "088_BA1_nuclear_RMRP",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"RMRP"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "088",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
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"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Common in population databases.\n\n* gnomAD popmax filtering allele frequency >0.00400\n * Maximum credible population allele frequency threshold determined using Whiffin/Ware calculator ([https://www.cardiodb.org/allelefrequencyapp/](https://www.cardiodb.org/allelefrequencyapp/)) and the following parameters:\n * Prevalence: 1:5,000\n * Allelic heterogeneity: 1\n * Genetic heterogeneity: 0.04 (based on the contribution of _RMRP_ variants to total SCID in the PIDTC 6901 cohort reported in Dvorak et al., 2019 (PMID: 30193840, Table 1): 3.6%, rounded to 4%)\n * Penetrance: 50%\n * Use caution when applying BA1 based on allele frequencies derived from gnomAD exome sequencing given the reduced coverage of certain regions of _RMRP_. Ensure at least 20X read depth for allele frequencies derived from exome sequencing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407204",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407204",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
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{
"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "PP4 applicability and strength is determined by the total points accumulated by a single affected individual according to the list below and the following total point ranges:\n\n\\<1 point: PP4 not met\n\n1-\\<2 points: PP4\n\n≥2 points: PP4\\_Moderate\n\nDiagnostic criteria for SCID/Leaky SCID/Omenn syndrome met1 1pt\n\nSCID gene panel or exome/genome sequencing conducted (only applicable if genetic testing did not provide an alternative genetic explanation for SCID/Leaky SCID/Omenn syndrome phenotype) 0.5pt\n\nFamily history of SCID 0.5pt\n\nFamily history of CHH 1pt\n\nMetaphyseal dysplasia (disproportionate short stature + radiographic evidence) 1pt\n\nSkeletal dysplasia gene panel or WES/WGS conducted with no alternative genetic diagnosis 1pt \n\nHypotrichosis 0.5 pt\n\nMacrocytic, hypoplastic anemia 0.25pt\n\nHirschsprung disease or congenital megacolon 0.25pt\n\nT-cell lymphopenia\\* (see notes) 0.5 pt\n\n3-fold or more reduction of mutant RMRP RNA (or cDNA) expression in peripheral blood mononuclear cells 2 pts\n\n1The diagnostic criteria should follow the PIDTC 2022 specification, summarized [here](https://docs.google.com/document/d/1Ag2g8DhdxkFyX62Tw-4-kUBcULZvDQtXC0j3ol9kxiM/edit). \n\n\\*Notes: \n\n1. If maternal T cells are present, the T lymphocyte profile is still considered to be T- (autologous T cells are absent).\n2. Allocate 0.25 points for T-cell lymphopenia only in cases where the SCID diagnostic criteria are not applied. It is important to note that if the SCID diagnostic criteria were applied, the points for the T-B+NK+ lymphocyte subset profile cannot be considered.",
"label": "PP4",
"ns": "088",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
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}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0018",
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"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "A patient score of ≥2 points (see instructions below).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
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"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "A patient score of 1-\\<2 points (see instructions below).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407201",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407201",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
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"created": "2025-05-14T19:02:27.498Z",
"creator": "haleygarrett",
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BS1",
"ns": "088",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
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"Pilot Rules In Prep": {
"completed": true
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"strengthDescriptor": [
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"id": "0090",
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"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency is greater than expected for disorder. \n\n* gnomAD popmax filtering allele frequency >0.00089\n * Maximum credible population allele frequency threshold determined using Whiffin/Ware calculator ([https://www.cardiodb.org/allelefrequencyapp/](https://www.cardiodb.org/allelefrequencyapp/)) and the following parameters:\n * Prevalence: 1:50,000\n * Allelic heterogeneity: 1\n * Genetic heterogeneity: 0.04 (based on the contribution of _RMRP_ variants to total SCID in the PIDTC 6901 cohort reported in Dvorak et al., 2019 (PMID: 30193840, Table 1): 3.6%, rounded to 4%)\n * Penetrance: 100%\n\nUse caution when applying BS1 based on allele frequencies derived from gnomAD exome sequencing given the reduced coverage of certain regions of _RMRP_. Ensure at least 20X read depth for allele frequencies derived from exome sequencing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "295407193",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/295407193",
"modified": "2026-01-20T16:25:38.168Z",
"modifier": "monicacsulit",
"rev": "_k7u31O----"
}
],
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{
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},
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"synonyms": [
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"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Approved For Release": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
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{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
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},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**Missense variants:** Do not use computational prediction models for conservation, evolution, etc. _In silico_ splicing predictors should be used for presumed missense variants to reveal possible splicing effects.\n\n**Non-canonical splicing variants:** Multiple _in silico_ splicing predictors support a deleterious effect.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527150",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527150",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
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{
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "PM6_VeryStrong: ≥ 4 de novo scores. For curation of de novo score see Tables 1 and 2. ",
"label": "PM6",
"ns": "089",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
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},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2-3.5 _de novo_ scores. For curation of _de novo_ score see **Tables 1** and **2**.",
"type": "EvidenceLineStrength"
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{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1-1.5 _de novo_ scores. For curation of _de novo_ score see **Tables 1** and **2**.",
"type": "EvidenceLineStrength"
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{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
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"Strength"
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"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 _de novo_ scores. For curation of _de novo_ score see **Tables 1** and **2**.",
"type": "EvidenceLineStrength"
}
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"entType": "CriteriaCode",
"ldhId": "1553527148",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527148",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
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{
"entContent": {
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"additionalComments": "",
"applicability": "Not applicable",
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"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PP2",
"ns": "089",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527141",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527141",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5AqK--E"
},
{
"entContent": {
"_uniqueProp": "089_BP1_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "A number of assumed “missense” variants are in fact splice variants. At least several splice prediction tools should be used.\n\nRecommended splice prediction programs: see PS1",
"label": "BP1",
"ns": "089",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0075",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0205",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "BP1 is applicable to APC with the exception of missense variants located in the first 15-amino acid repeat of the β-catenin binding domain (codon 1021-1035).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527140",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527140",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5Apu--p"
},
{
"entContent": {
"_uniqueProp": "089_PM5_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "089",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The reported missense variant was determined to be Pathogenic according to the APC-specific modifications.\n\nThere are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other different missense variants at these positions meet PM5\\_supporting. No missense variant has been classified as Pathogenic based on current evidence. \n\nGrantham´s distance of the variant under assessment must have an equal or higher score than the reported variant \\[Reference 3\\].",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The reported missense variant was determined to be Likely Pathogenic according to the APC-specific modifications.\n\nThere are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other different missense variants at these positions meet PM5\\_supporting. No missense variant has been classified as Pathogenic based on current evidence. \n\nGrantham´s distance of the variant under assessment must have an equal or higher score than the reported variant \\[Reference 3\\].",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527137",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527137",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5Apu--o"
},
{
"entContent": {
"_uniqueProp": "089_PS4_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "089",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥ 16 phenotype points. For phenotype points curation see **Table 1**.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "4-15.5 phenotype points. For phenotype points curation see **Table 1**.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "2-3.5 phenotype points. For phenotype points curation see **Table 1**.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1-1.5 phenotype point. For phenotype points curation see **Table 1**.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527135",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527135",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5AqK--I"
},
{
"entContent": {
"_uniqueProp": "089_PM2_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "General recommendation: Use the total population from the non-cancer dataset from gnomAD (v2.1.1)",
"label": "PM2",
"ns": "089",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Approved For Release": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
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]
},
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Rare in controls, defined by an allele frequency ≤ 0.0003% (0.000003) if the allele count is > 1 OR by an allele frequency \\< 0.001% (0.00001) if the allele count is ≤ 1.",
"type": "EvidenceLineStrength"
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]
},
"entType": "CriteriaCode",
"ldhId": "1553527134",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527134",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5AqK--H"
},
{
"entContent": {
"_uniqueProp": "089_BP6_nuclear_APC",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "089",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527159",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527159",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5Apy--C"
},
{
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "089",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥ 4 _de novo_ scores. For curation of _de novo_ score see **Tables 1** and **2**.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2-3.5 _de novo_ scores. For curation of _de novo_ score see **Tables 1** and **2**.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1-1.5 _de novo_ score. For curation of _de novo_ score see **Tables 1** and **2**.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527157",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527157",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5AqC--H"
},
{
"entContent": {
"_uniqueProp": "089_BS1_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "General recommendation: Use the non-cancer dataset from gnomAD (v2.1.1)",
"label": "BS1",
"ns": "089",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "GnomAD Popmax Filtering Allele Frequency (AF) **≥ 0.001%** (0.00001).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527152",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527152",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5Ap2--g"
},
{
"entContent": {
"_uniqueProp": "089_BA1_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "General recommendation: Use the non-cancer dataset from gnomAD (v2.1.1)",
"label": "BA1",
"ns": "089",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "GnomAD Popmax Filtering Allele Frequency (AF) **≥ 0.1%** (0.001).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527147",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527147",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5Ap2--f"
},
{
"entContent": {
"_uniqueProp": "089_BS3_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "089",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "**RNA assay** of a synonymous or intronic variant in constitutional patient sample demonstrates no mRNA aberration\n\n**AND**\n\nbiallelic expression is shown and/or nonsense-mediated decay inhibition was used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "**RNA assay** of a synonymous or intronic variant in constitutional patient sample demonstrates no mRNA aberration, without demonstration of biallelic expression or use of nonsense-mediated decay inhibition\n\n**OR**\n\n**Protein assay** show retention of β-catenin regulated transcription activity comparable to wild-type (only for variants within the β-catenin binding domain, which refers to codons 959-2129 of _APC_, see PMID: 33348689)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527138",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527138",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5AqK--D"
},
{
"entContent": {
"_uniqueProp": "089_BP7_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "The use of BP7 with BP4 is allowed.\n\nRecommended splice prediction programs: see PS1",
"label": "BP7",
"ns": "089",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) or intronic variant at or beyond +7/–21 for which multiple splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527149",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527149",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5Apy--A"
},
{
"entContent": {
"_uniqueProp": "089_BS2_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "The non-cancer dataset from gnomAD (v2.1.1) cannot be used for ”heterozygous healthy individuals”, because of the limited phenotype information and since it is usually already used for BA1/BS1. However, the non-cancer dataset from gnomAD (v2.1.1) can be used to search for homozygous individuals.",
"label": "BS2",
"ns": "089",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ 10 points for healthy individuals **OR** ≥ 2 times in homozygous state.\n\nA **healthy individual** worth 1 point is defined by:\n\nAge ≥ 50 years \n\\+ Less than 5 adenomatous polyps in a colonoscopy \n\\+ Absence of features in Table 1\n\n**OR**\n\nAge ≥ 50 years \n\\+ Colorectal cancer/polyposis was not the indication for testing\n\nA **healthy individual** worth 0.5 points is defined by keywords including control, non-cancer, normal, unaffected population.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ 3 points for healthy individuals.\n\nA **healthy individual** worth 1 point is defined by:\n\nAge ≥ 50 years \n\\+ Less than 5 adenomatous polyps in a colonoscopy \n\\+ Absence of features in Table 1\n\n**OR**\n\nAge ≥ 50 years \n\\+ Colorectal cancer/polyposis was not the indication for testing\n\nA **healthy individual** worth 0.5 points is defined by keywords including control, non-cancer, normal, unaffected population.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527142",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527142",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5AqC--F"
},
{
"entContent": {
"_uniqueProp": "089_BP2_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "089",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed _in trans_ with a (Likely) Pathogenic _APC_ variant **OR** ≥ 3 times in an unknown phase with different (Likely) Pathogenic _APC_ variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527136",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527136",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5AqC--E"
},
{
"entContent": {
"_uniqueProp": "089_PS1_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "Recommended splice prediction programs:\n\n* SpliceAI: https://spliceailookup.broadinstitute.org/,\n* MaxEntScan : http://hollywood.mit.edu/burgelab/maxent/Xmaxentscan_scoreseq.html for 5’splice sites and http://hollywood.mit.edu/burgelab/maxent/Xmaxentscan_scoreseq_acc.html for 3’splice sites \n* VarSeak: [https://varseak.bio/](https://varseak.bio/)\n\nFor SpliceAI a loss of the native splice site is considered for scores between 0.8 and 1. A gain of a cryptic splice site is considered strong for scores between 0.8 and 1 and as moderate for a score between 0.2 and 0.8. \n\nFor MaxEntScan predictions a score of >3 is required for credibility of a native site prediction and a threshold of -15% is considered for native splice site loss (Houdayer et al. 2012, PMID 22505045). A score >3 is used as a conservative measure for cryptic site use in the context of native site loss.",
"label": "PS1",
"ns": "089",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The previously established variant was classified as Pathogenic according to the APC-specific modifications.\n\nThis criterion can be applied to both missense and splice variants in _APC_. \n\n**Missense variants:** when the variant under assessment results in the same amino acid change as previously established Pathogenic variant(s). \n\nThere are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other variants leading to the same missense change at these positions meet PS1\\_Moderate. No missense variant has been classified as Pathogenic based on current evidence. \n\n**Splice variants**: when the variant under assessment affects splicing at the same nucleotide as a previously established Pathogenic variant. The splice prediction must be above defined thresholds (see instructions) or similar to the previously established variant by multiple _in silico_ predictors.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The previously established variant was classified as Likely Pathogenic according to the APC-specific modifications.\n\nThis criterion can be applied to both missense and splice variants in _APC_. \n\n**Missense variants:** when the variant under assessment results in the same amino acid change as previously established Likely Pathogenic variant(s). \n\nThere are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other variants leading to the same missense change at these positions meet PS1\\_Moderate. No missense variant has been classified as Pathogenic based on current evidence. \n\n**Splice variants**: when the variant under assessment affects splicing at the same nucleotide as a previously established Likely Pathogenic variant. The splice prediction must be above defined thresholds (see instructions) or similar to the previously established variant by multiple _in silico_ predictors.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527158",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527158",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5Apy--B"
},
{
"entContent": {
"_uniqueProp": "089_BP5_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "(Likely) Pathogenic variant in another adenomatous polyposis gene (heterozygous variants in _POLD1_ or _POLE_; biallelic variants in _MUTYH, NTHL1_ or _MSH3_; in patients with onset in childhood / adolescence: biallelic variants in _MLH1, MSH2, MSH6_ or _PMS2_). This rule is only applicable when a colorectal polyposis phenotype is present.",
"label": "BP5",
"ns": "089",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Only applicable for an alternate genetic basis of the colorectal polyposis phenotype.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527153",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527153",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5AqK--J"
},
{
"entContent": {
"_uniqueProp": "089_PM3_nuclear_APC",
"additionalComments": "",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "089",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
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]
},
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
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"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
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},
{
"entContent": {
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"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
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"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "089",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
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],
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"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527143",
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"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
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},
{
"entContent": {
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"applicability": "Applicable",
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"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "Recommended splice prediction programs: see PS1",
"label": "BP4",
"ns": "089",
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"applicability": "Not applicable",
"id": "0215",
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"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0213",
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"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"id": "0066",
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"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"id": "0214",
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"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
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},
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "**Missense variants:** BP4 is not applicable.\n\n**Synonymous (silent) or intronic variants**: Multiple in silico splicing predictors suggest no impact on gene or gene product.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527160",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527160",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
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{
"entContent": {
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"applicability": "Not applicable",
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"gene": [
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"geneType": "nuclear",
"label": "PP4",
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"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
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"completed": true
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"strength": "Stand Alone",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
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]
},
"entType": "CriteriaCode",
"ldhId": "1553527156",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527156",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5AqK--L"
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{
"entContent": {
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"additionalComments": "",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "089",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
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"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527155",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527155",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5Ap2--i"
},
{
"entContent": {
"_uniqueProp": "089_PP1_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "Affected individuals exhibit at least 0.5 point of the phenotype point system (see Table 1), for relatives also ≥ 10 or “multiple” colorectal adenomas are considered as 0.5 point.\n\nOnly genotype and phenotype positive individuals and obligate carriers with phenotype are counted (note: carriers who have received chemoprevention and may have a milder phenotype can also be counted).",
"label": "PP1",
"ns": "089",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Variant segregates in ≥ 7 meioses in ≥ 2 families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant segregates in 5-6 meioses in ≥ 1 family.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"May be used as stronger evidence with increasing segregation data"
]
},
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Variant segregates in 3-4 meioses in ≥ 1 family.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527154",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527154",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5Ap2--h"
},
{
"entContent": {
"_uniqueProp": "089_PS3_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "089",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "**RNA assays** show\n\n1. a premature stop codon \n OR\n2. inframe skipping of exon 13 or 14\n\n**AND** the absence of full-length transcript.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
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]
},
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**RNA assays** show\n\n1. a premature stop codon \n **OR**\n2. inframe skipping of exon 13 or 14\n\n**AND** \\< 10% of full-length transcript.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**RNA assays** show \n\n1. a premature stop codon AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides \n **OR**\n2. inframe skipping of exon 13 or 14 AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides \n **OR**\n3. other inframe skipping AND absent or \\< 10% full-length transcript.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**RNA assays** show \n\n1. inframe skipping of exons other than exon 13 or 14 AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides \n **OR**\n2. over-expression of an alternative transcript (exons 10, 11 or 15)\n\n**Protein assays** show\n\nIncreased β-catenin regulated transcription activity and/or decreased binding to β-catenin by surface plasmon resonance (only for variants within the β-catenin binding domain, which refers to codons 959-2129 of _APC_) \\[Reference 2\\].",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527151",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527151",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5AqK--I"
},
{
"entContent": {
"_uniqueProp": "089_PVS1_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PVS1",
"ns": "089",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
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"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (**Figure 1**) \\[Reference 1\\].",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (**Figure 1**) \\[Reference 1\\].",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (**Figure 1**) \\[Reference 1\\].",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (**Figure 1**) \\[Reference 1\\].",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527146",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527146",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5AqK--H"
},
{
"entContent": {
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"additionalComments": "",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PM1",
"ns": "089",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527145",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1553527145",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_inf5AqK--F"
},
{
"entContent": {
"_uniqueProp": "089_BS4_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "089",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
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"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use SpliceAI for splicing predictor with a cutoff score of 0.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988624",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988624",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Atq--W"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_BA1_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "090",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Appropriate to use for variants with a Popmax MAF of >0.1 in gnomAD.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988621",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988621",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Ati--G"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_PVS1_nuclear_VWF",
"additionalComments": "VWD type 2N is caused by qualitative protein defects and not null variants.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "090",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988619",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988619",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Atm--T"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_PS3_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "090",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Either (1) in a transgenic animal model, must demonstrate minimal to no function. (2) a Factor VIII binding assay using recombinant vWF resulting in decreased binding compared to WT.\n\nSee attached spreadsheet for examples of approved assay instances to use for this rule code. There are no universal thresholds for these assays; however, the relevant results should be described as clinically significant if assays were performed in a clinical laboratory or statistically significant if pertaining to research findings.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988615",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988615",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Atq--U"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_BS1_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "090",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Appropriate to use for variants with a Popmax MAF of >0.01 in gnomAD.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988602",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988602",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Ate-_M"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_PM2_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "090",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use code for variants with a popmax MAF of \\<0.005 in gnomAD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988627",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988627",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Ati--J"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_PP1_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "090",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Appropriate to use when a proband has three affected family members.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Appropriate to use when a proband has two affected family members.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Appropriate to use when a proband has one affected family member.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988617",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988617",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Ati--D"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_BP4_nuclear_VWF",
"additionalComments": "Not using at this time but will note CADD and SpliceAI scores and consider use during pilot testing. ",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "090",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use for missense variants that have a REVEL score of less than or equal to 0.290 AND SpliceAI cutoff of \\<0.1. Use SpliceAI cutoff of \\<0.1 for other variant types.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988616",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988616",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Ati--B"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_PS2_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"instructionsToUse": "Please note that presence of a second _VWF_ variant is required to use this rule code.",
"label": "PS2",
"ns": "090",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use proposed SVI point recommendations for **“Phenotype consistent with gene but not highly specific”** if the proband meets **PP4 criteria**. Use **“Phenotype highly specific for gene”** phenotype consistency if the proband meets **PP4\\_Moderate criteria**. See Table 1 attached. Required 4 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use proposed SVI point recommendations for **“Phenotype consistent with gene but not highly specific”** if the proband meets **PP4 criteria**. Use **“Phenotype highly specific for gene”** phenotype consistency if the proband meets **PP4\\_Moderate criteria**. See Table 1 attached. Required 2 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use proposed SVI point recommendations for **“Phenotype consistent with gene but not highly specific”** if the proband meets **PP4 criteria**. Use **“Phenotype highly specific for gene”** phenotype consistency if the proband meets **PP4\\_Moderate criteria**. See Table 1 attached. Required 1 point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use proposed SVI point recommendations for **“Phenotype consistent with gene but not highly specific”** if the proband meets **PP4 criteria**. If the proband meets PP4\\_Moderate criteria, use a moderate or higher evidence weight (see above). See Table 1 attached. Required 0.5 point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988613",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988613",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Ati--_"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_BS4_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "090",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Appropriate to use when two or more relatives have the phenotype consistent with VWD type 2 without harboring the variant identified in other affected family members. Additionally, there is not another established cause of type 2 VWD (e.g. - there are not multiple type 2 VWD diagnoses) segregating in the family.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Appropriate to use when only one relative has the phenotype consistent with VWD type 2 without harboring the variant identified in other affected family members. Additionally, there is not another established cause of type 2 VWD (e.g. - there are not multiple type 2 VWD diagnoses) segregating in the family.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988609",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988609",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Ate-_Q"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_PP5_nuclear_VWF",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"VWF"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "090",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988629",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988629",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Ati-_A"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_BP6_nuclear_VWF",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"VWF"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "090",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988628",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988628",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Ati--L"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_PM1_nuclear_VWF",
