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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": [
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"condition": ">=10",
"label": "Rule1, Condition1"
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],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
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"condition": ">=6",
"label": "Rule2, Condition2"
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"inference": "Likely Pathogenic",
"rule": "Rule2"
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"conditions": [
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"label": "Rule3, Condition1"
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"inference": "Uncertain Significance",
"rule": "Rule3"
},
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"conditions": [
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"condition": ">=-6",
"label": "Rule4, Condition1"
},
{
"condition": "<=-1",
"label": "Rule4, Condition2"
}
],
"inference": "Likely Benign",
"rule": "Rule4"
},
{
"conditions": [
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"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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{
"applicability": "Not Applicable",
"id": "0028",
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"text": "",
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],
"status": "approved",
"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": "",
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"geneType": "nuclear",
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{
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"applicability": "Not applicable",
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"text": "",
"type": "EvidenceLineStrength"
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"modifier": "makelly2",
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{
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"applicability": "Not applicable",
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"text": "",
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{
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"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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{
"applicability": "Not applicable",
"id": "0217",
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"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"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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]
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"modifier": "makelly2",
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{
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"MONDO:0005021",
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"MONDO:0005201",
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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": [],
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"completed": true
}
},
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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": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
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{
"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": [
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],
"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",
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"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": [
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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": "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",
"text": "Allele frequency is **≥0.0001 for** _**MYH7**_ 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[16](#pmid_29300386); Tavtigian _et al._ 2020[15](#pmid_32720330)). \n\nSee BA1 for additional specifications that also apply to BS1.",
"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": "135637772",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637772",
"modified": "2024-04-22T15:42:56.196Z",
"modifier": "makelly2",
"rev": "_inf5AqS--J"
},
{
"entContent": {
"_uniqueProp": "002_PS1_nuclear_MYH7",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "002",
"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.",
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"status": "approved",
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"strengthSepioID": "SEPIO:0000327",
"text": "Multiple lines of computational evidence suggest no impact on gene or gene product. \n\n* Splicing variants: Concordance of SpliceAl and VarSeak\n* Missense variants: REVEL scores \\< 0.5",
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"entContent": {
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"additionalComments": "PTEN EP Specification: PS3 may be applied to the following assays:\n * In vitro or in vivo 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 1998, Stambolic 1998, Han 2000, Rodriguez-Escudero 2011, Costa 2015, Malek 2017).\n * RNA, mini-gene, or other assay demonstrating an impact on splicing.\n\nPS3_Supporting: Abnormal in vitro cellular assay or transgenic model with phenotype different from wild-type that does not meet PS3. Examples of in vitro cellular assays to be considered for PS3_supporting evidence 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)",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
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"evidenceCategory": "Functional Data",
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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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"name": "National Institutes of Health (NIH)"
}
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{
"subject": "human"
},
{
"subject": "biology"
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{
"subject": "genomics"
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{
"subject": "variant"
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{
"subject": "variant classification"
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{
"subject": "clingen"
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{
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{
"subject": "standards"
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{
"subject": "SHOC2"
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{
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{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
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"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
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"SHOC2",
"SOS1",
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"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"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"
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{
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"text": "",
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"id": "0076",
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"text": "",
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{
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"applicability": "Not Applicable for this VCEP",
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"label": "BP6",
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"references": [
{
"id": "29543229",
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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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"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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{
"entContent": {
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"applicability": "Not applicable",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
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"text": "PM1 upgraded in strength to Strong",
"type": "EvidenceLineStrength"
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{
"applicability": "Applicable with VCEP specification",
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"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",
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{
"applicability": "Not applicable",
"id": "0054",
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"strength": "Supporting",
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"text": "",
"type": "EvidenceLineStrength"
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]
},
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"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
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{
"entContent": {
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"geneType": "nuclear",
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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"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
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"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
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"text": "",
"type": "EvidenceLineStrength"
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"id": "0079",
"instructionsToUse": "",
"specificationType": "General",
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"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",
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},
{
"entContent": {
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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.",
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"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"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 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": {
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"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.",
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"MONDO:0009026",
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],
"evidenceCategory": "De novo Data",
"gene": [
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"HRAS",
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"MAP2K2",
"NRAS",
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"RAF1",
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"SHOC2",
"SOS1",
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],
"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": [
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"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
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"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",
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638341",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
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},
{
"entContent": {
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"ns": "004",
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"sepioID": "SEPIO-CG:99044",
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"strengthDescriptor": [
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"status": "not approved",
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"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"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": "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",
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638340",
"modified": "2021-11-05T21:07:12.074Z",
"modifier": "genbadmin",
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},
{
"entContent": {
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"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.",
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"geneType": "nuclear",
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"ns": "004",
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"specificationType": [],
"strengthDescriptor": [
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"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0204",
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"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"
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{
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"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"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",
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"MONDO:0018997",
"MONDO:0021060",
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],
"evidenceCategory": "Functional Data",
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],
"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": {
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}
],
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"keywords": [
{
"subject": "human"
},
{
"subject": "biology"
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{
"subject": "variant"
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{
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{
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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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{
"applicability": "Not Applicable for this VCEP",
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"entContent": {
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"applicability": "Not Applicable for this VCEP",
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"instructionsToUse": "",
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"strengthSepioID": "",
"text": "",
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{
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"instructionsToUse": "",
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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": "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"
},
{
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"id": "0030",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/Rare in population databases (absent or ≤0.00007 (0.007%) for autosomal recessive, ≤0.00002 (0.002%) for autosomal dominant).\n* Background: Rarity or absence in the general population is not robust evidence for pathogenicity, particularly for autosomal recessive disorders. However, the ACMG/AMP Guidelines were devised in such a way that absence or rarity were considered moderate evidence towards pathogenicity, and the framework requires multiple pieces of evidence to classify a variant as likely pathogenic or pathogenic.",
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}
]
},
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"ldhId": "135638907",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638907",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Ap6--Z"
},
{
"entContent": {
"_uniqueProp": "005_PM1_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
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"COCH",
"GJB2",
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"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "005",
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"strengthDescriptor": [
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"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"
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{
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"id": "006",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Mutational hot spot or well-studied functional domain without benign variation (KCNQ4 pore-forming region).\n* KCNQ4 (NM_004700.4) gene - missense variants located within amino acids 271-292 can be awarded PM1. This region is the pore-forming intramembrane region where many variants that cause autosomal dominant hearing loss are located (Naito et al. 2013, PMID: 23717403; https://www.uniprot.org/uniprot/P56696). There are only two missense variants in this region in gnomAD, each with only single allele (http://gnomad.broadinstitute.org/; rs763326539: 1/33578 Latino chromosomes; rs55737429: 1/111720 European chromosomes).",
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},
{
"applicability": "Not Applicable for this VCEP",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
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"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
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},
{
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"additionalComments": null,
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"defaultStrength": "Pathogenic Supporting",
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"MYO6",
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"SLC26A4",
"TECTA",
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],
"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",
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"id": "0239",
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"text": "",
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{
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"id": "002",
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"specificationType": [],
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable for this VCEP",
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"specificationType": [],
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"text": "",
"type": "EvidenceLineStrength"
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{
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"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",
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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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"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
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"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",
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"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",
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"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "005",
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"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"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638884",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638884",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_inf5Api--t"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0010984",
"lbl": "Usher syndrome type 1D",
"meta": {
"basicPropertyValues": [
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"val": "https://github.com/monarch-initiative/mondo/issues/4521"
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{
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},
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],
"definition": {
"val": "A form of Usher syndrome type I that is caused by homozygous or compound heterozygous mutation in the gene encoding cadherin-23 (CDH23) on chromosome 10q22. It is inherited in an autosomal recessive manner.",
"xrefs": [
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]
},
"subsets": [
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],
"synonyms": [
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"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "USH1D",
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"xrefs": [
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},
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"val": "Usher syndrome type ID",
"xrefs": [
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]
},
{