"additionalComments": "Rule does not apply due to benign variation being present throughout the gene.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "090",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988626",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988626",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Atq--X"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_PP4_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "090",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The patient must have a clinical phenotype of excessive mucocutaneous bleeding and required laboratory values to use the PP4 rule code, including a low factor VIII activity level and evidence of decreased VWF:FVIII binding.\n\nAdditional consistent information should be noted but is not required, including either normal or low VWF:Ag, normal high molecular weight multimers, and sequencing with duplication/deletion analysis of the F8 gene.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988625",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988625",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Ata--z"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_PP3_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "090",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Appropriate to use for missense variants that have a REVEL score of greater or equal to 0.644 OR a SpliceAI score suggestive of a splicing defect (greater or equal to 0.5).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988623",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988623",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Ati--I"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_BP3_nuclear_VWF",
"additionalComments": "There are no known repetitive regions in the VWF gene without a known function. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "090",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988614",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988614",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Ati-_-"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_BP2_nuclear_VWF",
"additionalComments": "Do not use due to potential of variant being associated with VWD 2N (recessive disease).",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "090",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0084",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988612",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988612",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Ata--x"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_PM5_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "090",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use code when previously reported variant reaches a pathogenic classification using the VWD Type 2 rule specifications. Previously reported variant can be associated with a different type of VWD.\n\nCode may also be applied when two previously reported variants reach a likely pathogenic classification using the VWD Type 2 rule specifications. Previously reported variants can be associated with a different type of VWD.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use code when previously reported variant reaches a likely pathogenic classification using the VWD Type 2 rule specifications. Previously reported variant can be associated with a different type of VWD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988607",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988607",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Ati--8"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_PP2_nuclear_VWF",
"additionalComments": "Not applicable due to presence of benign variation throughout the VWF gene. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "090",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988622",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988622",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Ati-__"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_PS4_nuclear_VWF",
"additionalComments": "Use PM3 for proband counting.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"instructionsToUse": "Do not apply this code for variants that meet BS1 or BA1 criteria. Do not count proband used for PP4 in this code's proband count.",
"label": "PS4",
"ns": "090",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988618",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988618",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Atq--V"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_BP1_nuclear_VWF",
"additionalComments": "The VWF gene is not constrained for missense variation (gnomAD). ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "090",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988608",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988608",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Ata--v"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_BS3_nuclear_VWF",
"additionalComments": "There are no available assays that can clearly and dependably show no damaging protein effects. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "090",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988606",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988606",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Ate-_O"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_PM4_nuclear_VWF",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "090",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use with no specification.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988605",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988605",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Atm--R"
},
{
"created": "2024-07-09T13:43:01.455Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "090_PM3_nuclear_VWF",
"additionalComments": "These are dominant conditions, so this rule code does not apply.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"VWF"
],
"geneType": "nuclear",
"instructionsToUse": "May be applied when the variants on both alleles have MAFs below the BS1 threshold.",
"label": "PM3",
"ns": "090",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use SVI recommended point system for this code for probands with a VWD type 2N diagnosis. Total of 4 points required.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use SVI recommended point system for this code for probands with a VWD type 2N diagnosis. Total of 2 points required.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use SVI recommended point system for this code for probands with a VWD type 2N diagnosis. Total of 1 point required.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use SVI recommended point system for this code for probands with a VWD type 2N diagnosis. Total of 0.5 points required.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1807988603",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1807988603",
"modified": "2024-07-09T13:43:01.455Z",
"modifier": "leekristy",
"rev": "_inf5Atm--P"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0015631",
"lbl": "von Willebrand disease type 2N",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1091176565"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/266187"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/359732009"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1282975"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C131689"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_166093"
}
],
"definition": {
"val": "Type 2N von Willebrand disease (type 2N VWD) is a subtype of type 2 VWD characterized by a bleeding disorder associated with a marked decrease in the affinity of the Willebrand factor (von Willebrand factor; VWF) for factor VIII (FVIII).",
"xrefs": [
"Orphanet:166093"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_subtype_of_a_disorder",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "von Willebrand disease Normandy variant",
"xrefs": [
"NCIT:C131689"
]
},
{
"pred": "hasExactSynonym",
"val": "von Willebrand disease, type 2N",
"xrefs": [
"NCIT:C131689"
]
}
],
"xrefs": [
{
"val": "GARD:17024"
},
{
"val": "MEDGEN:266187"
},
{
"val": "NCIT:C131689"
},
{
"val": "Orphanet:166093"
},
{
"val": "SCTID:359732009"
},
{
"val": "UMLS:C1282975"
},
{
"val": "icd11.foundation:1091176565"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0015631",
"name": "von Willebrand disease type 2N"
},
"entId": "MONDO:0015631",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0015631",
"entType": "Disease",
"ldhId": "467885573",
"ldhIri": "https://cspec.genome.network/cspec/Disease/id/467885573",
"modified": "2025-10-07T16:14:23.253Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7xzGC---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056967233798100,
"agr": "HGNC:12726",
"ccds_id": [
"CCDS8539"
],
"date_approved_reserved": "1986-01-01",
"date_modified": "2021-05-26",
"ensembl_gene_id": "ENSG00000110799",
"entrez_id": "7450",
"gene_group": [
"Receptor ligands"
],
"gene_group_id": [
542
],
"hgnc_id": "HGNC:12726",
"iuphar": "ligandId:6755",
"location": "12p13.31",
"location_sortable": "12p13.31",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Von Willebrand Factor Database|http://vwf.group.shef.ac.uk/",
"LRG_587|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_587.xml"
],
"mane_select": [
"ENST00000261405.10",
"NM_000552.5"
],
"mgd_id": [
"MGI:98941"
],
"name": "von Willebrand factor",
"omim_id": [
"613160"
],
"orphanet": 120487,
"prev_symbol": [
"F8VWF"
],
"pubmed_id": [
2251280
],
"refseq_accession": [
"NM_000552"
],
"rgd_id": [
"RGD:621759"
],
"status": "Approved",
"symbol": "VWF",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001qnn.2",
"uniprot_ids": [
"P04275"
],
"uuid": "d06e9de2-4d03-4710-8a4f-542fcb6e4074",
"vega_id": "OTTHUMG00000168265"
}
},
"entId": "VWF",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:12726",
"entType": "Gene",
"ldhId": "467863817",
"ldhIri": "https://cspec.genome.network/cspec/Gene/id/467863817",
"modified": "2021-10-14T11:37:15.362Z",
"modifier": "genbadmin",
"rev": "_inf5COC--f"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "090_nuclear_VWF",
"geneType": "nuclear",
"generalComments": "Applying VWD type 2 variant curation guidance is complex. If you are unsure how to apply these rule specifications after reading guidance materials provided below, it may be best not to use these guidelines. Alternatively, you are welcome to submit variants for the ClinGen VWD VCEP to curate for you.",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal recessive inheritance",
"preferredMondoId": "MONDO:0015631",
"preferredTitle": "von Willebrand disease type 2N"
}
],
"gene": "VWF",
"preferredTranscript": "NM_000552.5"
}
],
"ns": "090",
"references": [],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Very Strong",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PM3_Strong",
"PP1_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Very Strong",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PM3",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Very Strong",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PM3",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Very Strong",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PM3_Strong",
"PP1_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PM3_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PM3",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PM3_Strong",
"PP1_Strong"
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],
"condition": "==1",
"label": "Rule10, Condition2",
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],
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"rule": "Rule10"
},
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"conditions": [
{
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"PS2",
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"condition": "==1",
"label": "Rule11, Condition2",
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}
],
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"rule": "Rule11"
},
{
"conditions": [
{
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"PS2",
"PS3",
"PM3_Strong",
"PP1_Strong"
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"PM5_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
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"partitionPath": "Pathogenic.Supporting"
}
],
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"rule": "Rule12"
},
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"PS2_Moderate",
"PM3",
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"PM5",
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"PP4_Moderate"
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"PM3",
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"PM5",
"PP1_Moderate",
"PP4_Moderate"
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"condition": "==2",
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{
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"PM2_Supporting",
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"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule14, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
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"PP1_Moderate",
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"condition": "==1",
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],
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"rule": "Rule15"
},
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"condition": "==2",
"label": "Rule20, Condition2",
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"BP7"
],
"condition": "==1",
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"partitionPath": "Benign.Supporting"
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],
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},
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"conditions": [
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"applicableCriteriaCodes": [
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"BP4",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
}
]
}
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"ldhId": "1529372875",
"ldhIri": "https://cspec.genome.network/cspec/RuleSet/id/1529372875",
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"shortTitle": "Lysosomal Storage Disorders Specification",
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},
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},
{
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],
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],
"title": "ClinGen Lysosomal Diseases Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for IDUA Version 1.2.0",
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"versioned": true
},
"entId": "GN091",
"entType": "SequenceVariantInterpretation",
"ld": {
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{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
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"additionalComments": "",
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"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BS4",
"ns": "091",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
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"text": "",
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"text": "",
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"instructionsToUse": "",
"specificationType": [
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],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Non-segregation with disease in a family i.e. variant is absent in an affected individual.",
"type": "EvidenceLineStrength"
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{
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"text": "",
"type": "EvidenceLineStrength"
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{
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"instructionsToUse": "",
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"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
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"defaultStrength": "Pathogenic Strong",
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],
"geneType": "nuclear",
"instructionsToUse": "Note: De novo variants are rarely reported in IDUA.",
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"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
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],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Variant occurs de novo in an affected individual, and the biological relationship of the parent without the variant is confirmed e.g. if the father is not heterozygous for an IDUA variant that has been detected in the patient, paternity must be confirmed.",
"type": "EvidenceLineStrength"
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{
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],
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"strengthSepioID": "SEPIO:0000216",
"text": "Variant occurs de novo in an affected individual, and the biological relationship of the parent without the variant is not confirmed.",
"type": "EvidenceLineStrength"
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"text": "",
"type": "EvidenceLineStrength"
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"applicability": "Not Applicable for this VCEP",
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"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
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"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
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"source": "PubMed",
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"strengthDescriptor": [
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"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
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"strength": "Very Strong",
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"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
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"type": "EvidenceLineStrength"
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{
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"strength": "Supporting",
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"type": "EvidenceLineStrength"
},
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"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
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"modified": "2026-01-23T15:06:26.324Z",
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{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
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"applicability": "Applicable",
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"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP4",
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"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "3 or more of the following criteria are met:\n\n* Deficient IDUA activity, within the affected range (usually non-detectable or stated to be in the affected range by lab) in fibroblasts, leukocytes, or plasma.\n * Do not count if one or more pseudodeficiency variants are reported to be present, or if the result was obtained on newborn screen without confirmatory enzyme testing.\n* Enzyme replacement therapy results in a significant reduction in urine GAGs (either total, or dermatan or heparan sulfate).\n* Elevated urinary and/or blood GAGs expressed as either total GAGs, specific GAG (heparan sulfate, dermatan sulfate, or endogenous biomarker) stated to be consistent with MPS I. \n* An individual with clinical features specific to MPS I; At minimum at least 2 of the following: dysostosis multiplex, hepatosplenomegaly, arthropathy, corneal involvement, valvular thickening; AND/OR case reported within the context of a larger clinically-diagnosed MPS I cohort, when published by groups with demonstrated experience (as determined at the discretion of the VCEP) in lysosomal disorders and the clinical care of affected individuals. When detailed clinical information is limited, confidence in the phenotypic classification is strengthened when the report originates from groups with established familiarity in the diagnosis and longitudinal management of MPS I.\n* Bone marrow transplant results in a significant reduction in urine GAGs (either total, or dermatan or heparan sulfate).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "2 of the following criteria are met:\n\n* Deficient IDUA activity, within the affected range (usually non-detectable or stated to be in the affected range by lab) in fibroblasts, leukocytes, or plasma.\n * Do not count if one or more pseudodeficiency variants are reported to be present, or if the result was obtained on newborn screen without confirmatory enzyme testing.\n* Enzyme replacement therapy results in a significant reduction in urine GAGs (either total, or dermatan or heparan sulfate).\n* Elevated urinary and/or blood GAGs expressed as either total GAGs, specific GAG (heparan sulfate, dermatan sulfate, or endogenous biomarker) stated to be consistent with MPS I.\n* An individual with clinical features specific to MPS I; At minimum at least 2 of the following: dysostosis multiplex, hepatosplenomegaly, arthropathy, corneal involvement, valvular thickening; AND/OR case reported within the context of a larger clinically-diagnosed MPS I cohort, when published by groups with demonstrated experience (as determined at the discretion of the VCEP) in lysosomal disorders and the clinical care of affected individuals. When detailed clinical information is limited, confidence in the phenotypic classification is strengthened when the report originates from groups with established familiarity in the diagnosis and longitudinal management of MPS I.\n* Bone marrow transplant results in a significant reduction in urine GAGs (either total, or dermatan or heparan sulfate).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611458",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611458",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZqa---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_PP1_nuclear_IDUA",
"additionalComments": "Sibships large enough to meet this criterion are extremely rare. In addition, because IDUA is the only gene involved in MPS 1, all patients are expected to be bi-allelic, regardless of whether the pathogenic variants can be, or have been, detected. A variant under assessment may not be the true pathogenic variant but instead in linkage disequilibrium with an unidentified pathogenic variant. For this reason, this criterion does not facilitate assessment of pathogenicity.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"instructionsToUse": "The combination of strengths for PP1 and PP4 MUST NOT exceed strong (2 x moderate, i.e. 4 points using Bayesian system) if cases are also being counted as probands under PM3.\n\nCounting segregations:\n\n* Do not count probands as a segregation.\n* Affected segregations = # affected individuals in the family with the variants minus 1.\n* Affected segregations are defined as affected family members (typically siblings) who harbor the variant in question and a second variant on the remaining allele.\n* Unaffected segregations are defined as unaffected family members, typically siblings, who are at risk to inherit the two variants (or one variant in homozygosity) identified in the proband. These individuals should be either homozygous normal or heterozygous for only one variant.\n* Unaffected, carrier parents DO NOT count as unaffected segregations.",
"label": "PP1",
"ns": "091",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See Appendix 5 for points system and guidance (based on PMID: 38103548).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "See Appendix 5 for points system and guidance (based on PMID: 38103548).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611453",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611453",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZ0O---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_BS1_nuclear_IDUA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"instructionsToUse": "Variants meeting only BS1 will be classified as likely benign.",
"label": "BS1",
"ns": "091",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Any variant with Grpmax >0.0025 in the most recent version of gnomAD (95% confidence interval, lower bound) (version # will be stated in the written summary).\n\nBS1 minor allele frequency cut-off calculated using [http://cardiodb.org/allelefrequencyapp](http://cardiodb.org/allelefrequencyapp) with prevalence = 1 in 40,000 (PMID: 33208168), genetic heterogeneity = 1.0 (IDUA is the only gene known to cause MPS1), allelic heterogeneity = ~0.5 (frequency of the most common known pathogenic variants in patients with MPS1 (PMID: 28595941, 29393969), and penetrance = 1.0.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611490",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611490",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZ7u---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_BS2_nuclear_IDUA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "091",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "BS2 can be applied if there is clear documentation that an individual of any age is either homozygous for the variant, or has the variant confirmed in trans with a pathogenic or likely pathogenic variant and has IDUA activity in the unaffected range as documented by standard diagnostic laboratory-based activity determination. Values for IDUA activity and the reference range for the laboratory must be provided.\n\nNote: Patients with late onset MPS1 can present late in life (5th\\-6th decade), can have mild symptoms, and may remain undiagnosed. Therefore, it is possible that individuals who are homozygous for hypomorphic IDUA variants could be present in population databases.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611489",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611489",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZ7C---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_PS4_nuclear_IDUA",
"additionalComments": "There are no case-control studies for MPS1. As this is a recessive disorder, the prevalence of the variant in affected individuals may not be increased compared to controls (who could be heterozygous carriers). The number of patients with the variant will be addressed by the PM3 evidence code.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "091",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0053",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0057",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0032",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611483",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611483",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZ3i---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_PM4_nuclear_IDUA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"instructionsToUse": "For in-frame deletions of one or more exons, use PVS1.
",
"label": "PM4",
"ns": "091",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Stop loss variants, and in frame deletion/insertions of two or more amino acids but less than one exon.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "In frame deletion/insertion of one amino acid.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611477",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611477",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZwG---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_BP2_nuclear_IDUA",
"additionalComments": "",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "091",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611473",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611473",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZvG---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_BA1_nuclear_IDUA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "091",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Any variant with Grpmax >0.005 in the most recent version of gnomAD (95% confidence interval, lower bound) (version # will be stated in the written summary)\n\nBA1 minor allele frequency cut-off calculated using [http://cardiodb.org/allelefrequencyapp](http://cardiodb.org/allelefrequencyapp) with prevalence = 1 in 40,000 (PMID: 33208168), genetic heterogeneity = 1.0 (IDUA is the only gene known to cause MPS1), allelic heterogeneity = 1.0, and penetrance = 1.0.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611459",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611459",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZs----"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_PM5_nuclear_IDUA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"instructionsToUse": "The classification of the other variant must be made following the Lysosomal Diseases VCEP specifications. To avoid circularity, the classification of the other variant should not use evidence from the variant being interrogated. If there is a question as to whether PM5 should be applied to variant A or variant B, use the classification of the variant with a greater level of evidence to support the classification of the variant with less evidence. \nThere is no splicing impact for either variant, shown by splicing assay or computational predictors (SpliceAI ≤0.1).",
"label": "PM5",
"ns": "091",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n\nStop loss variant if another stop loss variant has been determined to be pathogenic.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense change at an amino acid residue where a different missense change determined to be likely pathogenic has been seen before.\n\nStop loss variant if another stop loss variant has been determined to be likely pathogenic.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611488",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611488",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZ6m---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_PS1_nuclear_IDUA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"instructionsToUse": "The classification of the other variant must be made following the Lysosomal Diseases VCEP specifications. To avoid circularity, the classification of the other variant should not use evidence from the variant being interrogated. If there is a question as to whether PS1 should be applied to variant A or variant B, use the classification of the variant with a greater level of evidence to support the classification of the variant with less evidence. \nWhen applying PS1 for amino acid changes, there should be no splicing impact for either variant, shown by splicing assay or computational predictors (SpliceAI \\<0.1).",
"label": "PS1",
"ns": "091",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.Splice region variants following Table 3 in Walker et al (PMID: 37352859).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Same amino acid change as a previously established likely pathogenic variant regardless of nucleotide change. Splice region variants following Table 3 in Walker et al (PMID: 37352859).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Splice region variants following Table 3 in Walker et al (PMID: 37352859).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611486",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611486",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZ5q---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_PP3_nuclear_IDUA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"instructionsToUse": "We note that a publication on the use of in silico predictors for IDUA reported specificity of 88% and sensitivity of 75% for REVEL, using a 0.75 cutoff to create a binary classification (PMID: 34746235). REVEL performed well, although some other predictors, including BaysDel, had better sensitivity, specificity, and accuracy. We have decided to continue using REVEL and to follow the SVI guidance (Pejaver et al, PMID: 3641399), due to the ease of use of this predictor and the ability to apply weight of evidence based on score.",
"label": "PP3",
"ns": "091",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Any missense changes with a REVEL score >0.773 will meet PP3\\_Moderate (Based on Pejaver et al, PMID: 3641399; Note that the VCEP has chosen not to apply PP3 at strong).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Any missense changes with a REVEL score between 0.644 - 0.773 will meet PP3 (Pejaver et al., PMID: 3641399)\n* For in frame insertions and deletions, use Mutation Taster ([http://www.mutationtaster.org/](http://www.mutationtaster.org/) ; count if “disease-causing”), and MutPred-Indel ([https://mutpred2.mutdb.org/mutpredindel/](https://mutpred2.mutdb.org/mutpredindel/) ; score >0.5 for “pathogenic”). Apply PP3 if both predictors indicate that the variant is deleterious.\n* For non-canonical splice site variants (e.g., +3, -3), use SpliceAI ([https://spliceailookup.broadinstitute.org/](https://spliceailookup.broadinstitute.org/) ). A score of >0.2 is taken to indicate disruption of the splice site allowing PP3 to be applied (based on Walker et al, PMID: 37352859). Evidence for use of a cryptic splice site and the impact on the gene product should also be assessed. PP3 for splicing variants will be applied only in the absence of functional (RNA analysis) data.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611481",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611481",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZ2W---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_BP7_nuclear_IDUA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"instructionsToUse": "If a variant meets BP7, BP4 can also be applied. ",
"label": "BP7",
"ns": "091",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Experimental evidence (RT-PCR, RNA Seq, minigene) shows that the variant does not impact splicing. BP7\\_Strong (RNA) will be used only under strict circumstances in which it is clear that the allele with the variant is expressed at the normal level to avoid counting a “normal” result because the allele with the variant is absent due to nonsense-mediated decay (Walker et al, PMID: 37352859).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "BP7 can be applied if the variant is synonymous, unless the variant is in the first nucleotide or last three nucleotides of an exon, AND BP4 is met i.e. SpliceAI predicts no impact on splicing (score ≤ 0.10)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611480",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611480",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZ1m---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_PM1_nuclear_IDUA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "091",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/1856189/"
}
],
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Studies on functional domains (Bie et al, 2013, PMID: 24036510; Maita et al, 2013, PMID: 23959878; Saito et al, 2014, PMID: 24480078; Figueiredo et al, 2014, PMID: 25459762) have shown that the following residues are important to the function of IDUA:\n\nActive site nucleophiles: Glu182 and Glu299\n\nActive site pocket and substrate binding: Arg89, His91, Asn181, His262, Lys264, Asp301, Gly305, Trp306, Asp349, Arg363, Asn372.\n\nPM1 will be applied to any missense substitutions or inframe deletions of the above residues.\n\nThere are no benign or likely benign missense or infame deletions of these residues in ClinVar, or common missense or inframe deletions of these residues in gnomAD v4.1.0 (ClinVar and gnomAD v4.1.0 data accessed on October 30, 2024).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611479",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611479",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZ1K---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_PS3_nuclear_IDUA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"instructionsToUse": "Any variant meeting the requirements below can meet PS3 (at the appropriate strength). Note that these assays are in vitro, research-based, and may not truly reflect in vivo function. \n\nThere are several studies involving expression of IDUA sequence variants in cultured cells and subsequent measurement of enzyme activity. Some studies also include analysis of IDUA synthesis and processing by Western blot. Please see Appendix 3 for details on the methodology used in the studies that included the largest number of variants (up to 8 variants per study) (Beesley et al, 2001; Yogalingam et al, 2004, PMID: 15300847; Yu et al, 2020, PMID: 33198351). Additional studies on smaller numbers of variants have also been published (e.g. Bach et al, 1993, PMID: 8328452; Tieu et al, 1995, PMID: 7550232; Lee-Chen et al, 1999, PMID: 10466419; Prommajan et al, 2011, PMID: 21364962; Ngiwsara et al, 2017, PMID: 29282708). Historically, these assays have been broadly accepted in the analysis of IDUA variants as well as other enzymes involved in metabolic disease.\n\nNote: PS3 will not be used for RT-PCR assays proving evidence that a variant impacts splicing. Instead, this evidence will be used to assign the appropriate weight of evidence for PVS1, following the guidance of Walker et al (PMID: 37352859).",