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},
{
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"val": "USHER syndrome, type ID",
"xrefs": [
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]
},
{
"pred": "hasRelatedSynonym",
"val": "Ush1D/F, Cdh23/Pcdh15, digenic"
},
{
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"val": "Usher syndrome, type 1D",
"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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}
]
},
"type": "CLASS"
},
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"name": "Usher syndrome type 1D",
"preferredModeOfInheritance": {
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"sepioID": "HP:0000007"
}
},
"entId": "MONDO:0010984",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0010984",
"entType": "Disease",
"ldhId": "135642110",
"ldhIri": "https://cspec.genome.network/cspec/Disease/id/135642110",
"modified": "2025-10-07T16:13:18.828Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7w0Uy---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019501",
"lbl": "Usher syndrome",
"meta": {
"basicPropertyValues": [
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"val": "https://www.malacards.org/card/usher_syndrome"
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"val": "http://identifiers.org/meddra/10063396"
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"val": "http://id.who.int/icd/entity/1452641873"
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{
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"val": "http://identifiers.org/medgen/78754"
},
{
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"val": "http://identifiers.org/mesh/D052245"
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{
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"val": "http://purl.obolibrary.org/obo/DOID_0050439"
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{
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"val": "http://purl.obolibrary.org/obo/NCIT_C85217"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_886"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS276900"
}
],
"comments": [
"This term's classification was reviewed in the context of the Strategic Refinement project (2023) and was determined to be excluded from the 'nervous system disorder' (MONDO:0005071) ontology branch (https://orcid.org/0000-0001-9310-0163) and from the 'metabolic disease' (MONDO:0005066) ontology branch (https://orcid.org/0000-0002-1780-5230)"
],
"definition": {
"val": "A syndromic diseae characterized by the association of sensorineural deafness (usually congenital) with retinitis pigmentosa and progressive vision loss.",
"xrefs": [
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"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": {
"_uniqueProp": "006_PM6_nuclear_PAH",
"additionalComments": "",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009861"
],
"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": {
"_uniqueProp": "006_BS4_nuclear_PAH",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Segregation Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "006",
"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": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applicable as described",
"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": "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"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "006",
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"type": "EvidenceLineStrength"
}
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"text": "",
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{
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"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
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{
"applicability": "Not Applicable",
"id": "0098",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0076",
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"text": "",
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"text": "",
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"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": [
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],
"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"
}
]
},
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"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
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{
"entContent": {
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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{
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"applicability": "Not Applicable",
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"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",
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"text": "",
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"type": "EvidenceLineStrength"
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],
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"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
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"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
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"specificationType": [
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"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)",
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"text": "",
"type": "EvidenceLineStrength"
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"strength": "Very Strong",
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"specificationType": [
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"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applicable as described in SVI recommendations for in trans criterion",
"type": "EvidenceLineStrength"
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{
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"id": "007",
"instructionsToUse": "",
"specificationType": [
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],
"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": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Applicable as described in SVI recommendations for in trans criterion",
"type": "EvidenceLineStrength"
}
]
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"entType": "CriteriaCode",
"ldhId": "135638964",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638964",
"modified": "2024-07-16T15:03:45.686Z",
"modifier": "mweaver",
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],
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{
"entContent": {
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{
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{
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"rev": "_inf5Alm--B"
},
{
"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": "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": "Uncertain Significance",
"sepioId": "LN:LA26333-7"
},
"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"
},
"entType": "Assertion",
"ldhId": "135642233",
"ldhIri": "https://cspec.genome.network/cspec/Assertion/id/135642233",
"modified": null,
"rev": "_inf5Alm--_"
}
],
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "007_BP7_nuclear_CDH1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH1"
],
"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.",
"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": [],
"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": {
"_uniqueProp": "007_BP6_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": "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",
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"text": "",
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{
"applicability": "Not Applicable for this VCEP",
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"text": "",
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{
"applicability": "Not Applicable for this VCEP",
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{
"applicability": "Not Applicable for this VCEP",
"id": "0063",
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"modifier": "genbadmin",
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"strength": "Strong",
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"strengthSepioID": "SEPIO:0000216",
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"applicability": "Applicable with VCEP specification",
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"specificationType": [],
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639060",
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"modifier": "genbadmin",
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]
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"modified": "2021-11-05T21:09:50.549Z",
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{
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{
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"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
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{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
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"strengthSepioID": "SEPIO:0000216",
"text": "One patient meets the HDGC individual phenotype criteria w/o parental confirmation",
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},
{
"applicability": "Not Applicable for this VCEP",
"id": "0022",
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639052",
"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apa--R"
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{
"entContent": {
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"applicability": "Not Applicable for this VCEP",
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"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable for this VCEP",
"id": "0028",
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"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable for this VCEP",
"id": "006",
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"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable for this VCEP",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
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},
"entType": "CriteriaCode",
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639068",
"modified": "2022-01-19T20:33:33.902Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--W"
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{
"entContent": {
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"evidenceCategory": "Functional Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": "This rule can only be applied to demonstrate splicing defects.",
"label": "PS3",
"ns": "007",
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"strength": "Strong",
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"text": "RNA assay demonstrating abnormal out-of-frame transcripts.",
"type": "EvidenceLineStrength"
},
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"id": "0039",
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"strength": "Moderate",
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"text": "RNA assay demonstrating abnormal in-frame transcript.",
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},
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"id": "0045",
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"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
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]
},
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"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--R"
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"entContent": {
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"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",
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"text": "",
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"id": "0207",
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"text": "",
"type": "EvidenceLineStrength"
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"id": "0068",
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"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"
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{
"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"
}
]
},
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"ldhId": "135639054",
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"modified": "2021-11-05T21:09:50.549Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--Y"
},
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"applicability": "Not Applicable for this VCEP",
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{
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"text": "",
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"modified": "2022-01-19T20:33:33.902Z",
"modifier": "genbadmin",
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],
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{
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{
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"val": "http://identifiers.org/medgen/310839"
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"val": "http://purl.obolibrary.org/obo/DOID_0080764"
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}
],
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},
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{
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},
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"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": [
{
"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": [
"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"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639146",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639146",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZqG---"
},
{
"entContent": {
"_uniqueProp": "008_PP2_nuclear_RUNX1",
"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
}
},
"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",
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"id": "0061",
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"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639145",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639145",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZiC---"
},
{
"entContent": {
"_uniqueProp": "008_BA1_nuclear_RUNX1",
"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": [
{
"applicability": "Applicable",
"defaultPoint": "Not Applicable",
"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",
"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": "135639144",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639144",
"modified": "2026-02-13T22:45:40.936Z",
"modifier": "tildacarlelycke",
"rev": "_lDisZiq---"
},
{
"entContent": {
"_uniqueProp": "008_PS3_nuclear_RUNX1",
"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": [
{
"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": [
"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**.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"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"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"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",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639131",
"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": "",
"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": "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"
},
{
"applicability": "Applicable",
"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"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C162696"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_71290"
}
],
"definition": {
"val": "The disorder is characterized by thrombocytopenia of varying severity and a predisposition to hematologic malignancies. It may be caused due to germ line variations in the RUNX1, ETV6 or ANKRD26 genes.",
"xrefs": [
"PMID:28600339",
"https://clinicalgenome.org/affiliation/50034/"
]
},
"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#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": "hereditary thrombocytopenia and hematologic cancer predisposition syndrome"
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "familial platelet syndrome with predisposition to acute myelogenous leukaemia"
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "familial thrombocytopenia with propensity to acute myelogenous leukaemia"
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "thrombocytopenia, familial, with propensity to acute myelogenous leukaemia"
}
],
"xrefs": [
{
"val": "GARD:10352"
},
{
"val": "MESH:C563324"
},
{
"val": "NCIT:C162696"
},
{
"val": "Orphanet:71290"
},
{
"val": "SCTID:725034002"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0011071",
"name": "hereditary thrombocytopenia and hematologic cancer predisposition syndrome",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0011071",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0011071",
"entType": "Disease",
"ldhId": "135642158",
"ldhIri": "https://cspec.genome.network/cspec/Disease/id/135642158",
"modified": "2025-10-07T16:13:20.206Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7w1pq---"
}
],
"EvidenceCategory": [
{
"entContent": {
"label": "Other Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642490",
"ldhIri": "https://cspec.genome.network/cspec/EvidenceCategory/id/135642490",
"modified": null,
"rev": "_inf5Asm--r"
},
{
"entContent": {
"label": "Segregation Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642485",
"ldhIri": "https://cspec.genome.network/cspec/EvidenceCategory/id/135642485",
"modified": null,
"rev": "_inf5Asi---"
},
{
"entContent": {
"label": "Functional Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642491",
"ldhIri": "https://cspec.genome.network/cspec/EvidenceCategory/id/135642491",
"modified": null,
"rev": "_inf5Asi--B"
},
{
"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": "Allelic Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642488",
"ldhIri": "https://cspec.genome.network/cspec/EvidenceCategory/id/135642488",
"modified": null,
"rev": "_inf5Asi--A"
},
{
"entContent": {
"label": "Other Database",
"sepioId": ""
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"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"
},
{
"applicability": "Not applicable",
"defaultPoint": 2,
"id": "009",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639209",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639209",
"modified": "2025-11-20T20:05:08.056Z",
"modifier": "Megfrone",
"rev": "_koJc3XG---"
},
{
"entContent": {
"_uniqueProp": "009_BS2_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "Using TP53 multigene panel testing results from two diagnostic labs, we compared the proportion of cancer-free individuals by age 60 in _TP53_ carriers vs. TP53-negative controls. Of note, in the internal data the proportion of individuals with sarcoma diagnosed ≥ age 61 was higher in carriers (0.60%) than in non-carriers (0.12%) and was a significant predictor of pathogenicity when included in the model. Based on the correspondence between likelihood ratios of pathogenicity and different levels of strengths for ACMG/AMP rules in the study by Tavtigian et al, 2018 (PMID: 29300386), our most conservative results support the following rules application. Females counted towards BS2 should be unrelated probands. If there is any variant allele frequency (VAF) provided, variants with VAF ≤ 35%, suggestive of somatic origin, should not be included in these counts.",