"label": "PS3",
"ns": "091",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/18425781"
},
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/22644586"
}
],
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "When PS3\\_Supporting is met for enzyme activity AND there is expression data (Western blot, pulse chase) showing a clear difference in synthesis and/or processing of alpha-iduronidase, PS3 will be applied at moderate (e.g. Matte et al, 2003, PMID: 12559846; see Appendix 3).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "_In vitro_ expression studies: After assessment of the parameters listed below, results from such studies can be used at PS3\\_Supporting (see Appendix 3 for thresholds for specific studies; \\<2% activity (Beesley et al, 2001, PMID: 11735025; Yogalingam et al, 2004, PMID: 15300847; Matte et al, 2003); \\<1% activity / enzyme abundance (Yu et al, 2020. PMID: 33198351).\n\n* Were clones sequenced to verify that the variant is present and that no artifacts have been introduced during the site-directed mutagenesis process? \n* Were appropriate controls included? Examples \n * Negative controls: Empty vector, antisense (at least one appropriate negative control is required); \n * Positive control: Wild type IDUA, normal cells (at least one appropriate positive control is required)\n* Was the experiment replicated?\n* If cells have intrinsic IDUA activity e.g., COS cells, the level of activity should be stated so that this can be taken into account.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611470",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611470",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZyS---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_BP6_nuclear_IDUA",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "091",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611468",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611468",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZw6---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_PM3_nuclear_IDUA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"instructionsToUse": "* PM2\\_Supporting must be met in order to apply points to any case.\n* The patient must be described as having MPS1, at a minimum. If the case meets PP4 and PM3, both criteria are applied. However, our PP4 criterion need not necessarily be met in order to apply PM3, as long as the patient is stated to have MPS1.\n* For compound heterozygous cases, the second variant must have been classified by the Lysosomal Diseases VCEP.\n* For rare variants that are routinely observed to be in cis with a pseudodeficiency variant, substantial additional evidence must be available to support the pathogenicity of the variant. The variant must meet PM2\\_Supporting, functional data should be available to support a deleterious impact, and cases considered for PM3 must have other clinical and laboratory findings supporting a diagnosis of MPS1. We strongly recommend not applying this exception for a novel variant with a single report.\n* If multiple unrelated compound heterozygous cases have the same genotype, and the variants are not confirmed in trans, then no more than two cases should be used for assigning points (i.e. maximum of 1 point; similar to the guidance for homozygotes). This avoids over-counting evidence if the variants are actually in cis, and hence inherited together, in multiple individuals. Care must be taken to ensure that the reports do not represent the same case.\n* For a variant to be “confirmed in trans” in a compound heterozygous patient, parental testing in at least one parent, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed. Otherwise, the phase of the variants is unknown. Parental testing is not required for homozygous cases.\n* As noted in the SVI guidance for PM3, “To avoid circularity, in all instances (phasing confirmed or unknown), the classification of the variant on the other allele should not use evidence from the variant being interrogated.”",
"label": "PM3",
"ns": "091",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Detected in trans with a pathogenic variant. Points system based on [guidance](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf) from the ClinGen Sequence Variant Interpretation Working Group. See Appendix 4 for the Lysosomal Diseases VCEP's specification of PM3. Note that points will NOT be applied for any variants of uncertain significance confirmed in trans, due to the high number of pseudodeficiency variants in IDUA. \n\nThese variant interpretation guidelines should be used to determine the classification of the “other variant” in order to determine the appropriate number of points to assign.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Detected in trans with a pathogenic variant. Points system based on [guidance](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf) from the ClinGen Sequence Variant Interpretation Working Group. See Appendix 4 for the Lysosomal Diseases VCEP's specification of PM3. Note that points will NOT be applied for any variants of uncertain significance confirmed in trans, due to the high number of pseudodeficiency variants in IDUA. \n\nThese variant interpretation guidelines should be used to determine the classification of the “other variant” in order to determine the appropriate number of points to assign.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Detected in trans with a pathogenic variant. Points system based on [guidance](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf) from the ClinGen Sequence Variant Interpretation Working Group. See Appendix 4 for the Lysosomal Diseases VCEP's specification of PM3. Note that points will NOT be applied for any variants of uncertain significance confirmed in trans, due to the high number of pseudodeficiency variants in IDUA. \n\nThese variant interpretation guidelines should be used to determine the classification of the “other variant” in order to determine the appropriate number of points to assign.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Detected in trans with a pathogenic variant. Points system based on [guidance](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf) from the ClinGen Sequence Variant Interpretation Working Group. See Appendix 4 for the Lysosomal Diseases VCEP's specification of PM3. Note that points will NOT be applied for any variants of uncertain significance confirmed in trans, due to the high number of pseudodeficiency variants in IDUA. \n\nThese variant interpretation guidelines should be used to determine the classification of the “other variant” in order to determine the appropriate number of points to assign.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611467",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611467",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZti---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_BP5_nuclear_IDUA",
"additionalComments": "There is no known alternate molecular basis for deficiency of alpha-L-iduronidase activity, other than variants in IDUA.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"instructionsToUse": "There is no known alternate molecular basis for deficiency of alpha-L-iduronidase activity, other than variants in IDUA.",
"label": "BP5",
"ns": "091",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611451",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611451",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZzK---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_BP4_nuclear_IDUA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"instructionsToUse": "Variants meeting the combination of BS3\\_Supporting, BP4, and PM2\\_Supporting will be classified as likely benign.",
"label": "BP4",
"ns": "091",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* Missense changes with a REVEL score \\< 0.290 (threshold based on Pejaver et al; however, BP4 will only be applied at the supporting level). \n* For in frame insertions and deletions, use PROVEAN ([http://provean.jcvi.org/seq_submit.php](http://provean.jcvi.org/seq_submit.php) ; score >-2.5), Mutation Taster ([http://www.mutationtaster.org/](http://www.mutationtaster.org/) ; count if “polymorphism”, and MutPred-Indel ([http://mutpredindel.cs.indiana.edu/](http://mutpredindel.cs.indiana.edu/) ; score \\<0.5. Apply BP4 if all predictors indicate that the variant is benign.\n* For non-canonical splice site variants, use SpliceAI ([https://spliceailookup.broadinstitute.org/](https://spliceailookup.broadinstitute.org/) ) to assess the impact of variants that are not +/-1 or 2 canonical splice site variants. This criterion can be applied as PP3 (Splicing) for SpliceAI scores ≤0.1 (based on Walker et al, PMID: 37352859). \n* If there is any evidence for possible creation of a cryptic splice site, this criterion should not be applied.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611484",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611484",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZ4a---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_PP2_nuclear_IDUA",
"additionalComments": "Does not apply; there are benign and pathogenic missense variants in IDUA.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "091",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611482",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611482",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZ3S---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_BP3_nuclear_IDUA",
"additionalComments": "There are no known repetitive regions without known function in IDUA.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "091",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611472",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611472",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZuW---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_PM6_nuclear_IDUA",
"additionalComments": "See PS2.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "091",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611471",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611471",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZyu---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_PM2_nuclear_IDUA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PM2",
"ns": "091",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion will be applied at the supporting level based on [guidance](https://www.clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf) from the ClinGen Sequence Variant Interpretation Working Group.\n\nMinor allele frequency \\<0.025% (0.00025) in any continental population with >2000 alleles in the most recent version of gnomAD (version # will be stated in the written summary).\n\nVariants may be observed in the homozygous state because MPS1 can present in adulthood, and some variants may be hypomorphic. However, the presence and number of homozygotes should be noted.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611469",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611469",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZxi---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_BS3_nuclear_IDUA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"instructionsToUse": "Variants meeting the combination of BS3\\_Supporting, BP4, and PM2\\_Supporting will be classified as likely benign.",
"label": "BS3",
"ns": "091",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0072",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "The same assays outlined for PS3 will be used for BS3. Please see PS3 guidance for additional information on these assays. \n\nBS3\\_Supporting can be applied for expression of IDUA sequence variants in cultured cells and subsequent measurement of enzyme activity provided that there is no other evidence to suggest that the variant could be disease-causing e.g. mislocalization (see Appendix 3 for thresholds for specific studies: >10% activity (Beesley et al, 2001, PMID: 11735025; Yogalingam et al, 2004, PMID: 15300847; Matte et al, 2003); >~10% activity / enzyme abundance (Yu et al, 2020. PMID: 33198351).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611465",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611465",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZsy---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_BP1_nuclear_IDUA",
"additionalComments": "Does not apply. All types of variants cause MPS1.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "091",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611475",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611475",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZvm---"
},
{
"created": "2024-12-05T14:23:09.998Z",
"creator": "jennifer.goldstein@unc.edu",
"entContent": {
"_uniqueProp": "091_PVS1_nuclear_IDUA",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"IDUA"
],
"geneType": "nuclear",
"instructionsToUse": "Please consult the “PVS1 Decision Tree” (Appendix 2) for additional information. If PVS1 is applied, PM4 will not be applied. If an in-frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. Use the PVS1 decision tree to assess the impact of single and multi-exon duplications. \nUse SpliceAI in analysis of all canonical splice site variants (see PP3 and BP4 for details on thresholds). If there is a nearby (within +/- 20 nucleotides) splice site sequence that may reconstitute in-frame splicing, this should be taken into consideration. \n\nConsult Walker et al (PMID: 37352859) to apply PVS1 for splice motif variants.",
"label": "PVS1",
"ns": "091",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/1856189/"
}
],
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "* All nonsense and frameshift variants will meet PVS1 (Very Strong), unless the variant is predicted to be undetected by nonsense-mediated decay (NMD) i.e. if the resulting premature termination codon is in the last exon (exon 14) or in the last 50 nucleotides of the penultimate exon (exon 13; after c.1778, codon 592). In this case, PVS1\\_Moderate will be applied because \\<10% of the primary amino acid sequence is predicted to be lost (in this case, ~9.3%).\n* For all variants involving either the +1 or +2 position of GT donor splice sites, the exon immediately 5’ of the variant is predicted to be skipped, and for all variants involving either the -1 or -2 position of AG acceptor splice sites, the exon immediately 3’ of the variant is predicted to be skipped, unless indicated otherwise by RT-PCR or in silico prediction. For the predicted in frame/out of frame consequences for skipping any exon in IDUA, and recommended weight for PVS1, see Appendix 1.\n* Follow the recommendations of Walker et al (PMID: 37352859) for all variants occurring in splice motifs (the donor site motif = last 3 nucleotides of an exon and first 6 nucleotides of an intron; acceptor site motif = first nucleotide of an exon and 20 nucleotides upstream from the exon boundary).\n* If a single or multi-exon deletion results in an out-of-frame consequence, use PVS1 (Very Strong) if NMD is predicted to occur.\n* Initiation codon variants will meet PVS1.\n * The next in-frame methionine is at position 133. If used as a start signal, the signal sequence (amino acids 1-27) would be lost ([https://www.uniprot.org/uniprotkb/P35475/entry](https://www.uniprot.org/uniprotkb/P35475/entry))\n * There are 6 variants, upstream of Met133, that are classified as pathogenic in ClinVar (data accessed July 20, 2022) (Table 1).\n* If a deletion results in an in-frame consequence, the deletion must encompass one or more exons for PVS1 to apply. Consult Appendix 1 and use professional judgment regarding the strength of evidence to apply.\n* For duplications, consult the PVS1 decision tree and Appendix 1 to assess the impact of single and multi-exon duplications and apply PVS1 at the appropriate strength.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* For frameshift variants at the 3’ end of IDUA that are not predicted to undergo NMD i.e. PTC downstream of c.1778, consider the length of abnormal amino acid sequence that is added due to the frameshift. If >10% of the length of the normal sequence is altered, PVS1 can be applied at strong.\n* For all variants involving either the +1 or +2 position of GT donor splice sites, the exon immediately 5’ of the variant is predicted to be skipped, and for all variants involving either the -1 or -2 position of AG acceptor splice sites, the exon immediately 3’ of the variant is predicted to be skipped, unless indicated otherwise by RT-PCR or in silico prediction. For the predicted in frame/out of frame consequences for skipping any exon in IDUA, and recommended weight for PVS1, see Appendix 1.\n* Follow the recommendations of Walker et al (PMID: 37352859) for all variants occurring in splice motifs (the donor site motif = last 3 nucleotides of an exon and first 6 nucleotides of an intron; acceptor site motif = first nucleotide of an exon and 20 nucleotides upstream from the exon boundary).\n* If a deletion results in an in-frame consequence, the deletion must encompass one or more exons for PVS1 to apply. Consult Appendix 1 and use professional judgment regarding the strength of evidence to apply.\n* For duplications, consult the PVS1 decision tree and Appendix 1 to assess the impact of single and multi-exon duplications and apply PVS1 at the appropriate strength.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Any nonsense or frameshift variant that is predicted to be undetected by nonsense-mediated decay (NMD) i.e. if the resulting premature termination codon is in the last exon (exon 14) or in the last 50 nucleotides of the penultimate exon (exon 13; after c.1778, codon 592). In this case, PVS1\\_Moderate will be applied because \\<10% of the primary amino acid sequence is predicted to be lost ( ~9.3%).\n* For frameshift variants at the 3’ end of IDUA that are not predicted to undergo NMD i.e. PTC downstream of c.1778, consider the length of abnormal amino acid sequence that is added due to the frameshift. If \\<10% of the length of the normal sequence is altered, PVS1 can be applied at moderate.\n* For all variants involving either the +1 or +2 position of GT donor splice sites, the exon immediately 5’ of the variant is predicted to be skipped, and for all variants involving either the -1 or -2 position of AG acceptor splice sites, the exon immediately 3’ of the variant is predicted to be skipped, unless indicated otherwise by RT-PCR or in silico prediction. For the predicted in frame/out of frame consequences for skipping any exon in IDUA, and recommended weight for PVS1, see Appendix 1.\n* Follow the recommendations of Walker et al (PMID: 37352859) for all variants occurring in splice motifs (the donor site motif = last 3 nucleotides of an exon and first 6 nucleotides of an intron; acceptor site motif = first nucleotide of an exon and 20 nucleotides upstream from the exon boundary).\n* If a deletion results in an in-frame consequence, the deletion must encompass one or more exons for PVS1 to apply. Consult Appendix 1 and use professional judgment regarding the strength of evidence to apply.\n* For duplications, see the PVS1 decision tree and Appendix 1 to assess the impact of single and multi-exon duplications and apply PVS1 at the appropriate strength.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "87611452",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/87611452",
"modified": "2026-01-23T15:06:26.324Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_k8riZzq---"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0001586",
"lbl": "mucopolysaccharidosis type 1",
"meta": {
"basicPropertyValues": [
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{
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"val": "https://www.malacards.org/card/scheie_syndrome"
},
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},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10056886"
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{
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"val": "http://identifiers.org/snomedct/75610003"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0023786"
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{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_12802"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C85053"
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"val": "http://www.orpha.net/ORDO/Orphanet_579"
}
],
"definition": {
"val": "The most common type of mucopolysaccharidosis. It is inherited in an autosomal recessive pattern. It comprises a group of lysosomal storage diseases which includes the most severe form (Hurler syndrome) and the mildest form (Scheie syndrome).",
"xrefs": [
"NCIT:P378"
]
},
"subsets": [
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"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Alpha-L-iduronidase deficiency",
"xrefs": [
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"icd11.foundation:1539226250"
]
},
{
"pred": "hasExactSynonym",
"val": "MPS I - Hurler syndrome",
"xrefs": [
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]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "MPS1",
"xrefs": [
"Orphanet:579"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "MPSI",
"xrefs": [
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]
},
{
"pred": "hasExactSynonym",
"val": "Mucopolysaccharidosis Type I",
"xrefs": [
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"NORD:1462",
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]
},
{
"pred": "hasExactSynonym",
"val": "iduronidase deficiency disease",
"xrefs": [
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]
},
{
"pred": "hasExactSynonym",
"val": "lipochondrodystrophy",
"xrefs": [
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]
},
{
"pred": "hasExactSynonym",
"val": "mucopolysaccharidosis type 1",
"xrefs": [
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]
},
{
"pred": "hasExactSynonym",
"val": "mucopolysaccharidosis type I",
"xrefs": [
"MONDORULE:1",
"NCIT:C85053",
"Orphanet:579"
]
},
{
"pred": "hasExactSynonym",
"val": "mucopolysaccharidosis, MPS-I",
"xrefs": [
"DOID:12802"
]
},
{
"pred": "hasExactSynonym",
"val": "mucopolysaccharidosis, type 1",
"xrefs": [
"DOID:12802"
]
},
{
"pred": "hasNarrowSynonym",
"val": "Hurler syndrome"
},
{
"pred": "hasRelatedSynonym",
"val": "Hurler syndrome (subtype)",
"xrefs": [
"GARD:0010335"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Hurler-Scheie syndrome (subtype)",
"xrefs": [
"GARD:0010335"
]
},
{
"pred": "hasRelatedSynonym",
"val": "IDUA deficiency",
"xrefs": [
"GARD:0010335"
]
},
{
"pred": "hasRelatedSynonym",
"val": "MPS 1",
"xrefs": [
"GARD:0010335"
]
},
{
"pred": "hasRelatedSynonym",
"val": "MPS I",
"xrefs": [
"GARD:0010335"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Scheie syndrome (subtype) formerly known as Mucopoly-saccharidosis type V)",
"xrefs": [
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]
},
{
"pred": "hasRelatedSynonym",
"val": "attenuated MPS I (subtype, includes Hurler-Scheie and Scheie syndrome)",
"xrefs": [
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]
},
{
"pred": "hasRelatedSynonym",
"val": "mucopolysaccharidosis I"
},
{
"pred": "hasRelatedSynonym",
"val": "severe MPS I (subtype, also known as Hurler syndrome)",
"xrefs": [
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]
}
],
"xrefs": [
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{
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{
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},
{
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{
"val": "NANDO:2200547"
},
{
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},
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},
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},
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{
"val": "SCTID:75610003"
},
{
"val": "UMLS:C0023786"
},
{
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}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0001586",
"name": "mucopolysaccharidosis type 1"
},
"entId": "MONDO:0001586",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0001586",
"entType": "Disease",
"ldhId": "467883532",
"ldhIri": "https://cspec.genome.network/cspec/Disease/id/467883532",
"modified": "2025-10-07T16:11:22.005Z",
"modifier": "cspecAdministrator",
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}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056949806465000,
"agr": "HGNC:5391",
"alias_name": [
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],
"alias_symbol": [
"MPS1",
"MPSI"
],
"ccds_id": [
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"CCDS3343"
],
"date_approved_reserved": "2001-06-22",
"date_modified": "2021-05-26",
"date_name_changed": "2019-08-12",
"ena": [
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],
"ensembl_gene_id": "ENSG00000127415",
"entrez_id": "3425",
"enzyme_id": [
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],
"gene_group": [
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],
"gene_group_id": [
1650
],
"hgnc_id": "HGNC:5391",
"location": "4p16.3",
"location_sortable": "04p16.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_1277|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_1277.xml"
],
"mane_select": [
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"NM_000203.5"
],
"mgd_id": [
"MGI:96418"
],
"name": "alpha-L-iduronidase",
"omim_id": [
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],
"orphanet": 122572,
"prev_name": [
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],
"pubmed_id": [
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],
"refseq_accession": [
"NM_000203"
],
"rgd_id": [
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],
"status": "Approved",
"symbol": "IDUA",
"symbol_report_tag": [
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],
"ucsc_id": "uc003gby.5",
"uniprot_ids": [
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],
"uuid": "6eda0e13-ca99-48f3-9857-ebba3b419fec",
"vega_id": "OTTHUMG00000088901"
}
},
"entId": "IDUA",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:5391",
"entType": "Gene",
"ldhId": "467830262",
"ldhIri": "https://cspec.genome.network/cspec/Gene/id/467830262",
"modified": "2021-10-14T11:36:42.752Z",
"modifier": "genbadmin",
"rev": "_inf5BYe--M"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "091_nuclear_IDUA",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal recessive inheritance",
"preferredMondoId": "MONDO:0001586",
"preferredTitle": "mucopolysaccharidosis type 1"
}
],
"gene": "IDUA",
"preferredTranscript": "NM_000203.4"
}
],
"ns": "091",
"references": [],
"rules": {
"mainRules": [
{
"conditions": [
{
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
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"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165309",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165309",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5ZW---"
},
{
"entContent": {
"_uniqueProp": "092_BA1_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Apply based on maximum filter allele frequency observed in a gnomAD non-founder population, considering exome and genome data separately.\n\nDo not apply if read depth \\<20. Do not apply to well-established pathogenic founder variants.",
"label": "BA1",
"ns": "092",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165308",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165308",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5Ty---"
},
{
"entContent": {
"_uniqueProp": "092_PP5_nuclear_BRCA1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "092",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165304",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165304",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5aq---"
},
{
"entContent": {
"_uniqueProp": "092_BP1_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "See **Specifications Figure 1A** for process to apply codes according to variant type, location and predicted bioinformatic impact. _Missense prediction not applicable_.",
"label": "BP1",
"ns": "092",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "**Apply BP1\\_Strong** for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0205",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165301",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165301",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5We---"
},
{
"entContent": {
"_uniqueProp": "092_BS3_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "See **Specifications Figure 1C** for simplified flowchart/s to advise application of codes for functional data, in content of variant type and location within a (potentially) clinically important functional domain. Do not apply when conflicting results are present from well-established assays with sufficient controls, which cannot be explained by experimental design.\n\nSee **Specifications Figure 1B** for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.\n\nSee **Specifications Table 9**, provided as a separate file in excel format to facilitate searches and look-ups by variant c. and p. nomenclature. It includes PS3 and BS3 code recommendations and rationale for code application of published functional assays data that has been calibrated, and considered against predicted/reported splicing. This is not an exhaustive list; there will be ongoing consideration of additional published functional assay results.",
"label": "BS3",
"ns": "092",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of no damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as BP7 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165299",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165299",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5C6---"
},
{
"entContent": {
"_uniqueProp": "092_PS4_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Case dataset should be ethnicity and country-matched to control dataset. If case-control LR estimates are available for a given dataset, these should be used in preference to case-control OR data, under code PP4 (or BP5, if appropriate). Do not use Proband Counting as originally described.",
"label": "PS4",
"ns": "092",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Clarification",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). See Appendix F for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0057",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0032",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165296",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165296",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5Nu---"
},
{
"entContent": {
"_uniqueProp": "092_BP6_nuclear_BRCA1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "092",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165320",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165320",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5K----"
},
{
"entContent": {
"_uniqueProp": "092_PS3_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "See **Specifications Figure 1C** for simplified flowchart/s to advise application of codes for functional data, in content of variant type and location within a (potentially) clinically important functional domain. Do not apply when conflicting results are present from well-established assays with sufficient controls, which cannot be explained by experimental design.\n\nSee **Specifications Figure 1B** for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.\n\nSee **Specifications Table 9**, provided as a separate file in excel format to facilitate searches and look-ups by variant c. and p. nomenclature. It includes PS3 and BS3 code recommendations and rationale for code application of published functional assays data that has been calibrated, and considered against predicted/reported splicing. This is not an exhaustive list; there will be ongoing consideration of additional published functional assay results.",
"label": "PS3",
"ns": "092",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0045",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165312",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165312",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5R6---"
},
{
"entContent": {
"_uniqueProp": "092_PVS1_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "In alignment with SVI recommendations for PVS1 code application, evidence strength and description has been separated for different variant types. Apply according to PVS1 flowchart, which considers knowledge of clinically important functional domains. For predicted protein termination codon (PTC) variants, apply with exon-specific weights derived for the PM5\\_PTC code (See Appendix D for details).\n\n**See Specifications Table 4, provided as a separate searchable excel file, for a comprehensive summary of codes applicable for all variants considered against the** _**BRCA1**_ **and** _**BRCA2**_ **PVS1 decision trees (initiation, nonsense/frameshift, deletion, duplication, splice site (donor/acceptor +/- 1,2)) – organized by exon.** See Appendix Figure 3,4 and Table 5 for further justification.\n\nSee **Specifications** **Figure 1B** for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.",
"label": "PVS1",
"ns": "092",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165307",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165307",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5Hu---"
},
{
"entContent": {
"_uniqueProp": "092_PM1_nuclear_BRCA1",
"additionalComments": "Considered as component of bioinformatic analysis (PP3/BP4). ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "092",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165306",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165306",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5Ue---"
},
{
"entContent": {
"_uniqueProp": "092_PM3_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Co-occurrent P or LP variant should be assigned classification using VCEP specifications. \n\nVariant under assessment must be sufficiently rare (not meeting a benign population evidence code).\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points.\n\nFor related individuals score only most severe presentation.\n\nAlso see **Specifications Table 6** for additional stipulations",
"label": "PM3",
"ns": "092",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis _≤5yr_.\n\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3\\_Strong = ≥4 points",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"This requires testing of parents (or offspring) to determine phase."
]
},
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis _≤5yr_.\n\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3 = 2 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis _≤5yr_.\n\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3\\_Supporting = 1 point",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165305",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165305",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5Iy---"
},
{
"entContent": {
"_uniqueProp": "092_BS2_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Co-occurrent P or LP variant should be assigned classification using VCEP specifications. \n\nSee **Specifications Table 8** for approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points.\n\nAlso see **Specifications Table 8** for additional stipulations.",
"label": "BS2",
"ns": "092",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2 = ≥ 4 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2\\_Moderate = 2 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2\\_Supporting = 1 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165303",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165303",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5ba---"
},
{
"entContent": {
"_uniqueProp": "092_BP2_nuclear_BRCA1",
"additionalComments": "Applied only in the context of BS2.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "092",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0084",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165297",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165297",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5N----"
},
{
"entContent": {
"_uniqueProp": "092_PM2_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Observation of a variant only once in a gnomAD outbred population is not informative. Do not apply for insertion, deletion or delins variants. Do not apply if read depth \\<25 at region around the variant.",
"label": "PM2",
"ns": "092",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Population data for insertions/deletions may be poorly called by next-generation sequencing."
]
},
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165295",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165295",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5Fi---"
},
{
"entContent": {
"_uniqueProp": "092_PP4_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Use in the context of clinically calibrated evidence types, with sufficient detail to review data sources, types and weights. Published data points may include co-segregation with disease, co-occurrence with a pathogenic variant in the same gene, reported family history, breast tumor pathology, and case-control data. Can also apply for unpublished data, where there is no appropriate ACMG/AMP code. Assign weight based on combined LR for clinical data.\n\nCombined LR >0.48 and \\<2.08 doesn't provide supporting evidence in either direction (PP4 and BP5 not applicable).\n\nSee Specifications Table7 for example application.",
"label": "PP4",
"ns": "092",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4\\_Strong – LR ≥18.7:1\n\nPP4\\_Very Strong – LR ≥350:1\n\nSee Specifications Table7 and Appendix B for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4\\_Moderate – LR ≥4.3:1\n\nSee Specifications Table7 and Appendix B for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4 - LR ≥2.08:1 \n\nSee Specifications Table7 and Appendix B for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165317",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165317",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5MC---"
},
{
"entContent": {
"_uniqueProp": "092_PP1_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Recommend use of online tools COOL ([http://bjfenglab.org/)](http://bjfenglab.org/) or CAL-Leiden ([https://bioexp.net/cosegregation/](https://bioexp.net/cosegregation/)). \n\n**Stipulation**: to apply code as Pathogenic Very Strong, VUS should have bioinformatically predicted (or experimentally proven) effect on protein or mRNA splicing. If co-segregation score is from a single family, or several families from an isolated population, assess the possibility of a different causative pathogenic variant.\n\nLR >0.48 and \\<2.08 doesn't provide supporting evidence in either direction (PP1 and BS4 not applicable).",
"label": "PP1",
"ns": "092",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nPP1\\_Strong – LR ≥18.7:1\n\nPP1\\_Very Strong – LR ≥350:1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nPP1\\_Moderate – LR ≥4.3:1",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"May be used as stronger evidence with increasing segregation data"
]
},
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nPP1 - LR ≥2.08:1",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165315",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165315",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5Pe---"
},
{
"entContent": {
"_uniqueProp": "092_BS1_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Apply based on maximum filter allele frequency in a gnomAD non-founder population, considering exome and genome data separately.\n\nDo not apply if read depth \\<20. Do not apply to well-established pathogenic founder variants.",
"label": "BS1",
"ns": "092",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165313",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165313",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5A2---"
},
{
"entContent": {
"_uniqueProp": "092_BS4_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Recommend use of online tools COOL ([http://bjfenglab.org/)](http://bjfenglab.org/) or CAL-Leiden ([https://bioexp.net/cosegregation/](https://bioexp.net/cosegregation/)). \n\nLR >0.48 and \\<2.08 doesn't provide supporting evidence in either direction (PP1 and BS4 not applicable).",
"label": "BS4",
"ns": "092",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nBS4 - LR ≤0.05:1\n\nBS4\\_VeryStrong – LR ≤0.00285:1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nBS4\\_Moderate - LR ≤0.23:1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nBS4\\_Supporting - LR ≤0.48:1",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165300",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165300",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5Xu---"
},
{
"entContent": {
"_uniqueProp": "092_PP2_nuclear_BRCA1",
"additionalComments": "High frequency of benign missense variants.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "092",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165302",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165302",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5Vq---"
},
{
"entContent": {
"_uniqueProp": "092_PM5_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Only applied to genomic PTC changes (not splicing). Weight determined by exon where the termination codon occurs (may not be the same exon as the variant position). See Specifications Table 4, provided as a separate searchable excel file, for PM5\\_PTC codes applicable for predicted termination codon variants - organized by exon.",
"label": "PM5",
"ns": "092",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Other"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5\\_PTC code strengths applicable per exon. See Appendix D for additional details.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Other"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5\\_PTC code strengths applicable per exon. See Appendix D for additional details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Other"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5\\_PTC code strengths applicable per exon. See Appendix D for additional details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165298",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165298",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5ES---"
},
{
"entContent": {
"_uniqueProp": "092_PS1_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "For both missense and splicing scenarios, (Likely) Pathogenic variant classification should be assigned using VCEP specifications.\n\nFor application of PS1 for splicing predictions, **see Specifications Table 5.** The predicted event of the VUA must precisely match the predicted event of the known (likely) pathogenic variant (e.g. both predicted to lead to exon A skipping, or both to enhanced use of cryptic site B), AND the strength of the prediction for the VUA must be of similar or higher strength than the strength of the prediction for the known (likely) pathogenic variant. For an exonic variant, predicted or proven functional effect of missense substitution/s encoded by the variant and the previously classified pathogenic variant should also be considered before PS1 code application for splicing prediction.",
"label": "PS1",
"ns": "092",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Apply **PS1**, for predicted **missense** substitutions, where a previously classified **pathogenic** variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\n\nApply **PS1**, for exonic and intronic variants with same predicted impact on **splicing**, as a previously classified **pathogenic** variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. \n\nSee Specifications Table 5 and Appendix E, J and K for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Apply **PS1\\_Moderate**, for predicted **missense** substitutions, where previously classified **likely pathogenic** variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\n\nApply **PS1\\_Moderate**, for exonic and intronic variants with same predicted impact on **splicing**, as a previously classified **(likely) pathogenic** variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\n\nSee Specifications Table 5 and Appendix E, J and K for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Apply **PS1\\_Supporting**, for exonic and intronic variants with same predicted impact on **splicing,** as a previously classified **(likely) pathogenic** variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\n\nSee Specifications Table 5 and Appendix E, J and K for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165319",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165319",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5LG---"
},
{
"entContent": {
"_uniqueProp": "092_PS2_nuclear_BRCA1",
"additionalComments": "BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "092",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Not applicable",
"id": "0051",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165318",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165318",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5Ge---"
},
{
"entContent": {
"_uniqueProp": "092_BP5_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Use in the context of clinically calibrated evidence types, with sufficient detail to review data sources, types and weights. Published data points may include co-segregation with disease, co-occurrence with a pathogenic variant in the same gene, reported family history, breast tumor pathology, and case-control data. Can also apply for unpublished data, where there is no appropriate ACMG/AMP code. Assign weight based on combined LR for clinical data.\n\nCombined LR >0.48 and \\<2.08 doesn't provide supporting evidence in either direction (PP4 and BP5 not applicable).\n\nSee Specifications Table7 for example application.",
"label": "BP5",
"ns": "092",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5\\_VeryStrong - LR ≤0.00285:1\n\nBP5\\_Strong - LR ≤0.05:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5\\_Moderate - LR ≤0.23:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5 - LR ≤0.48:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165314",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614165314",
"modified": "2025-01-09T01:11:36.684Z",
"modifier": "michaelP",
"rev": "_jCgb5Qm---"
},
{
"entContent": {
"_uniqueProp": "092_PP3_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "See **Specifications** **Figure 1A** for process to apply codes according to variant type, location and predicted bioinformatic impact.",
"label": "PP3",
"ns": "092",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
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"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for application. This rule can be applied when curating for AR disease only. Please reference the attached, LZTR1-specific PVS1 Decision Tree before applying PVS1.",
"label": "PVS1",
"ns": "094",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828323702",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828323702",
"modified": "2024-12-03T02:21:58.468Z",
"modifier": "RFWebb",
"rev": "_i2nRA8i---"
},
{
"created": "2024-08-03T01:08:10.868Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "094_BS4_nuclear_LZTR1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"LZTR1"
],
"geneType": "nuclear",
"instructionsToUse": "Lack of segregation in affected members of a family.",
"label": "BS4",
"ns": "094",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Requires only one informative meiosis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828323695",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828323695",
"modified": "2024-12-03T02:21:58.468Z",
"modifier": "RFWebb",
"rev": "_i2nRB_S---"
},
{
"created": "2024-08-03T01:08:10.868Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "094_BS3_nuclear_LZTR1",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"LZTR1"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"label": "BS3",
"ns": "094",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828323694",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828323694",
"modified": "2024-12-03T02:21:58.468Z",
"modifier": "RFWebb",
"rev": "_i2nRA5G---"
},
{
"created": "2024-08-03T01:08:10.868Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "094_PM5_nuclear_LZTR1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LZTR1"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable for observed analogous residue positions in LZTR1. PM1 and PM5 may be used in conjunction at moderate levels, however, PM1 may not be applied if PM5\\_Strong is applied to avoid overweighting.",
"label": "PM5",
"ns": "094",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥2 different \\[likely\\] pathogenic residue changes at the same codon observed in ≥5 probands.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 \\[likely\\] pathogenic residue change at the same codon.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828323693",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828323693",
"modified": "2024-12-03T02:21:58.468Z",
"modifier": "RFWebb",
"rev": "_i2nRBD6---"
},
{
"created": "2024-08-03T01:08:10.868Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "094_PS4_nuclear_LZTR1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"LZTR1"
],
"geneType": "nuclear",
"instructionsToUse": "Please reference the Case Level Inheritance Flowchart before applying PS4.\n\n_Dominant-negative variants_: Strength adjustment using point-based scoring for autosomal dominant cases with RASopathy phenotypic specifications: full points (1) awarded with consistent RASopathy phenotype (See Table 1 in PMID: 30311384), reduced points (0.5) applicable to cases with minimal phenotypic information including prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES). Phenotypes for prenatal cases include hypertrophic cardiomyopathy, increased nuchal translucency, cystic hygroma, or hydrops.\n\nOR\n\n_Dominant loss-of-function variants_: Usage of this rule is case specific based on the inheritance of the variant and only PS4 OR PM3 can be applied to a single case. 1 point awarded for autosomal dominant cases with isolated schwannomatosis consistent with the loss-of-function disease mechanism. Loss-of-function variants observed in cases with autosomal recessive NS should only be counted using PM3.",
"label": "PS4",
"ns": "094",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥5 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥3 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥1 points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828323691",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828323691",
"modified": "2024-12-03T02:21:58.468Z",
"modifier": "RFWebb",
"rev": "_i2nRBPW---"
},
{
"created": "2024-08-03T01:08:10.868Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "094_BP3_nuclear_LZTR1",
"additionalComments": "No known benign repetitive areas in RASopathy genes.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LZTR1"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "094",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828323711",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828323711",
"modified": "2024-12-03T02:21:58.468Z",
"modifier": "RFWebb",
"rev": "_i2nRBEy---"
},
{
"created": "2024-08-03T01:08:10.868Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "094_BA1_nuclear_LZTR1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"LZTR1"
],
"geneType": "nuclear",
"instructionsToUse": "GnomAD filtering allele frequency ≥0.05%.",
"label": "BA1",
"ns": "094",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "GnomAD filtering allele frequency ≥0.05%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828323703",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828323703",
"modified": "2024-12-03T02:21:58.468Z",
"modifier": "RFWebb",
"rev": "_i2nRA4K---"
},
{
"created": "2024-08-03T01:08:10.868Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "094_BP2_nuclear_LZTR1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"LZTR1"
],
"geneType": "nuclear",
"instructionsToUse": "For each case, -1 point applies when phenotype inconsistent with a RASopathy and causative variant has been identified (ex. WES cases) OR alternative molecular cause of a RASopathy and the phenotype is consistent with expected severity of the RASopathy in the same gene (and/or in conjunction with BP5 in a different gene).",
"label": "BP2",
"ns": "094",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828323692",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828323692",
"modified": "2024-12-03T02:21:58.468Z",
"modifier": "RFWebb",
"rev": "_i2nRBAa---"
},
{
"created": "2024-08-03T01:08:10.868Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "094_BP5_nuclear_LZTR1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"LZTR1"
],
"geneType": "nuclear",
"instructionsToUse": "For each case, -1 point applies when phenotype inconsistent with a RASopathy and causative variant has been identified (ex. WES cases) OR alternative molecular cause of a RASopathy and the phenotype is consistent with expected severity of the RASopathy in a different gene (and/or in conjunction with BP2 in the same gene).",
"label": "BP5",
"ns": "094",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ (-4) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "≥ (-2) Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ (-1) Point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828323709",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828323709",
"modified": "2024-12-03T02:21:58.468Z",
"modifier": "RFWebb",
"rev": "_i2nRA72---"
},
{
"created": "2024-08-03T01:08:10.868Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "094_PS3_nuclear_LZTR1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"LZTR1"
],
"geneType": "nuclear",
"instructionsToUse": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Approved assays for PS3 usage are available in the supplemental materials.",
"label": "PS3",
"ns": "094",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Not Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Two or more different approved assays.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One approved assay.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828323707",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828323707",
"modified": "2024-12-03T02:21:58.468Z",
"modifier": "RFWebb",
"rev": "_i2nRA1i---"
},
{
"created": "2024-08-03T01:08:10.868Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "094_PM4_nuclear_LZTR1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LZTR1"
],
"geneType": "nuclear",
"instructionsToUse": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"label": "PM4",
"ns": "094",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "No known repetitive areas in gene. Use as described.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828323689",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828323689",
"modified": "2024-12-03T02:21:58.468Z",
"modifier": "RFWebb",
"rev": "_i2nRBIu---"
},
{
"created": "2024-08-03T01:08:10.868Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "094_PS1_nuclear_LZTR1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LZTR1"
],
"geneType": "nuclear",
"instructionsToUse": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"label": "PS1",
"ns": "094",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant in _LZTR1_ regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828323714",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828323714",
"modified": "2024-12-03T02:21:58.468Z",
"modifier": "RFWebb",
"rev": "_i2nRBBW---"
},
{
"created": "2024-08-03T01:08:10.868Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "094_PS2_nuclear_LZTR1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"LZTR1"
],
"geneType": "nuclear",
"instructionsToUse": "Follow SVI recommendations for point-based scoring in conjunction with PM6 (see Reference 1) and phenotypic specifications: full points (1 point) awarded with RASopathy phenotypes, reduced points (0.5 points) applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)).",
"label": "PS2",
"ns": "094",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 Points.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 Points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 Point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828323713",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828323713",
"modified": "2024-12-03T02:21:58.468Z",
"modifier": "RFWebb",
"rev": "_i2nRA6y---"
},
{
"created": "2024-08-03T01:08:10.868Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "094_PP3_nuclear_LZTR1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LZTR1"
],
"geneType": "nuclear",
"instructionsToUse": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"label": "PP3",
"ns": "094",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828323706",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828323706",
"modified": "2024-12-03T02:21:58.468Z",
"modifier": "RFWebb",
"rev": "_i2nRA3G---"
},
{
"created": "2024-08-03T01:08:10.868Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "094_PM3_nuclear_LZTR1",
"additionalComments": "Not applicable.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"LZTR1"
],
"geneType": "nuclear",
"instructionsToUse": "Please reference the Case Level Inheritance Flowchart before applying PM3.\n\nUsage of this rule is case specific based on the inheritance of the variant and only PS4 OR PM3 can be applied to a single case. Cases with autosomal recessive NS are scored using PM3, as defined by SVI. Cases with autosomal dominant isolated schwannomatosis should be counted using PS4.",
"label": "PM3",
"ns": "094",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥4 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥2 points.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"This requires testing of parents (or offspring) to determine phase."
]
},
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥1 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥0.5 points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828323700",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828323700",
"modified": "2024-12-03T02:21:58.468Z",
"modifier": "RFWebb",
"rev": "_i2nRBGu---"
},
{
"created": "2024-08-03T01:08:10.868Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "094_PP5_nuclear_LZTR1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"LZTR1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "094",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1828323699",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1828323699",
"modified": "2024-12-03T02:21:58.468Z",
"modifier": "RFWebb",
"rev": "_i2nRA9e---"
},
{
"created": "2024-08-03T01:08:10.868Z",
"creator": "cspecAdministrator",
"entContent": {
"_uniqueProp": "094_PP2_nuclear_LZTR1",
"additionalComments": "Not applicable because missense z score is <3.09 in gnomAD.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"LZTR1"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "094",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
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"ldhId": "1768711171",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711171",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
"rev": "_inf5Ate--O"
},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "095_PS2_nuclear_MYBPC3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "095",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0016",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Refer to SVI guidance on number/combination of cases required based on phenotype specificity[7](#url_c73e109e-b916-5a72-b7b1-1762446f3c11).\n\nFor most cardiomyopathies, it is recommended to default to **Phenotype consistency: “Phenotype consistent with gene but not highly specific”**. Clinical judgment is required for shifting to a higher or lower category. \n\nFor use as a STRONG or VERY STRONG criterion, ideally parents have been thoroughly clinically evaluated without evidence of cardiomyopathy (ideally using a combination of ECG and echocardiogram or cardiac MRI for maximum sensitivity).\n\nA family history consistent with _de novo_ inheritance should not have any clinical signs or symptoms suggestive of cardiomyopathy in a 1st or 2nd degree relative, for example: \n\n1. Sudden death under 60 years of age\n2. Heart transplant\n3. Implantable cardiac defibrillator (ICD) under 60 years of age\n4. Features of cardiomyopathy (e.g., systolic dysfunction, hypertrophy, left ventricular enlargement in an individual without risk factors).\n5. Other related/overlapping cardiomyopathies\n\nExamples of non-suspicious family history may include non-specific clinical features (e.g., palpitations, syncope, borderline/inconclusive echocardiogram findings, heart attack if age appropriate and suspected to result from coronary artery disease), but every attempt should be made to clarify features. \n\nGenerally, this criterion is only applicable in the ABSENCE of any other possible disease-causing variants. If other pathogenic or likely pathogenic variants are present, consider decreasing points assigned or overall weight.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "004",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711169",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711169",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
"rev": "_inf5Ate--L"
},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "095_PP3_nuclear_MYBPC3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "095",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "As many _in silico_ algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.\n\nUse of REVEL (Ioannidis _et al._ 2016[17](#pmid_27666373)) is recommended at thresholds of **≥0.70 for PP3**.\n\nClinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.\n\nPositive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.\n\n[SpliceAI](https://spliceailookup.broadinstitute.org)[2](#pmid_30661751) is recommended for evaluation of predicted splice impacts.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711162",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711162",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
"rev": "_inf5Ata--W"
},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "095_PM6_nuclear_MYBPC3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "095",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Refer to SVI guidance on number/combination of cases required based on phenotype specificity[7](#url_c73e109e-b916-5a72-b7b1-1762446f3c11).\n\nFor most cardiomyopathies, it is recommended to default to “phenotype consistent with gene but not highly specific”. Clinical judgment is required for shifting to a higher or lower phenotypic consistency. \n\nSee PS2 for additional considerations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711160",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711160",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
"rev": "_inf5AtW--b"
},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "095_BA1_nuclear_MYBPC3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "095",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency is **≥0.001** based on the **filtering allele frequency (FAF)** in **gnomAD** in the subpopulation with the highest frequency (popmax).\n\nThe values used to calculate the BA1 threshold were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/300 or lower).\n\nThe threshold is applicable when assessing variants in the context of autosomal dominant cardiomyopathy. \n\ngnomAD is the preferred database for this calculation. If a subpopulation specific FAF other than the popmax is needed, this value can be calculated using the AlleleFrequencyApp on the [CardioDB website](https://cardiodb.org/allelefrequencyapp/).\n\n1. Using the Inverse AF tab, enter in the population size and the number of alleles identified and it will calculate the FAF. \n2. Set confidence to 0.95 (95%).\n3. If the FAF is ≥0.001, this rule can be applied.\n\nThe FAF by platform (e.g., exome vs. genome; v.2.1.1 vs. v.3.1.1) should be considered, the larger population is most likely to have the most accurate representation of “true” population allele frequency.\n\nCaution is needed when considering any population cohorts that are smaller than the smallest subpopulations within gnomAD v.2.1.1 (e.g., ~5000 individuals or ~10,000 alleles). Despite this conservative nature of this threshold and approach, in smaller cohorts, the observed allele frequency may less accurately reflect the true allele frequency. Traditionally, once a variant is classified as Benign, it is rarely re-evaluated and so the highest confidence is needed to establish that classification on an allele frequency alone.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711159",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711159",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
"rev": "_inf5Ate--F"
},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "095_PM3_nuclear_MYBPC3",
"additionalComments": "While compound heterozygosity leading to a more severe phenotype has been documented, this rule was designed for traditional recessive inheritance. It is acknowledged that there is increasing evidence supporting that some of these genes/variants may also be recessive (e.g., MYL2, MYL3), but addressing those edge cases was outside the scope of this current guideline.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "095",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"This requires testing of parents (or offspring) to determine phase."
]
},
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711156",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711156",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
"rev": "_inf5Aq---L"
},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "095_BS2_nuclear_MYBPC3",
"additionalComments": "Inherited cardiomyopathies generally display reduced penetrance, variable expressivity, and adult-onset. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "095",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0069",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0076",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711154",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711154",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
"rev": "_inf5Ap2--f"
},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "095_BS4_nuclear_MYBPC3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "095",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Any non-segregations should be carefully evaluated to rule out a phenocopy or the presence of a second disease-causing variant before considering it as conflicting or benign evidence. \n\n1. The presence of “phenocopies” (e.g., athlete’s heart, hypertensive heart disease, ischemic cardiomyopathy, alcoholic cardiomyopathy, diabetic cardiomyopathy) can mimic non-segregation (i.e., lack of segregation) among affected individuals. \n2. Families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent ‘non-segregation’.\n\nBecause of these possibilities, **multiple (≥2) non-segregations** that are highly unlikely to be phenocopies or due to alternate variants (e.g., those without a possible alternate cause) **are required to apply this rule**. A higher number of non-segregations is necessary for instances where alternative causes are possible (e.g., non-segregation in a sibling with childhood onset cardiomyopathy versus a grandparent with hypertension and HCM).\n\nCareful consideration of the above points is required when using this data as conflicting evidence, especially when overall evidence supports likely pathogenic or pathogenic.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711151",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711151",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
"rev": "_inf5AqW--c"
},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "095_BS3_nuclear_MYBPC3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"instructionsToUse": "Evaluation of studies/assays is required prior to application of functional evidence at any strength.\n\nRefer to SVI guidance for functional evidence (Brnich _et al._ 2020[8](#pmid_31892348)).\n\nIn the context of cardiomyopathy, very few functional assays currently meet criteria sufficient for application of this rule at a STRONG level. Examples of the types of study/assays that MAY be relevant are described, but further definition of cardiomyopathy models/assays is outside the scope of these guidelines.",
"label": "BS3",
"ns": "095",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "See PS3 specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "See PS3 specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "See PS3 specifications.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711150",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711150",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
"rev": "_inf5AqW--b"
},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "095_PM5_nuclear_MYBPC3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "095",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion can be used at MODERATE if a different missense variant at the same codon has been classified as _pathogenic_ using these modified guidelines without application of PM5.\n\nThe impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to SUPPORTING if the predicted impact is not expected to be equivalent or more severe.\n\nPM5 should not be combined with PM1. If both are applicable at MODERATE weight, use of PM5 is most appropriate since it is variant specific.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion can be considered at SUPPORTING if a different missense variant at the same codon has been classified as _likely pathogenic_ using these modified guidelines without application of PM5.\n\nThe impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as likely pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to NOT APPLICABLE if the predicted impact is not expected to be equivalent or more severe.\n\nPM5 should not be combined with PM1. The one with the higher strength should be applied, but if both are applicable at SUPPORTING weight, use of PM5 is most appropriate since it is variant specific.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711149",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711149",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
"rev": "_inf5Ap2--e"
},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "095_BP2_nuclear_MYBPC3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "095",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Other variants must be pathogenic as defined by these specifications.\n\nTesting of parents or other informative relatives is often required to determine _cis_/_trans_ status.\n\nIf a variant is seen in _trans_ (or as double heterozygous) with another pathogenic variant in ≥2 cases and the phenotype is not more severe than when either of the two variants are seen in isolation, this rule may be applied (i.e., high confidence this variant is NOT contributing to disease).\n\n* \\<1% of cases of HCM have >1 pathogenic or likely pathogenic variant (0.6%; Alfares _et al._ 2015[20](#pmid_25611685)).\n\nThis rule cannot be applied when the variant has only been observed in _cis_ with a pathogenic variant as its significance in isolation is unknown in this scenario. \n\nCaution is needed if using this criterion as a primary piece of evidence for classifying a variant as likely benign/benign (i.e., only 2 SUPPORTING criteria are sufficient for a likely benign classification).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711148",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711148",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
"rev": "_inf5AqS--N"
},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "095_PM2_nuclear_MYBPC3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "095",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Population data for insertions/deletions may be poorly called by next-generation sequencing."