"label": "BS2",
"ns": "009",
"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": [
"gene-specific",
"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"
},
{
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"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"
},
"entType": "Assertion",
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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",
"ldhId": "135642233",
"ldhIri": "https://cspec.genome.network/cspec/Assertion/id/135642233",
"modified": null,
"rev": "_inf5Alm--_"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Benign",
"sepioId": "LN:LA6675-8"
},
"entType": "Assertion",
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"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": {
"curationActivity": "Variant Pathogenicity",
"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": "",
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"defaultStrength": "Pathogenic Moderate",
"disease": [
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"evidenceCategory": "Functional Data",
"gene": [
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"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/1856189/"
}
],
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"applicability": "Not applicable",
"id": "0230",
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"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"
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{
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"id": "0028",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "006",
"instructionsToUse": "",
"specificationType": [
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],
"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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"applicability": "Not Applicable for this VCEP",
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"defaultStrength": "Benign Supporting",
"disease": [
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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"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"
},
{
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"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": [
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],
"evidenceCategory": "Segregation Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "010",
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"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": {
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"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": [
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],
"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",
"label": "PS3",
"ns": "010",
"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": [],
"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": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n * RT-PCR evidence of mis-splicing for non-canonical intronic variants with no evidence of normal splice products. ",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0039",
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"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n * <5% wild type GAA activity when the variant is expressed in a heterologous cell type and evidence of abnormal GAA synthesis and/or processing.\n * RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.",
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},
{
"applicability": "Applicable as originally described",
"id": "0045",
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"specificationType": [
"Strength",
"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 * <30% wild type GAA activity when the variant is expressed in a heterologous cell type.\n * RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639300",
"modified": "2021-11-05T21:07:12.738Z",
"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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{
"applicability": "Not applicable",
"id": "0207",
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"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0208",
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"status": "not approved",
"strength": "Moderate",
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
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"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
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}
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},
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639297",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_inf5Api--E"
},
{
"entContent": {
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"geneType": "nuclear",
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"applicability": "Not applicable",
"id": "0235",
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"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
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"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
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"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"
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{
"applicability": "Not applicable",
"id": "0022",
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"text": "",
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]
},
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"modified": "2022-01-19T20:33:34.305Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--i"
},
{
"entContent": {
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{
"applicability": "Not applicable",
"id": "0226",
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"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0225",
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"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"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",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0085",
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"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"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"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639291",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639291",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--D"
},
{
"entContent": {
"_uniqueProp": "010_BS1_nuclear_GAA",
"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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"specificationType": [],
"strengthDescriptor": [
{
"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": "",
"specificationType": [
"Disease-specific"
],
"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"
},
{
"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": "135639287",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639287",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--C"
},
{
"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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],
"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": [
{
"id": "29543229",
"source": "PubMed",
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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": "638433025",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433025",
"modified": "2022-01-19T20:31:31.320Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--H"
},
{
"entContent": {
"_uniqueProp": "010_BP6_nuclear_GAA",
"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": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"GAA"
],
"instructionsToUse": "",
"label": "BP6",
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"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": "638433024",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433024",
"modified": "2022-01-19T20:31:31.320Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--K"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Benign",
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"disease": [
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],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BP7",
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"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",
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"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
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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.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
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"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_inf5Api--H"
},
{
"entContent": {
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"additionalComments": "* An individual could be a carrier of a pathogenic variant in GAA and have another disorder.\n* There is no known alternate molecular basis for deficiency of GAA activity, other than variants in GAA.",
"applicability": "Not Applicable for this VCEP",
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"disease": [
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"evidenceCategory": "Other Data",
"gene": [
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"geneType": "nuclear",
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"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0216",
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"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0073",
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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0078",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639305",
"modified": "2022-01-19T20:33:34.305Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--k"
},
{
"entContent": {
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