]
},
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The values used to calculate the PM2 thresholds were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/500 or lower), where the most frequent pathogenic variant accounts for no more than 2% of cases (e.g., has an allele frequency of ≤0.02 in cases based on the upper bound of 95% CI), and where the penetrance of a pathogenic variant is expected to be at least 50% (Kelly _et al._ 2018[15](#pmid_29300372)).\n\nA threshold of **≤0.00004** in the subpopulation with the highest frequency when using the upper bound of the 95% CI activates this rule.\n\n1. Alternatively, this is equivalent to the variant NOT being observed more than once (≤1 allele) in gnomAD v.2.1.1 in one of the non-founder populations (e.g., absence required from the Other and Ashkenazi Jewish subpopulations).\n2. Applying a threshold of ≤0.00004 (upper bound of 95% CI of the allele frequency in gnomAD) is equivalent to the variant being seen in a single subpopulation and that subpopulation meets any of the following:\n * **Allele Count (AC) in Allele Number (AN)**\n * ≤1 in ≥120,000\n * ≤2 in ≥160,000\n * ≤3 in ≥195,000\n * ≤4 in ≥230,000\n\ngnomAD is the preferred database for this calculation, but currently only displays the filtering allele frequency (FAF), which is equivalent to a lower bound estimate of the 95% CI, when the upper bound is what is needed.\n\n* Confidence interval tools, such as [Confit-de-MAF](https://www.genecalculators.net/confit-de-maf.html), can be used to determine the upper bound of the 95% CI of the observed allele frequency.\n\nDue to current technical limitations of next generation sequencing technologies, minor allele frequencies for complex variants (e.g., large indels) may not be accurately represented in population databases.\n\nCaution should be used when a variant is only identified, or over-represented, in one of the smaller gnomAD populations, as the gnomAD allele frequencies may not accurately represent the true population frequency.\n\nPopulation databases may contain affected or pre-symptomatic individuals for diseases with reduced penetrance/variable onset.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711146",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711146",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
"rev": "_inf5AqS--M"
},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "095_PM4_nuclear_MYBPC3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "095",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Strength of rule should be carefully considered and may require downgrading to SUPPORTING based on the predicted impact of the variant, including the size of the deletion/insertion, its location, and conservation of the region. \n\nFor genes where PVS1 is not applicable (i.e., where there is no evidence that pLOF variants cause disease), consider using this rule at MODERATE or SUPPORTING strength for truncating variants that do NOT undergo nonsense mediated decay (NMD).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711145",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711145",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
"rev": "_inf5AqS--L"
},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "095_PS1_nuclear_MYBPC3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PS1",
"ns": "095",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "No cardiomyopathy specifications. Apply as outlined by Richards _et al_. 2015[6](#pmid_25741868).\n\nExample of when rule should NOT be applied. NM\\_000256.3(_MYBPC3_): c.2308G>A (p.Asp770Asn) has an established impact on splicing leading to nonsense mediated decay (NMD) and should not be used to provide evidence for other variants observed to result in the same amino acid change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711170",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711170",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
"rev": "_inf5Ati--C"
},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "095_PP4_nuclear_MYBPC3",
"additionalComments": "Inherited cardiomyopathies have high locus heterogeneity as well as non-genetic etiologies. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "095",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711168",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711168",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
"rev": "_inf5Ate--K"
},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "095_BS1_nuclear_MYBPC3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "095",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency is **≥0.0002 for** _**MYBPC3**_ based on the **filtering allele frequency (FAF)** in **gnomAD** in the subpopulation with the highest frequency (popmax).\n\nCriterion BS1 may only be used as standalone evidence to classify a variant as Likely Benign in the absence of conflicting data. See SVI guidance (Tavtigian _et al._ 2018[18](#pmid_29300386); Tavtigian _et al._ 2020[19](#pmid_32720330)). \n\nSee BA1 for additional specifications that also apply to BS1.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711164",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711164",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
"rev": "_inf5Ati--_"
},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "095_PS3_nuclear_MYBPC3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"instructionsToUse": "Evaluation of studies/assays is required prior to application of functional evidence at any strength.\n\nRefer to SVI guidance for functional evidence (Brnich _et al._ 2020[8](#pmid_31892348)).\n\nIn the context of cardiomyopathy, very few functional assays currently meet criteria sufficient for application of this rule at a STRONG level. Examples of the types of study/assays that MAY be relevant are described, but further definition of cardiomyopathy models/assays is outside the scope of these guidelines.",
"label": "PS3",
"ns": "095",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**In vitro splicing assays (e.g., RNA studies)**\n\n_In vitro_ splicing assays may be considered as **STRONG** evidence, providing the following criteria are met.\n\n* Prior knowledge of predominant transcripts in cardiac tissue\n\nAnalysis undertaken using RNA extracted from cardiac tissue from the individual with the variant\n\nAnalysis undertaken using RNA extracted from whole blood providing the relevant transcripts (isoforms) are expressed in blood and are at sufficient levels to assess splice disruption.\n\nAssay shows a clear, reproducible and convincing effect on splicing (i.e. a distinct splice product, present at a level comparable to the splice product from the wild-type allele), which is not observed in controls\n\n* Confirmation of abnormal splice product by Sanger sequencing\n\n**NOTE:** Mini-gene assay in non-patient derived cell lines are NOT considered to provide STRONG evidence.\n\n**NOTE:** Whether to activate this rule needs to be reconciled with the variant spectrum and disease mechanism for the gene at hand (i.e., consider whether the effect is likely to lead to LOF or an in-frame alteration and whether this type of effect is expected to be disease causing) (Abou Tayoun _et al._ 2018[1](#pmid_30192042)).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**In vivo models (e.g., variant knock-in animal models)**\n\nMammalian variant-specific knock-in animal models that produce a phenotype consistent with the clinical phenotype in humans (e.g., structural and/or functional cardiac abnormalities, premature death, arrhythmia) may be considered as **MODERATE** evidence\n\n**NOTE:** The following assays/models do NOT meet criteria\n\n1. Assays that are known to be associated with non-specific cardiac phenotypes (e.g., morpholino-induced pericardial edema in zebrafish)\n2. In vivo evidence that is not variant specific, such as whole gene alterations (i.e., cDNA or whole gene transgenic mice and whole or partial gene knock-out mice)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "_**In vitro**_ **assays (e.g., biochemical assays of myofilament function, motility assays, human iPSC-CM)**\n\nWhile some _in vitro_ assays may provide evidence that a variant in a cardiomyopathy gene has an effect on protein and/or myofilament function, at present, there are no validated “gold-standard” assays that are considered to reliably predict the clinical phenotype.\n\nAs such, in the cardiomyopathy genes listed in these guidelines, data from individual _in vitro_ studies are unlikely to meet the criteria required to assign this rule at more than SUPPORTING level.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711163",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711163",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
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},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
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"additionalComments": "Application of this rule takes into consideration empirical data quantifying levels of rare missense variant enrichment in HCM referral cohorts compared to population-based cohorts (Walsh et al. 2019 PMID:30696458) rather than the missense constraint score in gnomAD. For MYBPC3, there is evidence for regional enrichment of rare missense variants (see PM1 specifications).",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "095",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711153",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711153",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
"rev": "_inf5AqG--o"
},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "095_BP1_nuclear_MYBPC3",
"additionalComments": "For the current genes where null variants are a known mechanism, pathogenic missense variants have also been reported.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "095",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711152",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711152",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
"rev": "_inf5Aq---K"
},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "095_PS4_nuclear_MYBPC3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "095",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "{Currently few well-designed case-control studies have been performed for inherited cardiomyopathies. Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). \n\nCohorts used in these analyses should meet the following criteria: \n\n1. The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype\\*). \n * When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded. This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).\n2. The controls should not be derived from study populations that might be enriched for the specified disorder.\n3. The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).\n4. The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).\n5. The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).\n6. The population diversity of the case and control cohorts are broadly similar.\n7. Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh _et al._ 2017[9](#pmid_27532257), [DECIPHER](https://www.deciphergenomics.org/gene/MYBPC3/patient-overlap/snvs)).\n\nTo account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:\n\n* **STRONG** evidence requires the lower bound of the 95% confidence interval (CI) around the odds ratio (OR) estimate to be **≥20**\n\nA PS4 calculator is available at [www.cardiodb.org](https://www.cardiodb.org/ps4_calculator/ps4_calculator.html).\n\nIf multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered). \n\n**\\*RELEVANT PHENOTYPES:**\n\n1. Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. \n2. For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. \n3. Additional considerations for LVNC and end-stage HCM: \n * Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson _et al._ 2017[10](#pmid_28395867); Oechslin _et al._ 2017[11](#pmid_28545618); Hershberger _et al._ 2017[12](#pmid_29212902); Ross _et al._ 2020[13](#pmid_31143950)), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).\n\nHCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Currently few well-designed case-control studies have been performed for inherited cardiomyopathies. Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). \n\nCohorts used in these analyses should meet the following criteria: \n\n1. The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype\\*). \n * When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded. This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).\n2. The controls should not be derived from study populations that might be enriched for the specified disorder.\n3. The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).\n4. The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).\n5. The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).\n6. The population diversity of the case and control cohorts are broadly similar.\n7. Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh _et al._ 2017[9](#pmid_27532257), [DECIPHER](https://www.deciphergenomics.org/gene/MYBPC3/patient-overlap/snvs)).\n\nTo account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:\n\n* **MODERATE** evidence requires the lower bound of the 95% CI around the OR to be **≥10**\n\nA PS4 calculator is available at [www.cardiodb.org](https://www.cardiodb.org/ps4_calculator/ps4_calculator.html).\n\nIf multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered). \n\n**\\*RELEVANT PHENOTYPES:**\n\n1. Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. \n2. For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. \n3. Additional considerations for LVNC and end-stage HCM: \n * Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson _et al._ 2017[10](#pmid_28395867); Oechslin _et al._ 2017[11](#pmid_28545618); Hershberger _et al._ 2017[12](#pmid_29212902); Ross _et al._ 2020[13](#pmid_31143950)), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).\n\nHCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Currently few well-designed case-control studies have been performed for inherited cardiomyopathies. Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). \n\nCohorts used in these analyses should meet the following criteria: \n\n1. The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype\\*). \n * When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded. This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).\n2. The controls should not be derived from study populations that might be enriched for the specified disorder.\n3. The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).\n4. The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).\n5. The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).\n6. The population diversity of the case and control cohorts are broadly similar.\n7. Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh _et al._ 2017[9](#pmid_27532257), [DECIPHER](https://www.deciphergenomics.org/gene/MYBPC3/patient-overlap/snvs)).\n\nTo account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:\n\n* **SUPPORTING** evidence requires the lower bound of the 95% CI around the OR to be **≥5**\n\nA PS4 calculator is available at [www.cardiodb.org](https://www.cardiodb.org/ps4_calculator/ps4_calculator.html).\n\nIf multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered). \n\n**\\*RELEVANT PHENOTYPES:**\n\n1. Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. \n2. For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. \n3. Additional considerations for LVNC and end-stage HCM: \n * Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson _et al._ 2017[10](#pmid_28395867); Oechslin _et al._ 2017[11](#pmid_28545618); Hershberger _et al._ 2017[12](#pmid_29212902); Ross _et al._ 2020[13](#pmid_31143950)), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).\n\nHCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711147",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711147",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
"rev": "_inf5Aq---J"
},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "095_BP4_nuclear_MYBPC3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "095",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "As many _in silico_ algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.\n\nUse of REVEL (Ioannidis _et al._ 2016[17](#pmid_27666373)) is recommended at thresholds of **≤0.40 for BP4**.\n\nClinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.\n\nPositive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.\n\n[SpliceAI](https://spliceailookup.broadinstitute.org)[2](#pmid_30661751) is recommended for evaluation of predicted splice impacts.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711172",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711172",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
"rev": "_inf5Ate--Q"
},
{
"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "095_BP7_nuclear_MYBPC3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYBPC3"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "095",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Also applicable to **intronic variants outside the splice consensus sequence (-4 and +7 outward)** for which splicing prediction algorithms predict no impact to the splice consensus sequence NOR the creation of a new splice site AND the nucleotide is not highly conserved.\n\nRule can be combined with BP4 to make a variant likely benign per Richards _et al._ 2015[6](#pmid_25741868).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768711161",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768711161",
"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
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"applicability": "Applicable",
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"evidenceCategory": "Computational And Predictive Data",
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],
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"instructionsToUse": "",
"label": "PVS1",
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"id": "0020",
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"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"id": "0026",
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"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
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"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
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"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
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"created": "2024-04-22T15:43:46.004Z",
"creator": "makelly2",
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"_uniqueProp": "095_PP5_nuclear_MYBPC3",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
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"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "095",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
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"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
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"ldhId": "1768711155",
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"modified": "2024-04-22T15:43:46.004Z",
"modifier": "makelly2",
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{
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{
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{
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"val": "hypertrophic subaortic stenosis"
},
{
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"val": "obstructive hypertrophic cardiomyopathy"
},
{
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},
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"modified": "2025-10-07T16:12:02.925Z",
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"date_modified": "2021-05-26",
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],
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658
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"location": "11p11.2",
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"locus_group": "protein-coding gene",
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"lsdb": [
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],
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],
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],
"name": "myosin binding protein C3",
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],
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],
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"status": "Approved",
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],
"ucsc_id": "uc058bdz.1",
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],
"uuid": "780d9df7-6d28-45af-98d3-8c15e9ab697e",
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},
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"modified": "2021-10-14T11:36:54.249Z",
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],
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{
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"geneType": "nuclear",
"genes": [
{
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"preferredMondoId": "MONDO:0005045",
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}
],
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],
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{
"auths": [
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"title": "Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion.",
"vol": "39",
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{
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],
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"title": "A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance.",
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{
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"et al."
],
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"id": "18337725",
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"source": "Eur J Hum Genet",
"title": "Micro-exons of the cardiac myosin binding protein C gene: flanking introns contain a disproportionately large number of hypertrophic cardiomyopathy mutations.",
"vol": "16",
"year": "2008"
},
{
"auths": [
"Carrier L",
"Mearini G",
"et al."
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"id": "26358504",
"iss": "(2)",
"namespace": "pmid",
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"source": "Gene",
"title": "Cardiac myosin-binding protein C (MYBPC3) in cardiac pathophysiology.",
"vol": "573",
"year": "2015"
},
{
"auths": [
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"Aziz N",
"et al."
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"source": "Genet Med",
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.",
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"year": "2015"
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{
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"title": "Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework.",
"vol": "12",
"year": "2019"
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{
"auths": [
"Walsh R",
"Thomson KL",
"et al."
],
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"namespace": "pmid",
"pages": "p. 192-203.",
"source": "Genet Med",
"title": "Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.",
"vol": "19",
"year": "2017"
},
{
"auths": [
"Anderson RH",
"Jensen B",
"et al."
],
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"id": "28395867",
"iss": "(6)",
"namespace": "pmid",
"pages": "p. 747-757.",
"source": "Can J Cardiol",
"title": "Key Questions Relating to Left Ventricular Noncompaction Cardiomyopathy: Is the Emperor Still Wearing Any Clothes?",
"vol": "33",
"year": "2017"
},
{
"auths": [
"Oechslin E",
"Jenni R"
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"doiStr": "10.1016/j.cjca.2017.04.003",
"id": "28545618",
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"pages": "p. 701-704.",
"source": "Can J Cardiol",
"title": "Nosology of Noncompaction Cardiomyopathy: The Emperor Still Wears Clothes!",
"vol": "33",
"year": "2017"
},
{
"auths": [
"Hershberger RE",
"Morales A",
"et al."
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"source": "Circ Cardiovasc Genet",
"title": "Is Left Ventricular Noncompaction a Trait, Phenotype, or Disease? The Evidence Points to Phenotype.",
"vol": "10",
"year": "2017"
},
{
"auths": [
"Ross SB",
"Jones K",
"et al."
],
"doiStr": "10.1093/eurheartj/ehz317",
"id": "31143950",
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"pages": "p. 1428-1436.",
"source": "Eur Heart J",
"title": "A systematic review and meta-analysis of the prevalence of left ventricular non-compaction in adults.",
"vol": "41",
"year": "2020"
},
{
"auths": [
"Walsh R",
"Mazzarotto F",
"et al."
],
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"iss": "(1)",
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"source": "Genome Med",
"title": "Quantitative approaches to variant classification increase the yield and precision of genetic testing in Mendelian diseases: the case of hypertrophic cardiomyopathy.",
"vol": "11",
"year": "2019"
},
{
"auths": [
"Kelly MA",
"Caleshu C",
"et al."
],
"doiStr": "10.1038/gim.2017.218",
"id": "29300372",
"iss": "(3)",
"namespace": "pmid",
"pages": "p. 351-359.",
"source": "Genet Med",
"title": "Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel.",
"vol": "20",
"year": "2018"
},
{
"auths": [
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],
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"pages": "p. 1077-1081.",
"source": "Am J Hum Genet",
"title": "Consideration of Cosegregation in the Pathogenicity Classification of Genomic Variants.",
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"year": "2016"
},
{
"auths": [
"Ioannidis NM",
"Rothstein JH",
"et al."
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"source": "Am J Hum Genet",
"title": "REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants.",
"vol": "99",
"year": "2016"
},
{
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"entType": "CriteriaCode",
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166138",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5ZK---"
},
{
"entContent": {
"_uniqueProp": "097_BS1_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Apply based on maximum filter allele frequency in a gnomAD non-founder population, considering exome and genome data separately.\n\nDo not apply if read depth \\<20. Do not apply to well-established pathogenic founder variants.",
"label": "BS1",
"ns": "097",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166136",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166136",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5bW---"
},
{
"entContent": {
"_uniqueProp": "097_PM3_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Co-occurrent P or LP variant should be assigned classification using VCEP specifications. \n\nVariant under assessment must be sufficiently rare (not meeting a benign population evidence code).\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points.\n\nFor related individuals score only most severe presentation.\n\nAlso see **Specifications Table 6** for additional stipulations",
"label": "PM3",
"ns": "097",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis _≤5yr_.\n\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3\\_Strong = ≥4 points",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"This requires testing of parents (or offspring) to determine phase."
]
},
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis _≤5yr_.\n\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3 = 2 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis _≤5yr_.\n\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3\\_Supporting = 1 point",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166128",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166128",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5oO---"
},
{
"entContent": {
"_uniqueProp": "097_PM2_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Observation of a variant only once in a gnomAD outbred population is not informative. Do not apply for insertion, deletion or delins variants. Do not apply if read depth \\<25 at region around the variant.",
"label": "PM2",
"ns": "097",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Population data for insertions/deletions may be poorly called by next-generation sequencing."
]
},
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166118",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166118",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5pW---"
},
{
"entContent": {
"_uniqueProp": "097_PP4_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Use in the context of clinically calibrated evidence types, with sufficient detail to review data sources, types and weights. Published data points may include co-segregation with disease, co-occurrence with a pathogenic variant in the same gene, reported family history, breast tumor pathology, and case-control data. Can also apply for unpublished data, where there is no appropriate ACMG/AMP code. Assign weight based on combined LR for clinical data.\n\nCombined LR >0.48 and \\<2.08 doesn't provide supporting evidence in either direction (PP4 and BP5 not applicable).\n\nSee Specifications Table7 for example application.",
"label": "PP4",
"ns": "097",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4\\_Strong – LR ≥18.7:1\n\nPP4\\_Very Strong – LR ≥350:1\n\nSee Specifications Table7 and Appendix B for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4\\_Moderate – LR ≥4.3:1\n\nSee Specifications Table7 and Appendix B for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4 - LR ≥2.08:1 \n\nSee Specifications Table7 and Appendix B for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166140",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166140",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5sW---"
},
{
"entContent": {
"_uniqueProp": "097_BP3_nuclear_BRCA2",
"additionalComments": "Captured by bioinformatic tool prediction, and domain analysis. See Appendix J for details",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "097",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166139",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166139",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5YW---"
},
{
"entContent": {
"_uniqueProp": "097_PVS1_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "In alignment with SVI recommendations for PVS1 code application, evidence strength and description has been separated for different variant types. Apply according to PVS1 flowchart, which considers knowledge of clinically important functional domains. For predicted protein termination codon (PTC) variants, apply with exon-specific weights derived for the PM5\\_PTC code (See Appendix D for details).\n\n**See Specifications Table 4, provided as a separate searchable excel file, for a comprehensive summary of codes applicable for all variants considered against the** _**BRCA1**_ **and** _**BRCA2**_ **PVS1 decision trees (initiation, nonsense/frameshift, deletion, duplication, splice site (donor/acceptor ±1,2)) – organized by exon.** See Appendix Figure 5,6 and Table 5 for further justification.\n\nSee **Specifications** **Figure 1B** for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.",
"label": "PVS1",
"ns": "097",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166130",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166130",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5uq---"
},
{
"entContent": {
"_uniqueProp": "097_PM1_nuclear_BRCA2",
"additionalComments": "Considered as component of bioinformatic analysis (PP3/BP4). ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "097",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166129",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166129",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5v2---"
},
{
"entContent": {
"_uniqueProp": "097_PP5_nuclear_BRCA2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "097",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166127",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166127",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5dq---"
},
{
"entContent": {
"_uniqueProp": "097_BS2_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Co-occurrent P or LP variant should be assigned classification using VCEP specifications. \n\nSee **Specifications Table 8** for approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points.\n\nAlso see **Specifications Table 8** for additional stipulations.",
"label": "BS2",
"ns": "097",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2 = ≥ 4 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2\\_Moderate = 2 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2\\_Supporting = 1 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166126",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166126",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5Se---"
},
{
"entContent": {
"_uniqueProp": "097_BP1_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "See **Specifications Figure 1A** for process to apply codes according to variant type, location and predicted bioinformatic impact. _Missense prediction not applicable_.",
"label": "BP1",
"ns": "097",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "**Apply BP1\\_Strong** for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0205",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166124",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166124",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5VK---"
},
{
"entContent": {
"_uniqueProp": "097_BS4_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Recommend use of online tools COOL ([http://bjfenglab.org/](http://bjfenglab.org/)) or CAL-Leiden ([https://bioexp.net/cosegregation/](https://bioexp.net/cosegregation/)). \nLR >0.48 and \\<2.08 doesn't provide supporting evidence in either direction (PP1 and BS4 not applicable).",
"label": "BS4",
"ns": "097",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nBS4 - LR ≤0.05:1\n\nBS4\\_VeryStrong – LR ≤0.00285:1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nBS4\\_Moderate - LR ≤0.23:1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nBS4\\_Supporting - LR ≤0.48:1",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166123",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166123",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5eu---"
},
{
"entContent": {
"_uniqueProp": "097_BS3_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "See **Specifications Figure 1C** for simplified flowchart/s to advise application of codes for functional data, in content of variant type and location within a (potentially) clinically important functional domain. Do not apply when conflicting results are present from well-established assays with sufficient controls, which cannot be explained by experimental design.\n\nSee **Specifications Figure 1B** for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.\n\nSee **Specifications Table 9,** provided as a separate file in excel format to facilitate searches and look-ups by variant c. and p. nomenclature. It includes PS3 and BS3 code recommendations and rationale for code application of published functional assays data that has been calibrated, and considered against predicted/reported splicing. This is not an exhaustive list; there will be ongoing consideration of additional published functional assay results.",
"label": "BS3",
"ns": "097",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of no damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as BP7 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166122",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166122",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5WG---"
},
{
"entContent": {
"_uniqueProp": "097_PS1_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "For both missense and splicing scenarios, (Likely) Pathogenic variant classification should be assigned using VCEP specifications.\n\nFor application of PS1 for splicing predictions, **see Specifications Table 5.** The predicted event of the VUA must precisely match the predicted event of the known (likely) pathogenic variant (e.g. both predicted to lead to exon A skipping, or both to enhanced use of cryptic site B), AND the strength of the prediction for the VUA must be of similar or higher strength than the strength of the prediction for the known (likely) pathogenic variant. For an exonic variant, predicted or proven functional effect of missense substitution/s encoded by the variant and the established pathogenic variant should also be considered before PS1 code application for splicing prediction.",
"label": "PS1",
"ns": "097",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Apply **PS1**, for predicted **missense** substitutions, where a previously classified **pathogenic** variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\n\nApply **PS1**, for exonic and intronic variants with same predicted impact on **splicing,** as a previously classified **pathogenic** variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. \n\nSee Specifications Table 5 and Appendix E, J and K for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Apply **PS1\\_Moderate**, for predicted **missense** substitutions, where a previously classified **likely pathogenic** variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\n\nApply **PS1\\_Moderate**, for exonic and intronic variants with same predicted impact on **splicing**, as a previously classified **(likely) pathogenic** variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\n\nSee Specifications Table 5 and Appendix E, J and K for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Apply **PS1**, for exonic and intronic variants with same predicted impact on **splicing**, as a previously classified **(likely) pathogenic** variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\n\nSee Specifications Table 5 and Appendix E, J and K for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166142",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166142",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5mO---"
},
{
"entContent": {
"_uniqueProp": "097_BP7_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "See **Specifications Figure 1B** for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained. Not applicable for missense variants inside a (potentially) clinically important functional domain as they may still impact protein function through the amino acid change.\n\nFollowing convention, this code is applied in addition to BP4 (no splicing prediction, Splice AI ≤0.1) to capture the low prior probability of pathogenicity of silent variants. Nucleotide conservation is not considered relevant. See **Specifications Figure 1A** for process to apply codes according to variant type, location and predicted bioinformatic impact.",
"label": "BP7",
"ns": "097",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function _as measured by effect on mRNA transcript profile – mRNA assay only._ Apply as BP7\\_Strong (RNA) for intronic and silent variants, as well as missense/in-frame variants located outside a (potentially) clinically important functional domain. Missense variants located inside a (potentially) clinically important functional domain must meet BS3 to be eligible for BP7\\_Strong (RNA). See Specifications Figure1B and Appendix E for details.\n\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Clarification",
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Silent variant inside a (potentially) clinically important functional domain, IF BP4 met.\n\nIntronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.\n\nSee Specifications Figure1A and Appendix J for additional details.\n\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166133",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166133",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5iy---"
},
{
"entContent": {
"_uniqueProp": "097_BA1_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Apply based on maximum filter allele frequency observed in a gnomAD non-founder population, considering exome and genome data separately.\n\nDo not apply if read depth \\<20. Do not apply to well-established pathogenic founder variants.",
"label": "BA1",
"ns": "097",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166131",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166131",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5nO---"
},
{
"entContent": {
"_uniqueProp": "097_PM5_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Only applied to genomic PTC changes (not splicing). Weight determined by exon where the termination codon occurs (may not be the same exon as the variant position). See Specifications Table 4, provided as a separate searchable excel file, for PM5\\_PTC codes applicable for predicted termination codon variants - organized by exon.",
"label": "PM5",
"ns": "097",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Other"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5\\_PTC code strengths applicable per exon. See Appendix D for additional details.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Other"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5\\_PTC code strengths applicable per exon. See Appendix D for additional details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Other"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5\\_PTC code strengths applicable per exon. See Appendix D for additional details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166121",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166121",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5fq---"
},
{
"entContent": {
"_uniqueProp": "097_BP5_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Use in the context of clinically calibrated evidence types, with sufficient detail to review data sources, types and weights. Published data points may include co-segregation with disease, co-occurrence with a pathogenic variant in the same gene, reported family history, breast tumor pathology, and case-control data. Can also apply for unpublished data, where there is no appropriate ACMG/AMP code. Assign weight based on combined LR for clinical data.\n\nCombined LR >0.48 and \\<2.08 doesn't provide supporting evidence in either direction (PP4 and BP5 not applicable).\n\nSee Specifications Table7 for example application.",
"label": "BP5",
"ns": "097",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5\\_VeryStrong – LR ≤0.00285:1\n\nBP5\\_Strong - LR ≤0.05:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5\\_Moderate - LR ≤0.23:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5 - LR ≤0.48:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166137",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166137",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5ae---"
},
{
"entContent": {
"_uniqueProp": "097_PS3_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "See **Specifications Figure 1C** for simplified flowchart/s to advise application of codes for functional data, in content of variant type and location within a (potentially) clinically important functional domain. Do not apply when conflicting results are present from well-established assays with sufficient controls, which cannot be explained by experimental design.\n\nSee **Specifications Figure 1B** for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.\n\nSee **Specifications Table 9,** provided as a separate file in excel format to facilitate searches and look-ups by variant c. and p. nomenclature. It includes PS3 and BS3 code recommendations and rationale for code application of published functional assays data that has been calibrated, and considered against predicted/reported splicing. This is not an exhaustive list; there will be ongoing consideration of additional published functional assay results.",
"label": "PS3",
"ns": "097",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0045",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166135",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166135",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5te---"
},
{
"entContent": {
"_uniqueProp": "097_PM6_nuclear_BRCA2",
"additionalComments": "BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "097",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166132",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166132",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5j2---"
},
{
"entContent": {
"_uniqueProp": "097_PS4_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Case dataset should be ethnicity and country-matched to control dataset. If case-control LR estimates are available for a given dataset, these should be used in preference to case-control OR data, under code PP4 (or BP5, if appropriate). Do not use Proband Counting as originally described.",
"label": "PS4",
"ns": "097",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Clarification",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). See Appendix F for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0057",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0032",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166119",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166119",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5Xi---"
},
{
"entContent": {
"_uniqueProp": "097_PM4_nuclear_BRCA2",
"additionalComments": "Considered as component of bioinformatic analysis (PP3/BP4).",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "097",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "009",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166117",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166117",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5qW---"
},
{
"entContent": {
"_uniqueProp": "097_BP6_nuclear_BRCA2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "097",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166143",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1614166143",
"modified": "2025-01-09T01:12:42.529Z",
"modifier": "michaelP",
"rev": "_jCgc5k6---"
},
{
"entContent": {
"_uniqueProp": "097_PS2_nuclear_BRCA2",
"additionalComments": "BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "097",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Not applicable",
"id": "0051",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
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{
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"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/BRCA2",
"LOVD - Leiden Open Variation Database|http://proteomics.bio21.unimelb.edu.au/lovd/genes/BRCA2",
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/FANCD1",
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"rgd_id": [
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"id": "0240",
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"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "No cardiomyopathy specifications. Apply as outlined by Richards _et al_. 2015[1](#pmid_25741868).\n\nExample of when rule should NOT be applied. NM\\_000256.3(_MYBPC3_): c.2308G>A (p.Asp770Asn) has an established impact on splicing leading to nonsense mediated decay (NMD) and should not be used to provide evidence for other variants observed to result in the same amino acid change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712804",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712804",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5AtW--j"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_PM6_nuclear_TNNI3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "098",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Refer to SVI guidance on number/combination of cases required based on phenotype specificity[2](#url_c73e109e-b916-5a72-b7b1-1762446f3c11).\n\nFor most cardiomyopathies, it is recommended to default to “phenotype consistent with gene but not highly specific”. Clinical judgment is required for shifting to a higher or lower phenotypic consistency. \n\nSee PS2 for additional considerations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712794",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712794",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Atm--D"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_BA1_nuclear_TNNI3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "098",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency is **≥0.001** based on the **filtering allele frequency (FAF)** in **gnomAD** in the subpopulation with the highest frequency (popmax).\n\nThe values used to calculate the BA1 threshold were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/300 or lower).\n\nThe threshold is applicable when assessing variants in the context of autosomal dominant cardiomyopathy. \n\ngnomAD is the preferred database for this calculation. If a subpopulation specific FAF other than the popmax is needed, this value can be calculated using the AlleleFrequencyApp on the [CardioDB website](https://cardiodb.org/allelefrequencyapp/).\n\n1. Using the Inverse AF tab, enter in the population size and the number of alleles identified and it will calculate the FAF. \n2. Set confidence to 0.95 (95%).\n3. If the FAF is ≥0.001, this rule can be applied.\n\nThe FAF by platform (e.g., exome vs. genome; v.2.1.1 vs. v.3.1.1) should be considered, the larger population is most likely to have the most accurate representation of “true” population allele frequency.\n\nCaution is needed when considering any population cohorts that are smaller than the smallest subpopulations within gnomAD v.2.1.1 (e.g., ~5000 individuals or ~10,000 alleles). Despite this conservative nature of this threshold and approach, in smaller cohorts, the observed allele frequency may less accurately reflect the true allele frequency. Traditionally, once a variant is classified as Benign, it is rarely re-evaluated and so the highest confidence is needed to establish that classification on an allele frequency alone.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712793",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712793",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Ate--d"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_BP1_nuclear_TNNI3",
"additionalComments": "For the current genes where null variants are a known mechanism, pathogenic missense variants have also been reported.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "098",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712786",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712786",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Ati--F"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_PS4_nuclear_TNNI3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "098",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Currently few well-designed case-control studies have been performed for inherited cardiomyopathies. Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). \n\nCohorts used in these analyses should meet the following criteria: \n\n1. The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype\\*). \n * When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded. This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).\n2. The controls should not be derived from study populations that might be enriched for the specified disorder.\n3. The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).\n4. The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).\n5. The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).\n6. The population diversity of the case and control cohorts are broadly similar.\n7. Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh _et al._ 2017[5](#pmid_27532257), [DECIPHER](https://www.deciphergenomics.org/gene/TNNI3/patient-overlap/snvs)).\n\nTo account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:\n\n* **STRONG** evidence requires the lower bound of the 95% confidence interval (CI) around the odds ratio (OR) estimate to be **≥20**\n\nA PS4 calculator is available at [www.cardiodb.org](https://www.cardiodb.org/ps4_calculator/ps4_calculator.html).\n\nIf multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered). \n\n**\\*RELEVANT PHENOTYPES:**\n\n1. Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. \n2. For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. \n3. Additional considerations for LVNC and end-stage HCM: \n * Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson _et al._ 2017[6](#pmid_28395867); Oechslin _et al._ 2017[7](#pmid_28545618); Hershberger _et al._ 2017[8](#pmid_29212902); Ross _et al._ 2020[9](#pmid_31143950)), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).\n\nHCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Currently few well-designed case-control studies have been performed for inherited cardiomyopathies. Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). \n\nCohorts used in these analyses should meet the following criteria: \n\n1. The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype\\*). \n * When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded. This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).\n2. The controls should not be derived from study populations that might be enriched for the specified disorder.\n3. The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).\n4. The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).\n5. The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).\n6. The population diversity of the case and control cohorts are broadly similar.\n7. Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh _et al._ 2017[5](#pmid_27532257), [DECIPHER](https://www.deciphergenomics.org/gene/TNNI3/patient-overlap/snvs)).\n\nTo account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:\n\n* **MODERATE** evidence requires the lower bound of the 95% CI around the OR to be **≥10**\n\nA PS4 calculator is available at [www.cardiodb.org](https://www.cardiodb.org/ps4_calculator/ps4_calculator.html).\n\nIf multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered). \n\n**\\*RELEVANT PHENOTYPES:**\n\n1. Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. \n2. For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. \n3. Additional considerations for LVNC and end-stage HCM: \n * Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson _et al._ 2017[6](#pmid_28395867); Oechslin _et al._ 2017[7](#pmid_28545618); Hershberger _et al._ 2017[8](#pmid_29212902); Ross _et al._ 2020[9](#pmid_31143950)), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).\n\nHCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Currently few well-designed case-control studies have been performed for inherited cardiomyopathies. Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). \n\nCohorts used in these analyses should meet the following criteria: \n\n1. The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype\\*). \n * When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded. This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).\n2. The controls should not be derived from study populations that might be enriched for the specified disorder.\n3. The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).\n4. The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).\n5. The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).\n6. The population diversity of the case and control cohorts are broadly similar.\n7. Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh _et al._ 2017[5](#pmid_27532257), [DECIPHER](https://www.deciphergenomics.org/gene/TNNI3/patient-overlap/snvs)).\n\nTo account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:\n\n* **SUPPORTING** evidence requires the lower bound of the 95% CI around the OR to be **≥5**\n\nA PS4 calculator is available at [www.cardiodb.org](https://www.cardiodb.org/ps4_calculator/ps4_calculator.html).\n\nIf multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered). \n\n**\\*RELEVANT PHENOTYPES:**\n\n1. Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. \n2. For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. \n3. Additional considerations for LVNC and end-stage HCM: \n * Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson _et al._ 2017[6](#pmid_28395867); Oechslin _et al._ 2017[7](#pmid_28545618); Hershberger _et al._ 2017[8](#pmid_29212902); Ross _et al._ 2020[9](#pmid_31143950)), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).\n\nHCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712781",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712781",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Ate--T"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_PM4_nuclear_TNNI3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "098",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Strength of rule should be carefully considered and may require downgrading to SUPPORTING based on the predicted impact of the variant, including the size of the deletion/insertion, its location, and conservation of the region. \n\nFor genes where PVS1 is not applicable (i.e., where there is no evidence that pLOF variants cause disease), consider using this rule at MODERATE or SUPPORTING strength for truncating variants that do NOT undergo nonsense mediated decay (NMD).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712779",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712779",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Ati--D"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_PP4_nuclear_TNNI3",
"additionalComments": "Inherited cardiomyopathies have high locus heterogeneity as well as non-genetic etiologies. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "098",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
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]
},
"entType": "CriteriaCode",
"ldhId": "1768712802",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712802",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5AtW--h"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_BP3_nuclear_TNNI3",
"additionalComments": "Not applicable to the current genes. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "098",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712801",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712801",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5AtW--g"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_PM1_nuclear_TNNI3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "098",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable to missense variants in _TNNI3_ in the specific regions listed below (Walsh _et al._ 2019[10](#pmid_30696458)). \n\n1. Transcripts ENST00000344887 and NM\\_000363.5\n2. Codons 141-209\n\nData from HCM case cohorts was used to derive these cluster regions. Therefore, this rule should NOT be applied when additional evidence for the variant supports that the variant causes a phenotype other than HCM (e.g., variant seen in multiple DCM cases).\n\nEnrichment was not observed for DCM in any genes.\n\nRule should NOT be combined with PM5 because presence of pathogenic variants in the same codon/region were used to determine clustering and would be double-counting evidence.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712791",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712791",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Atm--C"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_BS2_nuclear_TNNI3",
"additionalComments": "Inherited cardiomyopathies generally display reduced penetrance, variable expressivity, and adult-onset. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "098",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0069",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0076",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712788",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712788",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Ata--Z"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_PS2_nuclear_TNNI3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "098",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0016",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Refer to SVI guidance on number/combination of cases required based on phenotype specificity[2](#url_c73e109e-b916-5a72-b7b1-1762446f3c11).\n\nFor most cardiomyopathies, it is recommended to default to **Phenotype consistency: “Phenotype consistent with gene but not highly specific”**. Clinical judgment is required for shifting to a higher or lower category. \n\nFor use as a STRONG or VERY STRONG criterion, ideally parents have been thoroughly clinically evaluated without evidence of cardiomyopathy (ideally using a combination of ECG and echocardiogram or cardiac MRI for maximum sensitivity).\n\nA family history consistent with _de novo_ inheritance should not have any clinical signs or symptoms suggestive of cardiomyopathy in a 1st or 2nd degree relative, for example: \n\n1. Sudden death under 60 years of age\n2. Heart transplant\n3. Implantable cardiac defibrillator (ICD) under 60 years of age\n4. Features of cardiomyopathy (e.g., systolic dysfunction, hypertrophy, left ventricular enlargement in an individual without risk factors).\n5. Other related/overlapping cardiomyopathies\n\nExamples of non-suspicious family history may include non-specific clinical features (e.g., palpitations, syncope, borderline/inconclusive echocardiogram findings, heart attack if age appropriate and suspected to result from coronary artery disease), but every attempt should be made to clarify features. \n\nGenerally, this criterion is only applicable in the ABSENCE of any other possible disease-causing variants. If other pathogenic or likely pathogenic variants are present, consider decreasing points assigned or overall weight.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "004",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712803",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712803",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Atm--E"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_PS3_nuclear_TNNI3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"instructionsToUse": "Evaluation of studies/assays is required prior to application of functional evidence at any strength.\n\nRefer to SVI guidance for functional evidence (Brnich _et al._ 2020[4](#pmid_31892348)).\n\nIn the context of cardiomyopathy, very few functional assays currently meet criteria sufficient for application of this rule at a STRONG level. Examples of the types of study/assays that MAY be relevant are described, but further definition of cardiomyopathy models/assays is outside the scope of these guidelines.",
"label": "PS3",
"ns": "098",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**In vitro splicing assays (e.g., RNA studies)**\n\n_In vitro_ splicing assays may be considered as **STRONG** evidence, providing the following criteria are met.\n\n* Prior knowledge of predominant transcripts in cardiac tissue\n\nAnalysis undertaken using RNA extracted from cardiac tissue from the individual with the variant\n\nAnalysis undertaken using RNA extracted from whole blood providing the relevant transcripts (isoforms) are expressed in blood and are at sufficient levels to assess splice disruption.\n\nAssay shows a clear, reproducible and convincing effect on splicing (i.e. a distinct splice product, present at a level comparable to the splice product from the wild-type allele), which is not observed in controls\n\n* Confirmation of abnormal splice product by Sanger sequencing\n\n**NOTE:** Mini-gene assay in non-patient derived cell lines are NOT considered to provide STRONG evidence.\n\n**NOTE:** Whether to activate this rule needs to be reconciled with the variant spectrum and disease mechanism for the gene at hand (i.e., consider whether the effect is likely to lead to LOF or an in-frame alteration and whether this type of effect is expected to be disease causing) (Abou Tayoun _et al._ 2018[3](#pmid_30192042)).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**In vivo models (e.g., variant knock-in animal models)**\n\nMammalian variant-specific knock-in animal models that produce a phenotype consistent with the clinical phenotype in humans (e.g., structural and/or functional cardiac abnormalities, premature death, arrhythmia) may be considered as **MODERATE** evidence\n\n**NOTE:** The following assays/models do NOT meet criteria\n\n1. Assays that are known to be associated with non-specific cardiac phenotypes (e.g., morpholino-induced pericardial edema in zebrafish)\n2. In vivo evidence that is not variant specific, such as whole gene alterations (i.e., cDNA or whole gene transgenic mice and whole or partial gene knock-out mice)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "_**In vitro**_ **assays (e.g., biochemical assays of myofilament function, motility assays, human iPSC-CM)**\n\nWhile some _in vitro_ assays may provide evidence that a variant in a cardiomyopathy gene has an effect on protein and/or myofilament function, at present, there are no validated “gold-standard” assays that are considered to reliably predict the clinical phenotype.\n\nAs such, in the cardiomyopathy genes listed in these guidelines, data from individual _in vitro_ studies are unlikely to meet the criteria required to assign this rule at more than SUPPORTING level.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712797",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712797",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Ate--h"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_PP3_nuclear_TNNI3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "098",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "As many _in silico_ algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.\n\nUse of REVEL (Ioannidis _et al._ 2016[13](#pmid_27666373)) is recommended at thresholds of **≥0.70 for PP3**.\n\nClinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.\n\nPositive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.\n\n[SpliceAI](https://spliceailookup.broadinstitute.org)[14](#pmid_30661751) is recommended for evaluation of predicted splice impacts.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712796",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712796",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Ate--f"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_PM3_nuclear_TNNI3",
"additionalComments": "While compound heterozygosity leading to a more severe phenotype has been documented, this rule was designed for traditional recessive inheritance. It is acknowledged that there is increasing evidence supporting that some of these genes/variants may also be recessive (e.g., MYL2, MYL3), but addressing those edge cases was outside the scope of this current guideline.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "098",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"This requires testing of parents (or offspring) to determine phase."
]
},
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712790",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712790",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Ate--c"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_PM5_nuclear_TNNI3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "098",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion can be used at MODERATE if a different missense variant at the same codon has been classified as _pathogenic_ using these modified guidelines without application of PM5.\n\nThe impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to SUPPORTING if the predicted impact is not expected to be equivalent or more severe.\n\nPM5 should not be combined with PM1. If both are applicable at MODERATE weight, use of PM5 is most appropriate since it is variant specific.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion can be considered at SUPPORTING if a different missense variant at the same codon has been classified as _likely pathogenic_ using these modified guidelines without application of PM5.\n\nThe impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as likely pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to NOT APPLICABLE if the predicted impact is not expected to be equivalent or more severe.\n\nPM5 should not be combined with PM1. The one with the higher strength should be applied, but if both are applicable at SUPPORTING weight, use of PM5 is most appropriate since it is variant specific.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712783",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712783",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5AtW--d"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_BP2_nuclear_TNNI3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "098",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Other variants must be pathogenic as defined by these specifications.\n\nTesting of parents or other informative relatives is often required to determine _cis_/_trans_ status.\n\nIf a variant is seen in _trans_ (or as double heterozygous) with another pathogenic variant in ≥2 cases and the phenotype is not more severe than when either of the two variants are seen in isolation, this rule may be applied (i.e., high confidence this variant is NOT contributing to disease).\n\n* \\<1% of cases of HCM have >1 pathogenic or likely pathogenic variant (0.6%; Alfares _et al._ 2015[17](#pmid_25611685)).\n\nThis rule cannot be applied when the variant has only been observed in _cis_ with a pathogenic variant as its significance in isolation is unknown in this scenario. \n\nCaution is needed if using this criterion as a primary piece of evidence for classifying a variant as likely benign/benign (i.e., only 2 SUPPORTING criteria are sufficient for a likely benign classification).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712782",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712782",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Atm--B"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_BP4_nuclear_TNNI3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "098",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "As many _in silico_ algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.\n\nUse of REVEL (Ioannidis et al. 2016[13](#pmid_27666373)) is recommended at thresholds of **≤0.40 for BP4**.\n\nClinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.\n\nPositive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.\n\n[SpliceAI](https://spliceailookup.broadinstitute.org)[14](#pmid_30661751) is recommended for evaluation of predicted splice impacts.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712806",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712806",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Ati--I"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_BS1_nuclear_TNNI3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "098",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency is **≥0.0001 for** _**TNNI3**_ based on the **filtering allele frequency (FAF)** in **gnomAD** in the subpopulation with the highest frequency (popmax).\n\nCriterion BS1 may only be used as standalone evidence to classify a variant as Likely Benign in the absence of conflicting data. See SVI guidance (Tavtigian _et al._ 2018[15](#pmid_29300386); Tavtigian _et al._ 2020[16](#pmid_32720330)). \n\nSee BA1 for additional specifications that also apply to BS1.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712798",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712798",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Ate--j"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_PP2_nuclear_TNNI3",
"additionalComments": "Application of this rule takes into consideration empirical data quantifying levels of rare missense variant enrichment in HCM referral cohorts compared to population-based cohorts (Walsh et al. 2019 PMID:30696458) rather than the missense constraint score in gnomAD. For TNNI3, there is evidence for regional enrichment of rare missense variants (see PM1 specifications).",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "098",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712787",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712787",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5AtW--f"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_BS3_nuclear_TNNI3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"instructionsToUse": "Evaluation of studies/assays is required prior to application of functional evidence at any strength.\n\nRefer to SVI guidance for functional evidence (Brnich _et al._ 2020[4](#pmid_31892348)).\n\nIn the context of cardiomyopathy, very few functional assays currently meet criteria sufficient for application of this rule at a STRONG level. Examples of the types of study/assays that MAY be relevant are described, but further definition of cardiomyopathy models/assays is outside the scope of these guidelines.",
"label": "BS3",
"ns": "098",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "See PS3 specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "See PS3 specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "See PS3 specifications.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712784",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712784",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Ati--E"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_BP6_nuclear_TNNI3",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "098",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712805",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712805",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5AtW--l"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_PP1_nuclear_TNNI3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "098",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at **≥7** **segregations** (LOD score of 2.1) for **STRONG**.\n\nAlthough rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)[12](#pmid_27236918) can be considered: \n\n* STRONG evidence requires ≥5 segregations (LOD score of 1.5)\n\nOnly genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.\n\nPhenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis. \n\nImportant considerations include:\n\n1. Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant. If linkage disequilibrium is a concern, consider downgrading strength of segregation. \n2. Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1.\n3. Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. \n4. Caution is needed when distantly related (≥3rd degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at **≥5** **segregations** (LOD score of 1.5) for **MODERATE**.\n\nAlthough rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)[12](#pmid_27236918) can be considered: \n\n* MODERATE evidence requires ≥4 segregations (LOD score of 1.2)\n\nOnly genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.\n\nPhenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis. \n\nImportant considerations include:\n\n1. Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant. If linkage disequilibrium is a concern, consider downgrading strength of segregation. \n2. Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).\n3. Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. \n4. Caution is needed when distantly related (≥3rd degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"May be used as stronger evidence with increasing segregation data"
]
},
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at **≥3** **segregations** (LOD score of 0.9) for **SUPPORTING**. The thresholds as proposed by Jarvik and Browning (2016)[12](#pmid_27236918) are the same at ≥3 segregations (LOD score of 0.9) for supporting.\n\nOnly genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.\n\nPhenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis. \n\nImportant considerations include:\n\n1. Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant. If linkage disequilibrium is a concern, consider downgrading strength of segregation. \n2. Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).\n3. Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. \n4. Caution is needed when distantly related (≥3rd degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",
"type": "EvidenceLineStrength"
}
]
},
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"ldhId": "1768712800",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712800",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Ate--l"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_BP5_nuclear_TNNI3",
"additionalComments": "Co-occurrence with an established pathogenic or likely pathogenic variant for a non-cardiomyopathy related disease does not reduce the likelihood that a variant is independently disease-causing for cardiomyopathy.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "098",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712799",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712799",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Ati--H"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_BP7_nuclear_TNNI3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "098",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
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"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Also applicable to **intronic variants outside the splice consensus sequence (-4 and +7 outward)** for which splicing prediction algorithms predict no impact to the splice consensus sequence NOR the creation of a new splice site AND the nucleotide is not highly conserved.\n\nRule can be combined with BP4 to make a variant likely benign per Richards _et al._ 2015[1](#pmid_25741868).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712795",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712795",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Ata--b"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_PVS1_nuclear_TNNI3",
"additionalComments": "Not currently applicable to TNNI3. See PM4 for truncating variants that do NOT undergo NMD.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PVS1",
"ns": "098",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Not applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712792",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712792",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Ati--G"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_PP5_nuclear_TNNI3",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "098",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712789",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712789",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Ate--a"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "098_BS4_nuclear_TNNI3",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"TNNI3"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "098",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
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"completed": true
}
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"applicability": "Not applicable",
"id": "0229",
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"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0227",
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"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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"additionalComments": {
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]
},