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"specificationType": [],
"strengthDescriptor": [
{
"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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{
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"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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"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
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"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
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"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_inf5Apa--D"
},
{
"entContent": {
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"additionalComments": "Does not apply. All types of variants cause Pompe disease.",
"applicability": "Not Applicable for this VCEP",
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"defaultStrength": "Benign Supporting",
"disease": [
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BP1",
"ns": "010",
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"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0206",
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"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0204",
"instructionsToUse": "",
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"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0075",
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"status": "not approved",
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"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
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"id": "0205",
"instructionsToUse": "",
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"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0082",
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"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": {
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"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": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639307",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639307",
"modified": "2022-01-19T20:33:34.305Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--a"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0009290",
"lbl": "glycogen storage disease II",
"meta": {
"basicPropertyValues": [
{
"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:0009290"
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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": "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",
"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",
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"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"
},
{
"applicability": "Applicable as originally described",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"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"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639465",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639465",
"modified": "2022-05-12T15:33:55.804Z",
"modifier": "neethus",
"rev": "_inf5Ap6--O"
},
{
"entContent": {
"_uniqueProp": "012_BP2_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Allelic Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "012",
"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 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",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Population Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "012",
"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": "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": {
"_uniqueProp": "012_PM1_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Functional Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "012",
"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": "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) \n* PM1 should not be applied at a moderate weight with PS1/PM5, see PM1_Supporting.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0054",
"instructionsToUse": "",
"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": {
"_uniqueProp": "012_BA1_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Population Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "012",
"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": "Popmax allele frequency >0.0038 (0.38%)",
"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": "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"
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},
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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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"type": "EvidenceLineStrength"
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"applicability": "Not applicable",
"id": "0077",
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"status": "not approved",
"strength": "Supporting",
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"text": "",
"type": "EvidenceLineStrength"
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135639456",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--T"
},
{
"entContent": {
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"strength": "Very Strong",
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"modified": null,
"rev": "_inf5Asm--o"
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{
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},
"entType": "EvidenceCategory",
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},
{
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"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--_"
},
{
"entContent": {
"_uniqueProp": "013_PM5_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LDLR"
],
"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",
"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 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.",
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{
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{
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{
"entContent": {
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{
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{
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"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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"id": "0078",
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"status": "approved",
"strength": "Supporting",
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"text": "Variant found in a case with an alternate molecular basis for disease",
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]
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"ldhId": "135637949",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637949",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
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{
"entContent": {
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"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0074",
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"status": "not approved",
"strength": "Strong",
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"text": "",
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"status": "not approved",
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"text": "",
"type": "EvidenceLineStrength"
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"id": "0081",
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"status": "approved",
"strength": "Supporting",
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"text": "In-frame deletions/insertions in a repetitive region without a known function",
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]
},
"entType": "CriteriaCode",
"ldhId": "135637943",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637943",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--X"
},
{
"entContent": {
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"additionalComments": "",
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"applicability": "Not applicable",
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"text": "",
"type": "EvidenceLineStrength"
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{
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{
"applicability": "Not applicable",
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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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]
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"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--K"
},
{
"entContent": {
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"applicability": "Not applicable",
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"strength": "Stand Alone",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0016",
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{
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"id": "004",
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"status": "not approved",
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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",
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"text": "",
"type": "EvidenceLineStrength"
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]
},
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"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
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{
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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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"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",
"rev": "_inf5Api--T"
},
{
"entContent": {
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"gene": [