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"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Any non-segregations should be carefully evaluated to rule out a phenocopy or the presence of a second disease-causing variant before considering it as conflicting or benign evidence. \n\n1. The presence of “phenocopies” (e.g., athlete’s heart, hypertensive heart disease, ischemic cardiomyopathy, alcoholic cardiomyopathy, diabetic cardiomyopathy) can mimic non-segregation (i.e., lack of segregation) among affected individuals. \n2. Families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent ‘non-segregation’.\n\nBecause of these possibilities, **multiple (≥2) non-segregations** that are highly unlikely to be phenocopies or due to alternate variants (e.g., those without a possible alternate cause) **are required to apply this rule**. A higher number of non-segregations is necessary for instances where alternative causes are possible (e.g., non-segregation in a sibling with childhood onset cardiomyopathy versus a grandparent with hypertension and HCM).\n\nCareful consideration of the above points is required when using this data as conflicting evidence, especially when overall evidence supports likely pathogenic or pathogenic.",
"type": "EvidenceLineStrength"
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"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
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"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
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},
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712785",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Ate--X"
},
{
"created": "2024-04-22T15:44:14.699Z",
"creator": "makelly2",
"entContent": {
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"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PM2",
"ns": "098",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
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"completed": true
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"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
"additionalComments": {
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]
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"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The values used to calculate the PM2 thresholds were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/500 or lower), where the most frequent pathogenic variant accounts for no more than 2% of cases (e.g., has an allele frequency of ≤0.02 in cases based on the upper bound of 95% CI), and where the penetrance of a pathogenic variant is expected to be at least 50% (Kelly _et al._ 2018[11](#pmid_29300372)).\n\nA threshold of **≤0.00004** in the subpopulation with the highest frequency when using the upper bound of the 95% CI activates this rule.\n\n1. Alternatively, this is equivalent to the variant NOT being observed more than once (≤1 allele) in gnomAD v.2.1.1 in one of the non-founder populations (e.g., absence required from the Other and Ashkenazi Jewish subpopulations).\n2. Applying a threshold of ≤0.00004 (upper bound of 95% CI of the allele frequency in gnomAD) is equivalent to the variant being seen in a single subpopulation and that subpopulation meets any of the following:\n * **Allele Count (AC) in Allele Number (AN)**\n * ≤1 in ≥120,000\n * ≤2 in ≥160,000\n * ≤3 in ≥195,000\n * ≤4 in ≥230,000\n\ngnomAD is the preferred database for this calculation, but currently only displays the filtering allele frequency (FAF), which is equivalent to a lower bound estimate of the 95% CI, when the upper bound is what is needed.\n\n* Confidence interval tools, such as [Confit-de-MAF](https://www.genecalculators.net/confit-de-maf.html), can be used to determine the upper bound of the 95% CI of the observed allele frequency.\n\nDue to current technical limitations of next generation sequencing technologies, minor allele frequencies for complex variants (e.g., large indels) may not be accurately represented in population databases.\n\nCaution should be used when a variant is only identified, or over-represented, in one of the smaller gnomAD populations, as the gnomAD allele frequencies may not accurately represent the true population frequency.\n\nPopulation databases may contain affected or pre-symptomatic individuals for diseases with reduced penetrance/variable onset.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768712780",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768712780",
"modified": "2024-04-22T15:44:14.699Z",
"modifier": "makelly2",
"rev": "_inf5Atm--A"
}
],
"Disease": [
{
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"lbl": "hypertrophic cardiomyopathy",
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"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0005045"
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"val": "http://identifiers.org/snomedct/233873004"
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"val": "http://linkedlifedata.com/resource/umls/id/C0007194"
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"val": "http://www.orpha.net/ORDO/Orphanet_217569"
},
{
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"val": "http://purl.bioontology.org/ontology/ICD10CM/I42.1"
},
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"val": "http://purl.bioontology.org/ontology/ICD10CM/I42.2"
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"namespace": "GN099",
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"shortTitle": "Cardiomyopathy Specification",
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"title": "ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TNNT2 Version 1.0.0",
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"created": "2024-04-22T15:44:40.957Z",
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"additionalComments": "",
"applicability": "Applicable",
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"evidenceCategory": "De novo Data",
"gene": [
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"geneType": "nuclear",
"label": "PS2",
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"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
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"applicability": "Not Applicable",
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"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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"text": "Refer to SVI guidance on number/combination of cases required based on phenotype specificity[2](#url_c73e109e-b916-5a72-b7b1-1762446f3c11).\n\nFor most cardiomyopathies, it is recommended to default to **Phenotype consistency: “Phenotype consistent with gene but not highly specific”**. Clinical judgment is required for shifting to a higher or lower category. \n\nFor use as a STRONG or VERY STRONG criterion, ideally parents have been thoroughly clinically evaluated without evidence of cardiomyopathy (ideally using a combination of ECG and echocardiogram or cardiac MRI for maximum sensitivity).\n\nA family history consistent with _de novo_ inheritance should not have any clinical signs or symptoms suggestive of cardiomyopathy in a 1st or 2nd degree relative, for example: \n\n1. Sudden death under 60 years of age\n2. Heart transplant\n3. Implantable cardiac defibrillator (ICD) under 60 years of age\n4. Features of cardiomyopathy (e.g., systolic dysfunction, hypertrophy, left ventricular enlargement in an individual without risk factors).\n5. Other related/overlapping cardiomyopathies\n\nExamples of non-suspicious family history may include non-specific clinical features (e.g., palpitations, syncope, borderline/inconclusive echocardiogram findings, heart attack if age appropriate and suspected to result from coronary artery disease), but every attempt should be made to clarify features. \n\nGenerally, this criterion is only applicable in the ABSENCE of any other possible disease-causing variants. If other pathogenic or likely pathogenic variants are present, consider decreasing points assigned or overall weight.",
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"status": "approved",
"strength": "Moderate",
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"text": "",
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"status": "approved",
"strength": "Supporting",
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"text": "",
"type": "EvidenceLineStrength"
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"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
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"additionalComments": "Inherited cardiomyopathies have high locus heterogeneity as well as non-genetic etiologies. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PP4",
"ns": "099",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
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"applicability": "Not applicable",
"id": "0239",
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"strength": "Stand Alone",
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"type": "EvidenceLineStrength"
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"id": "002",
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"type": "EvidenceLineStrength"
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"strength": "Strong",
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"created": "2024-04-22T15:44:40.957Z",
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"additionalComments": "Co-occurrence with an established pathogenic or likely pathogenic variant for a non-cardiomyopathy related disease does not reduce the likelihood that a variant is independently disease-causing for cardiomyopathy.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BP5",
"ns": "099",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
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"strength": "Very Strong",
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"type": "EvidenceLineStrength"
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"applicability": "Not applicable",
"id": "0073",
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"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
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"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
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]
},
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"ldhId": "1768714454",
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"modified": "2024-04-22T15:44:40.957Z",
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{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
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"applicability": "Applicable",
"baseStrength": "Benign",
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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"geneType": "nuclear",
"label": "BP7",
"ns": "099",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
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"applicability": "Not applicable",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0219",
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"strength": "Very Strong",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
"id": "0065",
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"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
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"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
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"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
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"text": "Also applicable to **intronic variants outside the splice consensus sequence (-4 and +7 outward)** for which splicing prediction algorithms predict no impact to the splice consensus sequence NOR the creation of a new splice site AND the nucleotide is not highly conserved.\n\nRule can be combined with BP4 to make a variant likely benign per Richards _et al._ 2015[1](#pmid_25741868).",
"type": "EvidenceLineStrength"
}
]
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"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
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"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
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"additionalComments": "For the current genes where null variants are a known mechanism, pathogenic missense variants have also been reported.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BP1",
"ns": "099",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
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{
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"gene": [
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],
"geneType": "nuclear",
"label": "PS4",
"ns": "099",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
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"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable",
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"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
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"text": "Currently few well-designed case-control studies have been performed for inherited cardiomyopathies. Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). \n\nCohorts used in these analyses should meet the following criteria: \n\n1. The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype\\*). \n * When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded. This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).\n2. The controls should not be derived from study populations that might be enriched for the specified disorder.\n3. The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).\n4. The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).\n5. The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).\n6. The population diversity of the case and control cohorts are broadly similar.\n7. Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh _et al._ 2017[5](#pmid_27532257), [DECIPHER](https://www.deciphergenomics.org/gene/TNNT2/patient-overlap/snvs)).\n\nTo account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:\n\n* **STRONG** evidence requires the lower bound of the 95% confidence interval (CI) around the odds ratio (OR) estimate to be **≥20**\n\nA PS4 calculator is available at [www.cardiodb.org](https://www.cardiodb.org/ps4_calculator/ps4_calculator.html).\n\nIf multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered). \n\n**\\*RELEVANT PHENOTYPES:**\n\n1. Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. \n2. For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. \n3. Additional considerations for LVNC and end-stage HCM: \n * Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson _et al._ 2017[6](#pmid_28395867); Oechslin _et al._ 2017[7](#pmid_28545618); Hershberger _et al._ 2017[8](#pmid_29212902); Ross _et al._ 2020[9](#pmid_31143950)), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).\n\nHCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Currently few well-designed case-control studies have been performed for inherited cardiomyopathies. Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). \n\nCohorts used in these analyses should meet the following criteria: \n\n1. The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype\\*). \n * When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded. This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).\n2. The controls should not be derived from study populations that might be enriched for the specified disorder.\n3. The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).\n4. The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).\n5. The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).\n6. The population diversity of the case and control cohorts are broadly similar.\n7. Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh _et al._ 2017[5](#pmid_27532257), [DECIPHER](https://www.deciphergenomics.org/gene/TNNT2/patient-overlap/snvs)).\n\nTo account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:\n\n* **MODERATE** evidence requires the lower bound of the 95% CI around the OR to be **≥10**\n\nA PS4 calculator is available at [www.cardiodb.org](https://www.cardiodb.org/ps4_calculator/ps4_calculator.html).\n\nIf multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered). \n\n**\\*RELEVANT PHENOTYPES:**\n\n1. Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. \n2. For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. \n3. Additional considerations for LVNC and end-stage HCM: \n * Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson _et al._ 2017[6](#pmid_28395867); Oechslin _et al._ 2017[7](#pmid_28545618); Hershberger _et al._ 2017[8](#pmid_29212902); Ross _et al._ 2020[9](#pmid_31143950)), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).\n\nHCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",
"type": "EvidenceLineStrength"
},
{
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"id": "0032",
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"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Currently few well-designed case-control studies have been performed for inherited cardiomyopathies. Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). \n\nCohorts used in these analyses should meet the following criteria: \n\n1. The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype\\*). \n * When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded. This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).\n2. The controls should not be derived from study populations that might be enriched for the specified disorder.\n3. The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).\n4. The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).\n5. The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).\n6. The population diversity of the case and control cohorts are broadly similar.\n7. Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh _et al._ 2017[5](#pmid_27532257), [DECIPHER](https://www.deciphergenomics.org/gene/TNNT2/patient-overlap/snvs)).\n\nTo account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:\n\n* **SUPPORTING** evidence requires the lower bound of the 95% CI around the OR to be **≥5**\n\nA PS4 calculator is available at [www.cardiodb.org](https://www.cardiodb.org/ps4_calculator/ps4_calculator.html).\n\nIf multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered). \n\n**\\*RELEVANT PHENOTYPES:**\n\n1. Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. \n2. For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. \n3. Additional considerations for LVNC and end-stage HCM: \n * Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson _et al._ 2017[6](#pmid_28395867); Oechslin _et al._ 2017[7](#pmid_28545618); Hershberger _et al._ 2017[8](#pmid_29212902); Ross _et al._ 2020[9](#pmid_31143950)), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).\n\nHCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714436",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714436",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5Ata--e"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_PM4_nuclear_TNNT2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "099",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Strength of rule should be carefully considered and may require downgrading to SUPPORTING based on the predicted impact of the variant, including the size of the deletion/insertion, its location, and conservation of the region. \n\nFor genes where PVS1 is not applicable (i.e., where there is no evidence that pLOF variants cause disease), consider using this rule at MODERATE or SUPPORTING strength for truncating variants that do NOT undergo nonsense mediated decay (NMD).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714434",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714434",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5Ata--d"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_BP6_nuclear_TNNT2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "099",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714460",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714460",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5Atm--M"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_PS1_nuclear_TNNT2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PS1",
"ns": "099",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "No cardiomyopathy specifications. Apply as outlined by Richards _et al_. 2015[1](#pmid_25741868).\n\nExample of when rule should NOT be applied. NM\\_000256.3(_MYBPC3_): c.2308G>A (p.Asp770Asn) has an established impact on splicing leading to nonsense mediated decay (NMD) and should not be used to provide evidence for other variants observed to result in the same amino acid change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714459",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714459",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5Atm--L"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_PS3_nuclear_TNNT2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"instructionsToUse": "Evaluation of studies/assays is required prior to application of functional evidence at any strength.\n\nRefer to SVI guidance for functional evidence (Brnich _et al._ 2020[4](#pmid_31892348)).\n\nIn the context of cardiomyopathy, very few functional assays currently meet criteria sufficient for application of this rule at a STRONG level. Examples of the types of study/assays that MAY be relevant are described, but further definition of cardiomyopathy models/assays is outside the scope of these guidelines.",
"label": "PS3",
"ns": "099",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**In vitro splicing assays (e.g., RNA studies)**\n\n_In vitro_ splicing assays may be considered as **STRONG** evidence, providing the following criteria are met.\n\n* Prior knowledge of predominant transcripts in cardiac tissue\n\nAnalysis undertaken using RNA extracted from cardiac tissue from the individual with the variant\n\nAnalysis undertaken using RNA extracted from whole blood providing the relevant transcripts (isoforms) are expressed in blood and are at sufficient levels to assess splice disruption.\n\nAssay shows a clear, reproducible and convincing effect on splicing (i.e. a distinct splice product, present at a level comparable to the splice product from the wild-type allele), which is not observed in controls\n\n* Confirmation of abnormal splice product by Sanger sequencing\n\n**NOTE:** Mini-gene assay in non-patient derived cell lines are NOT considered to provide STRONG evidence.\n\n**NOTE:** Whether to activate this rule needs to be reconciled with the variant spectrum and disease mechanism for the gene at hand (i.e., consider whether the effect is likely to lead to LOF or an in-frame alteration and whether this type of effect is expected to be disease causing) (Abou Tayoun _et al._ 2018[3](#pmid_30192042)).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**In vivo models (e.g., variant knock-in animal models)**\n\nMammalian variant-specific knock-in animal models that produce a phenotype consistent with the clinical phenotype in humans (e.g., structural and/or functional cardiac abnormalities, premature death, arrhythmia) may be considered as **MODERATE** evidence\n\n**NOTE:** The following assays/models do NOT meet criteria\n\n1. Assays that are known to be associated with non-specific cardiac phenotypes (e.g., morpholino-induced pericardial edema in zebrafish)\n2. In vivo evidence that is not variant specific, such as whole gene alterations (i.e., cDNA or whole gene transgenic mice and whole or partial gene knock-out mice)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "_**In vitro**_ **assays (e.g., biochemical assays of myofilament function, motility assays, human iPSC-CM)**\n\nWhile some _in vitro_ assays may provide evidence that a variant in a cardiomyopathy gene has an effect on protein and/or myofilament function, at present, there are no validated “gold-standard” assays that are considered to reliably predict the clinical phenotype.\n\nAs such, in the cardiomyopathy genes listed in these guidelines, data from individual _in vitro_ studies are unlikely to meet the criteria required to assign this rule at more than SUPPORTING level.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714452",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714452",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5Ati--L"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_PP3_nuclear_TNNT2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "099",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "As many _in silico_ algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.\n\nUse of REVEL (Ioannidis _et al._ 2016[13](#pmid_27666373)) is recommended at thresholds of **≥0.70 for PP3**.\n\nClinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.\n\nPositive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.\n\n[SpliceAI](https://spliceailookup.broadinstitute.org)[14](#pmid_30661751) is recommended for evaluation of predicted splice impacts.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714451",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714451",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5Atm--J"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_BA1_nuclear_TNNT2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "099",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency is **≥0.001** based on the **filtering allele frequency (FAF)** in **gnomAD** in the subpopulation with the highest frequency (popmax).\n\nThe values used to calculate the BA1 threshold were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/300 or lower).\n\nThe threshold is applicable when assessing variants in the context of autosomal dominant cardiomyopathy. \n\ngnomAD is the preferred database for this calculation. If a subpopulation specific FAF other than the popmax is needed, this value can be calculated using the AlleleFrequencyApp on the [CardioDB website](https://cardiodb.org/allelefrequencyapp/).\n\n1. Using the Inverse AF tab, enter in the population size and the number of alleles identified and it will calculate the FAF. \n2. Set confidence to 0.95 (95%).\n3. If the FAF is ≥0.001, this rule can be applied.\n\nThe FAF by platform (e.g., exome vs. genome; v.2.1.1 vs. v.3.1.1) should be considered, the larger population is most likely to have the most accurate representation of “true” population allele frequency.\n\nCaution is needed when considering any population cohorts that are smaller than the smallest subpopulations within gnomAD v.2.1.1 (e.g., ~5000 individuals or ~10,000 alleles). Despite this conservative nature of this threshold and approach, in smaller cohorts, the observed allele frequency may less accurately reflect the true allele frequency. Traditionally, once a variant is classified as Benign, it is rarely re-evaluated and so the highest confidence is needed to establish that classification on an allele frequency alone.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714448",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714448",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5Ata--n"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_BP4_nuclear_TNNT2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "099",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "As many _in silico_ algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.\n\nUse of REVEL (Ioannidis et al. 2016[13](#pmid_27666373)) is recommended at thresholds of **≤0.40 for BP4**.\n\nClinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.\n\nPositive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.\n\n[SpliceAI](https://spliceailookup.broadinstitute.org)[14](#pmid_30661751) is recommended for evaluation of predicted splice impacts.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714461",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714461",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5Atm--N"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_BP3_nuclear_TNNT2",
"additionalComments": "Not applicable to the current genes. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "099",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714456",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714456",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5Ati--O"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_PP1_nuclear_TNNT2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "099",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at **≥7** **segregations** (LOD score of 2.1) for **STRONG**.\n\nAlthough rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)[12](#pmid_27236918) can be considered: \n\n* STRONG evidence requires ≥5 segregations (LOD score of 1.5)\n\nOnly genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.\n\nPhenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis. \n\nImportant considerations include:\n\n1. Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant. If linkage disequilibrium is a concern, consider downgrading strength of segregation. \n2. Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1.\n3. Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. \n4. Caution is needed when distantly related (≥3rd degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at **≥5** **segregations** (LOD score of 1.5) for **MODERATE**.\n\nAlthough rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)[12](#pmid_27236918) can be considered: \n\n* MODERATE evidence requires ≥4 segregations (LOD score of 1.2)\n\nOnly genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.\n\nPhenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis. \n\nImportant considerations include:\n\n1. Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant. If linkage disequilibrium is a concern, consider downgrading strength of segregation. \n2. Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).\n3. Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. \n4. Caution is needed when distantly related (≥3rd degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"May be used as stronger evidence with increasing segregation data"
]
},
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at **≥3** **segregations** (LOD score of 0.9) for **SUPPORTING**. The thresholds as proposed by Jarvik and Browning (2016)[12](#pmid_27236918) are the same at ≥3 segregations (LOD score of 0.9) for supporting.\n\nOnly genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.\n\nPhenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis. \n\nImportant considerations include:\n\n1. Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant. If linkage disequilibrium is a concern, consider downgrading strength of segregation. \n2. Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).\n3. Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. \n4. Caution is needed when distantly related (≥3rd degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714455",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714455",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5Ata--q"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_PM1_nuclear_TNNT2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "099",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Applicable to missense variants in _TNNT2_ in the specific regions listed below (Walsh _et al._ 2019[10](#pmid_30696458)). \n\n1. Transcripts ENST00000367318 with codons 79-179\n2. ENST00000656932.1 and NM\\_001276345.2 with codons 89-189\n\nData from HCM case cohorts was used to derive these cluster regions. Therefore, this rule should NOT be applied when additional evidence for the variant supports that the variant causes a phenotype other than HCM (e.g., variant seen in multiple DCM cases).\n\nEnrichment was not observed for DCM in any genes.\n\nRule should NOT be combined with PM5 because presence of pathogenic variants in the same codon/region were used to determine clustering and would be double-counting evidence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714446",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714446",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5Ate--r"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_PP5_nuclear_TNNT2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "099",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714444",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714444",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5AtW--o"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_BS4_nuclear_TNNT2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "099",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Any non-segregations should be carefully evaluated to rule out a phenocopy or the presence of a second disease-causing variant before considering it as conflicting or benign evidence. \n\n1. The presence of “phenocopies” (e.g., athlete’s heart, hypertensive heart disease, ischemic cardiomyopathy, alcoholic cardiomyopathy, diabetic cardiomyopathy) can mimic non-segregation (i.e., lack of segregation) among affected individuals. \n2. Families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent ‘non-segregation’.\n\nBecause of these possibilities, **multiple (≥2) non-segregations** that are highly unlikely to be phenocopies or due to alternate variants (e.g., those without a possible alternate cause) **are required to apply this rule**. A higher number of non-segregations is necessary for instances where alternative causes are possible (e.g., non-segregation in a sibling with childhood onset cardiomyopathy versus a grandparent with hypertension and HCM).\n\nCareful consideration of the above points is required when using this data as conflicting evidence, especially when overall evidence supports likely pathogenic or pathogenic.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714440",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714440",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5Atm--G"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_BS3_nuclear_TNNT2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"instructionsToUse": "Evaluation of studies/assays is required prior to application of functional evidence at any strength.\n\nRefer to SVI guidance for functional evidence (Brnich _et al._ 2020[4](#pmid_31892348)).\n\nIn the context of cardiomyopathy, very few functional assays currently meet criteria sufficient for application of this rule at a STRONG level. Examples of the types of study/assays that MAY be relevant are described, but further definition of cardiomyopathy models/assays is outside the scope of these guidelines.",
"label": "BS3",
"ns": "099",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "See PS3 specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "See PS3 specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "See PS3 specifications.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714439",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714439",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5AtW--m"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_PM2_nuclear_TNNT2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "099",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Population data for insertions/deletions may be poorly called by next-generation sequencing."
]
},
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The values used to calculate the PM2 thresholds were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/500 or lower), where the most frequent pathogenic variant accounts for no more than 2% of cases (e.g., has an allele frequency of ≤0.02 in cases based on the upper bound of 95% CI), and where the penetrance of a pathogenic variant is expected to be at least 50% (Kelly _et al._ 2018[11](#pmid_29300372)).\n\nA threshold of **≤0.00004** in the subpopulation with the highest frequency when using the upper bound of the 95% CI activates this rule.\n\n1. Alternatively, this is equivalent to the variant NOT being observed more than once (≤1 allele) in gnomAD v.2.1.1 in one of the non-founder populations (e.g., absence required from the Other and Ashkenazi Jewish subpopulations).\n2. Applying a threshold of ≤0.00004 (upper bound of 95% CI of the allele frequency in gnomAD) is equivalent to the variant being seen in a single subpopulation and that subpopulation meets any of the following:\n * **Allele Count (AC) in Allele Number (AN)**\n * ≤1 in ≥120,000\n * ≤2 in ≥160,000\n * ≤3 in ≥195,000\n * ≤4 in ≥230,000\n\ngnomAD is the preferred database for this calculation, but currently only displays the filtering allele frequency (FAF), which is equivalent to a lower bound estimate of the 95% CI, when the upper bound is what is needed.\n\n* Confidence interval tools, such as [Confit-de-MAF](https://www.genecalculators.net/confit-de-maf.html), can be used to determine the upper bound of the 95% CI of the observed allele frequency.\n\nDue to current technical limitations of next generation sequencing technologies, minor allele frequencies for complex variants (e.g., large indels) may not be accurately represented in population databases.\n\nCaution should be used when a variant is only identified, or over-represented, in one of the smaller gnomAD populations, as the gnomAD allele frequencies may not accurately represent the true population frequency.\n\nPopulation databases may contain affected or pre-symptomatic individuals for diseases with reduced penetrance/variable onset.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714435",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714435",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5Ati--J"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_BS1_nuclear_TNNT2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "099",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency is **≥0.0001 for** _**TNNT2**_ based on the **filtering allele frequency (FAF)** in **gnomAD** in the subpopulation with the highest frequency (popmax).\n\nCriterion BS1 may only be used as standalone evidence to classify a variant as Likely Benign in the absence of conflicting data. See SVI guidance (Tavtigian _et al._ 2018[15](#pmid_29300386); Tavtigian _et al._ 2020[16](#pmid_32720330)). \n\nSee BA1 for additional specifications that also apply to BS1.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714453",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714453",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5Ati--M"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_PM6_nuclear_TNNT2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "099",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Refer to SVI guidance on number/combination of cases required based on phenotype specificity[2](#url_c73e109e-b916-5a72-b7b1-1762446f3c11).\n\nFor most cardiomyopathies, it is recommended to default to “phenotype consistent with gene but not highly specific”. Clinical judgment is required for shifting to a higher or lower phenotypic consistency. \n\nSee PS2 for additional considerations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714449",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714449",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5Ati--K"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_PVS1_nuclear_TNNT2",
"additionalComments": "Not currently applicable to TNNT2. See PM4 for truncating variants that do NOT undergo NMD.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PVS1",
"ns": "099",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Not applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714447",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714447",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5AtW--q"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_PM3_nuclear_TNNT2",
"additionalComments": "While compound heterozygosity leading to a more severe phenotype has been documented, this rule was designed for traditional recessive inheritance. It is acknowledged that there is increasing evidence supporting that some of these genes/variants may also be recessive (e.g., MYL2, MYL3), but addressing those edge cases was outside the scope of this current guideline.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "099",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"This requires testing of parents (or offspring) to determine phase."
]
},
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714445",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714445",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5Ata--m"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_BS2_nuclear_TNNT2",
"additionalComments": "Inherited cardiomyopathies generally display reduced penetrance, variable expressivity, and adult-onset. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "099",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0069",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0076",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714443",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714443",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5Ata--k"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_PP2_nuclear_TNNT2",
"additionalComments": "Application of this rule takes into consideration empirical data quantifying levels of rare missense variant enrichment in HCM referral cohorts compared to population-based cohorts (Walsh et al. 2019 PMID:30696458) rather than the missense constraint score in gnomAD. For TNNT2, there is evidence for regional enrichment of rare missense variants (see PM1 specifications).",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "099",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714442",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714442",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5Atm--H"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_PM5_nuclear_TNNT2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "099",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion can be used at MODERATE if a different missense variant at the same codon has been classified as _pathogenic_ using these modified guidelines without application of PM5.\n\nThe impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to SUPPORTING if the predicted impact is not expected to be equivalent or more severe.\n\nPM5 should not be combined with PM1. If both are applicable at MODERATE weight, use of PM5 is most appropriate since it is variant specific.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion can be considered at SUPPORTING if a different missense variant at the same codon has been classified as _likely pathogenic_ using these modified guidelines without application of PM5.\n\nThe impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as likely pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to NOT APPLICABLE if the predicted impact is not expected to be equivalent or more severe.\n\nPM5 should not be combined with PM1. The one with the higher strength should be applied, but if both are applicable at SUPPORTING weight, use of PM5 is most appropriate since it is variant specific.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768714438",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768714438",
"modified": "2024-04-22T15:44:40.957Z",
"modifier": "makelly2",
"rev": "_inf5Ate--q"
},
{
"created": "2024-04-22T15:44:40.957Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "099_BP2_nuclear_TNNT2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"TNNT2"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "099",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
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"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "As many _in silico_ algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.\n\nUse of REVEL (Ioannidis _et al._ 2016[13](#pmid_27666373)) is recommended at thresholds of **≥0.70 for PP3**.\n\nClinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.\n\nPositive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.\n\n[SpliceAI](https://spliceailookup.broadinstitute.org)[14](#pmid_30661751) is recommended for evaluation of predicted splice impacts.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768716026",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768716026",
"modified": "2024-04-22T15:45:11.035Z",
"modifier": "makelly2",
"rev": "_inf5Atm--R"
},
{
"created": "2024-04-22T15:45:11.035Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "100_BS2_nuclear_TPM1",
"additionalComments": "Inherited cardiomyopathies generally display reduced penetrance, variable expressivity, and adult-onset. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"TPM1"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "100",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0069",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0076",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768716018",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768716018",
"modified": "2024-04-22T15:45:11.035Z",
"modifier": "makelly2",
"rev": "_inf5AtW--w"
},
{
"created": "2024-04-22T15:45:11.035Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "100_PP2_nuclear_TPM1",
"additionalComments": "Application of this rule takes into consideration empirical data quantifying levels of rare missense variant enrichment in HCM referral cohorts compared to population-based cohorts (Walsh et al. 2019 PMID:30696458) rather than the missense constraint score in gnomAD. For TNNI3, there is evidence for regional enrichment of rare missense variants (see PM1 specifications).",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"TPM1"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "100",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Application of this rule takes into consideration empirical data quantifying levels of rare missense variant enrichment in HCM referral cohorts compared to population-based cohorts (Walsh _et al._ 2019[12](#pmid_30696458)) rather than the missense constraint score in gnomAD. \n\nOn the basis of data from Walsh _et al._ 2019[12](#pmid_30696458), **PP2 is currently** **only applicable to** _**TPM1**_ **for HCM** (transcripts ENST00000403994 and NM\\_001018005.2)_._\n\nData from HCM case cohorts was used to derive these cluster regions. Therefore, this rule should NOT be applied when additional evidence for the variant supports that the variant causes a phenotype other than HCM (e.g., variant seen in multiple DCM cases).\n\nEnrichment was not observed for DCM in any genes.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768716017",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768716017",
"modified": "2024-04-22T15:45:11.035Z",
"modifier": "makelly2",
"rev": "_inf5Ati--Q"
},
{
"created": "2024-04-22T15:45:11.035Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "100_PS4_nuclear_TPM1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"TPM1"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "100",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Currently few well-designed case-control studies have been performed for inherited cardiomyopathies. Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). \n\nCohorts used in these analyses should meet the following criteria: \n\n1. The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype\\*). \n * When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded. This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).\n2. The controls should not be derived from study populations that might be enriched for the specified disorder.\n3. The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).\n4. The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).\n5. The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).\n6. The population diversity of the case and control cohorts are broadly similar.\n7. Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh _et al._ 2017[5](#pmid_27532257), [DECIPHER](https://www.deciphergenomics.org/gene/TPM1/patient-overlap/snvs)).\n\nTo account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:\n\n* **STRONG** evidence requires the lower bound of the 95% confidence interval (CI) around the odds ratio (OR) estimate to be **≥20**\n\nA PS4 calculator is available at [www.cardiodb.org](https://www.cardiodb.org/ps4_calculator/ps4_calculator.html).\n\nIf multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered). \n\n**\\*RELEVANT PHENOTYPES:**\n\n1. Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. \n2. For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. \n3. Additional considerations for LVNC and end-stage HCM: \n * Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson _et al._ 2017[6](#pmid_28395867); Oechslin _et al._ 2017[7](#pmid_28545618); Hershberger _et al._ 2017[8](#pmid_29212902); Ross _et al._ 2020[9](#pmid_31143950)), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).\n\nHCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Currently few well-designed case-control studies have been performed for inherited cardiomyopathies. Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). \n\nCohorts used in these analyses should meet the following criteria: \n\n1. The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype\\*). \n * When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded. This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).\n2. The controls should not be derived from study populations that might be enriched for the specified disorder.\n3. The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).\n4. The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).\n5. The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).\n6. The population diversity of the case and control cohorts are broadly similar.\n7. Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh _et al._ 2017[5](#pmid_27532257), [DECIPHER](https://www.deciphergenomics.org/gene/TPM1/patient-overlap/snvs)).\n\nTo account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:\n\n* **MODERATE** evidence requires the lower bound of the 95% CI around the OR to be **≥10**\n\nA PS4 calculator is available at [www.cardiodb.org](https://www.cardiodb.org/ps4_calculator/ps4_calculator.html).\n\nIf multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered). \n\n**\\*RELEVANT PHENOTYPES:**\n\n1. Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. \n2. For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. \n3. Additional considerations for LVNC and end-stage HCM: \n * Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson _et al._ 2017[6](#pmid_28395867); Oechslin _et al._ 2017[7](#pmid_28545618); Hershberger _et al._ 2017[8](#pmid_29212902); Ross _et al._ 2020[9](#pmid_31143950)), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).\n\nHCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Currently few well-designed case-control studies have been performed for inherited cardiomyopathies. Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). \n\nCohorts used in these analyses should meet the following criteria: \n\n1. The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype\\*). \n * When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded. This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).\n2. The controls should not be derived from study populations that might be enriched for the specified disorder.\n3. The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).\n4. The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).\n5. The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).\n6. The population diversity of the case and control cohorts are broadly similar.\n7. Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh _et al._ 2017[5](#pmid_27532257), [DECIPHER](https://www.deciphergenomics.org/gene/TPM1/patient-overlap/snvs)).\n\nTo account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:\n\n* **SUPPORTING** evidence requires the lower bound of the 95% CI around the OR to be **≥5**\n\nA PS4 calculator is available at [www.cardiodb.org](https://www.cardiodb.org/ps4_calculator/ps4_calculator.html).\n\nIf multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered). \n\n**\\*RELEVANT PHENOTYPES:**\n\n1. Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. \n2. For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. \n3. Additional considerations for LVNC and end-stage HCM: \n * Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson _et al._ 2017[6](#pmid_28395867); Oechslin _et al._ 2017[7](#pmid_28545618); Hershberger _et al._ 2017[8](#pmid_29212902); Ross _et al._ 2020[9](#pmid_31143950)), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).\n\nHCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768716011",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768716011",
"modified": "2024-04-22T15:45:11.035Z",
"modifier": "makelly2",
"rev": "_inf5Ati--P"
},
{
"created": "2024-04-22T15:45:11.035Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "100_BP3_nuclear_TPM1",
"additionalComments": "Not applicable to the current genes. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TPM1"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "100",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768716031",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768716031",
"modified": "2024-04-22T15:45:11.035Z",
"modifier": "makelly2",
"rev": "_inf5Ati--R"
},
{
"created": "2024-04-22T15:45:11.035Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "100_PM6_nuclear_TPM1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"TPM1"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "100",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Refer to SVI guidance on number/combination of cases required based on phenotype specificity[2](#url_c73e109e-b916-5a72-b7b1-1762446f3c11).\n\nFor most cardiomyopathies, it is recommended to default to “phenotype consistent with gene but not highly specific”. Clinical judgment is required for shifting to a higher or lower phenotypic consistency. \n\nSee PS2 for additional considerations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768716024",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768716024",
"modified": "2024-04-22T15:45:11.035Z",
"modifier": "makelly2",
"rev": "_inf5Atm--Q"
},
{
"created": "2024-04-22T15:45:11.035Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "100_BA1_nuclear_TPM1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"TPM1"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "100",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency is **≥0.001** based on the **filtering allele frequency (FAF)** in **gnomAD** in the subpopulation with the highest frequency (popmax).\n\nThe values used to calculate the BA1 threshold were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/300 or lower).\n\nThe threshold is applicable when assessing variants in the context of autosomal dominant cardiomyopathy. \n\ngnomAD is the preferred database for this calculation. If a subpopulation specific FAF other than the popmax is needed, this value can be calculated using the AlleleFrequencyApp on the [CardioDB website](https://cardiodb.org/allelefrequencyapp/).\n\n1. Using the Inverse AF tab, enter in the population size and the number of alleles identified and it will calculate the FAF. \n2. Set confidence to 0.95 (95%).\n3. If the FAF is ≥0.001, this rule can be applied.\n\nThe FAF by platform (e.g., exome vs. genome; v.2.1.1 vs. v.3.1.1) should be considered, the larger population is most likely to have the most accurate representation of “true” population allele frequency.\n\nCaution is needed when considering any population cohorts that are smaller than the smallest subpopulations within gnomAD v.2.1.1 (e.g., ~5000 individuals or ~10,000 alleles). Despite this conservative nature of this threshold and approach, in smaller cohorts, the observed allele frequency may less accurately reflect the true allele frequency. Traditionally, once a variant is classified as Benign, it is rarely re-evaluated and so the highest confidence is needed to establish that classification on an allele frequency alone.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768716023",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768716023",
"modified": "2024-04-22T15:45:11.035Z",
"modifier": "makelly2",
"rev": "_inf5Ata--_"
},
{
"created": "2024-04-22T15:45:11.035Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "100_BP1_nuclear_TPM1",
"additionalComments": "For the current genes where null variants are a known mechanism, pathogenic missense variants have also been reported.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TPM1"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "100",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768716016",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768716016",
"modified": "2024-04-22T15:45:11.035Z",
"modifier": "makelly2",
"rev": "_inf5Ate--A"
},
{
"created": "2024-04-22T15:45:11.035Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "100_PM2_nuclear_TPM1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"TPM1"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "100",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Population data for insertions/deletions may be poorly called by next-generation sequencing."
]
},
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The values used to calculate the PM2 thresholds were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/500 or lower), where the most frequent pathogenic variant accounts for no more than 2% of cases (e.g., has an allele frequency of ≤0.02 in cases based on the upper bound of 95% CI), and where the penetrance of a pathogenic variant is expected to be at least 50% (Kelly _et al._ 2018[10](#pmid_29300372)).\n\nA threshold of **≤0.00004** in the subpopulation with the highest frequency when using the upper bound of the 95% CI activates this rule.\n\n1. Alternatively, this is equivalent to the variant NOT being observed more than once (≤1 allele) in gnomAD v.2.1.1 in one of the non-founder populations (e.g., absence required from the Other and Ashkenazi Jewish subpopulations).\n2. Applying a threshold of ≤0.00004 (upper bound of 95% CI of the allele frequency in gnomAD) is equivalent to the variant being seen in a single subpopulation and that subpopulation meets any of the following:\n * **Allele Count (AC) in Allele Number (AN)**\n * ≤1 in ≥120,000\n * ≤2 in ≥160,000\n * ≤3 in ≥195,000\n * ≤4 in ≥230,000\n\ngnomAD is the preferred database for this calculation, but currently only displays the filtering allele frequency (FAF), which is equivalent to a lower bound estimate of the 95% CI, when the upper bound is what is needed.\n\n* Confidence interval tools, such as [Confit-de-MAF](https://www.genecalculators.net/confit-de-maf.html), can be used to determine the upper bound of the 95% CI of the observed allele frequency.\n\nDue to current technical limitations of next generation sequencing technologies, minor allele frequencies for complex variants (e.g., large indels) may not be accurately represented in population databases.\n\nCaution should be used when a variant is only identified, or over-represented, in one of the smaller gnomAD populations, as the gnomAD allele frequencies may not accurately represent the true population frequency.\n\nPopulation databases may contain affected or pre-symptomatic individuals for diseases with reduced penetrance/variable onset.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768716010",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768716010",
"modified": "2024-04-22T15:45:11.035Z",
"modifier": "makelly2",
"rev": "_inf5Ate--v"
},
{
"created": "2024-04-22T15:45:11.035Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "100_PM4_nuclear_TPM1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TPM1"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "100",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Strength of rule should be carefully considered and may require downgrading to SUPPORTING based on the predicted impact of the variant, including the size of the deletion/insertion, its location, and conservation of the region. \n\nFor genes where PVS1 is not applicable (i.e., where there is no evidence that pLOF variants cause disease), consider using this rule at MODERATE or SUPPORTING strength for truncating variants that do NOT undergo nonsense mediated decay (NMD).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768716009",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768716009",
"modified": "2024-04-22T15:45:11.035Z",
"modifier": "makelly2",
"rev": "_inf5Ate--t"
},
{
"created": "2024-04-22T15:45:11.035Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "100_BP4_nuclear_TPM1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TPM1"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "100",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "As many _in silico_ algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.\n\nUse of REVEL (Ioannidis et al. 2016[13](#pmid_27666373)) is recommended at thresholds of **≤0.40 for BP4**.\n\nClinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.\n\nPositive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.\n\n[SpliceAI](https://spliceailookup.broadinstitute.org)[14](#pmid_30661751) is recommended for evaluation of predicted splice impacts.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768716036",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768716036",
"modified": "2024-04-22T15:45:11.035Z",
"modifier": "makelly2",
"rev": "_inf5Ate--4"
},
{
"created": "2024-04-22T15:45:11.035Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "100_PS1_nuclear_TPM1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TPM1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PS1",
"ns": "100",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "No cardiomyopathy specifications. Apply as outlined by Richards _et al_. 2015[1](#pmid_25741868).\n\nExample of when rule should NOT be applied. NM\\_000256.3(_MYBPC3_): c.2308G>A (p.Asp770Asn) has an established impact on splicing leading to nonsense mediated decay (NMD) and should not be used to provide evidence for other variants observed to result in the same amino acid change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768716034",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768716034",
"modified": "2024-04-22T15:45:11.035Z",
"modifier": "makelly2",
"rev": "_inf5Ata--C"
},
{
"created": "2024-04-22T15:45:11.035Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "100_PS2_nuclear_TPM1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"TPM1"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "100",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0016",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Refer to SVI guidance on number/combination of cases required based on phenotype specificity[2](#url_c73e109e-b916-5a72-b7b1-1762446f3c11).\n\nFor most cardiomyopathies, it is recommended to default to **Phenotype consistency: “Phenotype consistent with gene but not highly specific”**. Clinical judgment is required for shifting to a higher or lower category. \n\nFor use as a STRONG or VERY STRONG criterion, ideally parents have been thoroughly clinically evaluated without evidence of cardiomyopathy (ideally using a combination of ECG and echocardiogram or cardiac MRI for maximum sensitivity).\n\nA family history consistent with _de novo_ inheritance should not have any clinical signs or symptoms suggestive of cardiomyopathy in a 1st or 2nd degree relative, for example: \n\n1. Sudden death under 60 years of age\n2. Heart transplant\n3. Implantable cardiac defibrillator (ICD) under 60 years of age\n4. Features of cardiomyopathy (e.g., systolic dysfunction, hypertrophy, left ventricular enlargement in an individual without risk factors).\n5. Other related/overlapping cardiomyopathies\n\nExamples of non-suspicious family history may include non-specific clinical features (e.g., palpitations, syncope, borderline/inconclusive echocardiogram findings, heart attack if age appropriate and suspected to result from coronary artery disease), but every attempt should be made to clarify features. \n\nGenerally, this criterion is only applicable in the ABSENCE of any other possible disease-causing variants. If other pathogenic or likely pathogenic variants are present, consider decreasing points assigned or overall weight.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "004",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768716033",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768716033",
"modified": "2024-04-22T15:45:11.035Z",
"modifier": "makelly2",
"rev": "_inf5Ate--M"
},
{
"created": "2024-04-22T15:45:11.035Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "100_PP1_nuclear_TPM1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"TPM1"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "100",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at **≥7** **segregations** (LOD score of 2.1) for **STRONG**.\n\nAlthough rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)[11](#pmid_27236918) can be considered: \n\n* STRONG evidence requires ≥5 segregations (LOD score of 1.5)\n\nOnly genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.\n\nPhenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis. \n\nImportant considerations include:\n\n1. Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant. If linkage disequilibrium is a concern, consider downgrading strength of segregation. \n2. Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1.\n3. Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. \n4. Caution is needed when distantly related (≥3rd degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at **≥5** **segregations** (LOD score of 1.5) for **MODERATE**.\n\nAlthough rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)[11](#pmid_27236918) can be considered: \n\n* MODERATE evidence requires ≥4 segregations (LOD score of 1.2)\n\nOnly genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.\n\nPhenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis. \n\nImportant considerations include:\n\n1. Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant. If linkage disequilibrium is a concern, consider downgrading strength of segregation. \n2. Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).\n3. Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. \n4. Caution is needed when distantly related (≥3rd degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"May be used as stronger evidence with increasing segregation data"
]
},
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at **≥3** **segregations** (LOD score of 0.9) for **SUPPORTING**. The thresholds as proposed by Jarvik and Browning (2016)[11](#pmid_27236918) are the same at ≥3 segregations (LOD score of 0.9) for supporting.\n\nOnly genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.\n\nPhenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis. \n\nImportant considerations include:\n\n1. Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant. If linkage disequilibrium is a concern, consider downgrading strength of segregation. \n2. Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).\n3. Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. \n4. Caution is needed when distantly related (≥3rd degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768716030",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768716030",
"modified": "2024-04-22T15:45:11.035Z",
"modifier": "makelly2",
"rev": "_inf5Ate--K"
},
{
"created": "2024-04-22T15:45:11.035Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "100_PS3_nuclear_TPM1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"TPM1"
],
"geneType": "nuclear",
"instructionsToUse": "Evaluation of studies/assays is required prior to application of functional evidence at any strength.\n\nRefer to SVI guidance for functional evidence (Brnich _et al._ 2020[4](#pmid_31892348)).\n\nIn the context of cardiomyopathy, very few functional assays currently meet criteria sufficient for application of this rule at a STRONG level. Examples of the types of study/assays that MAY be relevant are described, but further definition of cardiomyopathy models/assays is outside the scope of these guidelines.",
"label": "PS3",
"ns": "100",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**In vitro splicing assays (e.g., RNA studies)**\n\n_In vitro_ splicing assays may be considered as **STRONG** evidence, providing the following criteria are met.\n\n* Prior knowledge of predominant transcripts in cardiac tissue\n\nAnalysis undertaken using RNA extracted from cardiac tissue from the individual with the variant\n\nAnalysis undertaken using RNA extracted from whole blood providing the relevant transcripts (isoforms) are expressed in blood and are at sufficient levels to assess splice disruption.\n\nAssay shows a clear, reproducible and convincing effect on splicing (i.e. a distinct splice product, present at a level comparable to the splice product from the wild-type allele), which is not observed in controls\n\n* Confirmation of abnormal splice product by Sanger sequencing\n\n**NOTE:** Mini-gene assay in non-patient derived cell lines are NOT considered to provide STRONG evidence.\n\n**NOTE:** Whether to activate this rule needs to be reconciled with the variant spectrum and disease mechanism for the gene at hand (i.e., consider whether the effect is likely to lead to LOF or an in-frame alteration and whether this type of effect is expected to be disease causing) (Abou Tayoun _et al._ 2018[3](#pmid_30192042)).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**In vivo models (e.g., variant knock-in animal models)**\n\nMammalian variant-specific knock-in animal models that produce a phenotype consistent with the clinical phenotype in humans (e.g., structural and/or functional cardiac abnormalities, premature death, arrhythmia) may be considered as **MODERATE** evidence\n\n**NOTE:** The following assays/models do NOT meet criteria\n\n1. Assays that are known to be associated with non-specific cardiac phenotypes (e.g., morpholino-induced pericardial edema in zebrafish)\n2. In vivo evidence that is not variant specific, such as whole gene alterations (i.e., cDNA or whole gene transgenic mice and whole or partial gene knock-out mice)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "_**In vitro**_ **assays (e.g., biochemical assays of myofilament function, motility assays, human iPSC-CM)**\n\nWhile some _in vitro_ assays may provide evidence that a variant in a cardiomyopathy gene has an effect on protein and/or myofilament function, at present, there are no validated “gold-standard” assays that are considered to reliably predict the clinical phenotype.\n\nAs such, in the cardiomyopathy genes listed in these guidelines, data from individual _in vitro_ studies are unlikely to meet the criteria required to assign this rule at more than SUPPORTING level.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768716027",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768716027",
"modified": "2024-04-22T15:45:11.035Z",
"modifier": "makelly2",
"rev": "_inf5Ate--I"
},
{
"created": "2024-04-22T15:45:11.035Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "100_PVS1_nuclear_TPM1",
"additionalComments": "Not currently applicable to TPM1. See PM4 for truncating variants that do NOT undergo NMD.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TPM1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PVS1",
"ns": "100",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Not applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768716022",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768716022",
"modified": "2024-04-22T15:45:11.035Z",
"modifier": "makelly2",
"rev": "_inf5AtW--y"
},
{
"created": "2024-04-22T15:45:11.035Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "100_PM1_nuclear_TPM1",
"additionalComments": "Application of this rule takes into consideration empirical data quantifying levels of rare missense variant enrichment in HCM referral cohorts compared to population-based cohorts (Walsh et al. 2019 PMID:30696458). For TPM1, there is evidence for gene-level enrichment of rare missense variants (see PP2 specifications).",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"TPM1"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "100",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768716021",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768716021",
"modified": "2024-04-22T15:45:11.035Z",
"modifier": "makelly2",
"rev": "_inf5Ate--0"
},
{
"created": "2024-04-22T15:45:11.035Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "100_PM5_nuclear_TPM1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TPM1"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "100",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion can be used at MODERATE if a different missense variant at the same codon has been classified as _pathogenic_ using these modified guidelines without application of PM5.\n\nThe impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to SUPPORTING if the predicted impact is not expected to be equivalent or more severe.\n\nPM5 should not be combined with PM1. If both are applicable at MODERATE weight, use of PM5 is most appropriate since it is variant specific.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion can be considered at SUPPORTING if a different missense variant at the same codon has been classified as _likely pathogenic_ using these modified guidelines without application of PM5.\n\nThe impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as likely pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to NOT APPLICABLE if the predicted impact is not expected to be equivalent or more severe.\n\nPM5 should not be combined with PM1. The one with the higher strength should be applied, but if both are applicable at SUPPORTING weight, use of PM5 is most appropriate since it is variant specific.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768716013",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768716013",
"modified": "2024-04-22T15:45:11.035Z",
"modifier": "makelly2",
"rev": "_inf5Atm--O"
},
{
"created": "2024-04-22T15:45:11.035Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "100_BP6_nuclear_TPM1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"TPM1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "100",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768716035",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768716035",
"modified": "2024-04-22T15:45:11.035Z",
"modifier": "makelly2",
"rev": "_inf5Ata--E"
},
{
"created": "2024-04-22T15:45:11.035Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "100_BP5_nuclear_TPM1",
"additionalComments": "Co-occurrence with an established pathogenic or likely pathogenic variant for a non-cardiomyopathy related disease does not reduce the likelihood that a variant is independently disease-causing for cardiomyopathy.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"TPM1"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "100",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1768716029",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/1768716029",
"modified": "2024-04-22T15:45:11.035Z",
"modifier": "makelly2",
"rev": "_inf5Atm--S"
},
{
"created": "2024-04-22T15:45:11.035Z",
"creator": "makelly2",
"entContent": {
"_uniqueProp": "100_BS1_nuclear_TPM1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"TPM1"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "100",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
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"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency is **≥0.0001 for** _**TPM1**_ based on the **filtering allele frequency (FAF)** in **gnomAD** in the subpopulation with the highest frequency (popmax).\n\nCriterion BS1 may only be used as standalone evidence to classify a variant as Likely Benign in the absence of conflicting data. See SVI guidance (Tavtigian _et al._ 2018[15](#pmid_29300386); Tavtigian _et al._ 2020[16](#pmid_32720330)). \n\nSee BA1 for additional specifications that also apply to BS1.",
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"id": "0223",
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"status": "approved",
"strength": "Moderate",
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"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0086",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
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"creator": "makelly2",
"entContent": {
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],
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"text": "",
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"text": "",
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"strength": "Very Strong",
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"text": "",
"type": "EvidenceLineStrength"
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"specificationType": [
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],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "See PS3 specifications.",
"type": "EvidenceLineStrength"
},
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"id": "0100",
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"specificationType": [
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],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "See PS3 specifications.",
"type": "EvidenceLineStrength"
},
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"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
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"text": "",
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"text": "",
"type": "EvidenceLineStrength"
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"id": "0068",
"instructionsToUse": "",
"status": "approved",
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"text": "",
"type": "EvidenceLineStrength"
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"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
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"text": "",
"type": "EvidenceLineStrength"
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"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
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{
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{
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],
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{
"auths": [
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"Aziz N",
"et al."
],
"doiStr": "10.1038/gim.2015.30",
"id": "25741868",
"iss": "(5)",
"namespace": "pmid",
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"source": "Genet Med",
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.",
"vol": "17",
"year": "2015"
},
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{
"auths": [
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"Pesaran T",
"et al."
],
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"id": "30192042",
"iss": "(11)",
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"pages": "p. 1517-1524.",
"source": "Hum Mutat",
"title": "Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion.",
"vol": "39",
"year": "2018"
},
{
"auths": [
"Brnich SE",
"Abou Tayoun AN",
"et al."
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"id": "31892348",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 3.",
"source": "Genome Med",
"title": "Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework.",
"vol": "12",
"year": "2019"
},
{
"auths": [
"Walsh R",
"Thomson KL",
"et al."
],
"doiStr": "10.1038/gim.2016.90",
"id": "27532257",
"iss": "(2)",
"namespace": "pmid",
"pages": "p. 192-203.",
"source": "Genet Med",
"title": "Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.",
"vol": "19",
"year": "2017"
},
{
"auths": [
"Anderson RH",
"Jensen B",
"et al."
],
"doiStr": "10.1016/j.cjca.2017.01.017",
"id": "28395867",
"iss": "(6)",
"namespace": "pmid",
"pages": "p. 747-757.",
"source": "Can J Cardiol",
"title": "Key Questions Relating to Left Ventricular Noncompaction Cardiomyopathy: Is the Emperor Still Wearing Any Clothes?",
"vol": "33",
"year": "2017"
},
{
"auths": [
"Oechslin E",
"Jenni R"
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"id": "28545618",
"iss": "(6)",
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"pages": "p. 701-704.",
"source": "Can J Cardiol",
"title": "Nosology of Noncompaction Cardiomyopathy: The Emperor Still Wears Clothes!",
"vol": "33",
"year": "2017"
},
{
"auths": [
"Hershberger RE",
"Morales A",
"et al."
],
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"id": "29212902",
"iss": "(6)",
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"pages": "",
"source": "Circ Cardiovasc Genet",
"title": "Is Left Ventricular Noncompaction a Trait, Phenotype, or Disease? The Evidence Points to Phenotype.",
"vol": "10",
"year": "2017"
},
{
"auths": [
"Ross SB",
"Jones K",
"et al."
],
"doiStr": "10.1093/eurheartj/ehz317",
"id": "31143950",
"iss": "(14)",
"namespace": "pmid",
"pages": "p. 1428-1436.",
"source": "Eur Heart J",
"title": "A systematic review and meta-analysis of the prevalence of left ventricular non-compaction in adults.",
"vol": "41",
"year": "2020"
},
{
"auths": [
"Kelly MA",
"Caleshu C",
"et al."
],
"doiStr": "10.1038/gim.2017.218",
"id": "29300372",
"iss": "(3)",
"namespace": "pmid",
"pages": "p. 351-359.",
"source": "Genet Med",
"title": "Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel.",
"vol": "20",
"year": "2018"
},
{
"auths": [
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"Browning BL"
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