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"geneType": "nuclear",
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"ns": "014",
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"sepioID": "SEPIO-CG:99023",
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"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
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"status": "not approved",
"strength": "Stand Alone",
"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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"id": "0050",
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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",
"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": "135637914",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637914",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_inf5Api--S"
},
{
"entContent": {
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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 with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"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": "135637860",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637860",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_inf5Api--J"
},
{
"entContent": {
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"additionalComments": "",
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"disease": [
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],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PM5",
"ns": "014",
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"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": "135637858",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637858",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_inf5Apa--F"
},
{
"entContent": {
"_uniqueProp": "014_BP6_nuclear_POLG",
"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": [
"POLG"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "014",
"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": "638433198",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433198",
"modified": "2022-01-19T20:31:32.743Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--J"
},
{
"entContent": {
"_uniqueProp": "014_PM1_nuclear_ETHE1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Functional Data",
"gene": [
"ETHE1"
],
"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": "135637955",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637955",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--i"
},
{
"entContent": {
"_uniqueProp": "014_PM6_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "De novo Data",
"gene": [
"ETHE1"
],
"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": "135637939",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637939",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--U"
},
{
"entContent": {
"_uniqueProp": "014_PM3_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Allelic Data",
"gene": [
"ETHE1"
],
"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",
"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%. ",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Population Data",
"gene": [
"ETHE1"
],
"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": ">0.0002 (>0.020%)",
"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": "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": [
"MONDO:0044970"
],
"evidenceCategory": "Population Data",
"gene": [
"POLG"
],
"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": [
"POLG"
],
"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": [
"MONDO:0044970"
],
"evidenceCategory": "Segregation Data",
"gene": [
"POLG"
],
"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",
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{
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{
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{
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"strength": "Strong",
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{
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"ldhId": "638433145",
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"modifier": "genbadmin",
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{
"entContent": {
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{
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"strength": "Moderate",
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{
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"text": "",
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{
"applicability": "Not applicable",
"id": "0013",
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"status": "not approved",
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"strengthSepioID": "SEPIO:0000330",
"text": "",
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"applicability": "Not applicable",
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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": "",
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{
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"text": "",
"type": "EvidenceLineStrength"
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"applicability": "Not applicable",
"id": "0034",
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"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"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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"entType": "CriteriaCode",
"ldhId": "135637951",
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"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
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},
{
"entContent": {
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"applicability": "Not applicable",
"id": "0242",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0031",
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"strengthSepioID": "SEPIO:0000220",
"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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"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0045",
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"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Reduced ETHE1 persulfide dioxygenase",
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]
},
"entType": "CriteriaCode",
"ldhId": "135637944",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637944",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--A"
},
{
"entContent": {
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"disease": [
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"geneType": "nuclear",
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"ns": "014",
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"applicability": "Not applicable",
"id": "0241",
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"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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{
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"id": "0051",
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"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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{
"applicability": "Not applicable",
"id": "004",
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"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0043",
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"status": "not approved",
"strength": "Supporting",
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"text": "",
"type": "EvidenceLineStrength"
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"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
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},
{
"entContent": {
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"id": "0229",
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"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0227",
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"status": "not approved",
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"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0071",
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"id": "0228",
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"status": "not approved",
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"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0077",
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"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
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"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--_"
},
{
"entContent": {
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"applicability": "Not Applicable for this VCEP",
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"disease": [
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"id": "0226",
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"status": "not approved",
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"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0225",
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"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"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",
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"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
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{
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"id": "0085",
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"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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"disease": [
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],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
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"ns": "014",
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"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
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"id": "0215",
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"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": "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"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637919",
"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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"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Segregation Data",
"gene": [
"POLG"
],
"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"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"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",
"rev": "_inf5Api--Q"
},
{
"entContent": {
"_uniqueProp": "014_BS3_nuclear_POLG",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Functional Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "014",
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"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": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637909",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637909",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--A"
},
{
"entContent": {
"_uniqueProp": "014_PS3_nuclear_PDHA1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Functional Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "014",
"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": "Not applicable",
"id": "0052",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"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": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637892",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637892",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--s"
},
{
"entContent": {
"_uniqueProp": "014_PS1_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "014",
"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": "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": "135637888",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637888",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--K"
},
{
"entContent": {
"_uniqueProp": "014_PM6_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "De novo Data",
"gene": [
"PDHA1"
],
"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": "135637887",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637887",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--J"
},
{
"entContent": {
"_uniqueProp": "014_PM5_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "014",
"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": "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": "135637884",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637884",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--L"
},
{
"entContent": {
"_uniqueProp": "014_PM2_nuclear_SLC19A3",
"additionalComments": "MAF - ><0.00005 (0.0050%). Notes: Per SVI: Use a threshold an order of magnitude below BS1 threshold",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Population Data",
"gene": [
"SLC19A3"
],
"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": "<0.00005 (<0.0050%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0030",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"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": {
"_uniqueProp": "014_PM1_nuclear_SLC19A3",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Functional Data",
"gene": [
"SLC19A3"
],
"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": "135637877",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637877",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--Y"
},
{
"entContent": {
"_uniqueProp": "014_PP5_nuclear_POLG",
"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": [
"POLG"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "014",
"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": "638433199",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433199",
"modified": "2022-01-19T20:31:32.743Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--N"
},
{
"entContent": {
"_uniqueProp": "014_BA1_nuclear_ETHE1",
"additionalComments": "MAF - >0.01(>1.0%), Prevalence - <1/1,000,000, Allelic Heterogeneity - 100%, Penetrance - 100%. ",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
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],
"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BA1",
"ns": "014",
"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": ">0.001 (>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": "135637950",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637950",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_inf5Apu--T"
},
{
"entContent": {
"_uniqueProp": "014_PVS1_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PVS1",
"ns": "014",
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"applicability": "Not applicable",
"id": "0245",
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"strength": "Stand Alone",
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"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",
"ldhId": "135637948",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637948",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--W"
},
{
"entContent": {
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"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"label": "PS4",
"ns": "014",
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"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": "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"
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{
"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": "",
"baseStrength": "Pathogenic",
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"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": "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": {
"_uniqueProp": "014_BP2_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0011229"
],
"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": "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",
"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": "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"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637902",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637902",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--I"
},
{
"entContent": {
"_uniqueProp": "014_PP3_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PDHA1"
],
"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": "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": {
"_uniqueProp": "014_BP5_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Other Data",
"gene": [
"PDHA1"
],
"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": "135637897",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135637897",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_inf5Api--O"
},
{
"entContent": {
"_uniqueProp": "014_PVS1_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "014",
"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": "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": {
"_uniqueProp": "014_BP3_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PDHA1"
],
"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"
},
{
"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": {
"_uniqueProp": "014_PS2_nuclear_PDHA1",
"additionalComments": "Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "De novo Data",
"gene": [
"PDHA1"
],
"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": {
"_uniqueProp": "014_BP2_nuclear_PDHA1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Allelic Data",
"gene": [
"PDHA1"
],
"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": {
"_uniqueProp": "014_BS4_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Segregation Data",
"gene": [
"PDHA1"
],
"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"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"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": {
"_uniqueProp": "014_PM3_nuclear_PDHA1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Allelic Data",
"gene": [
"PDHA1"
],
"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": {
"_uniqueProp": "014_BP7_nuclear_SLC19A3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "014",
"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 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"
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{
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{
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"modifier": "genbadmin",
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},
{
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{
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{
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],
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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: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": "638433256",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433256",
"modified": "2022-01-19T20:31:33.145Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--X"
},
{
"entContent": {
"_uniqueProp": "015_PP4_mitochondrial",
"additionalComments": "Other causes of ETC enzyme deficiency must be excluded, to the best of current ability, by comprehensive mtDNA and nDNA sequencing. Nuclear DNA genes including ETC complex subunits, assembly factors, and translation components should be thoroughly evaluated with no pathogenic or likely pathogenic variants (present in trans if autosomal recessive inheritance) that could be causative detected. See Supplemental file for list of genes.",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "PP4",
"ns": "015",
"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": "Decreased ETC enzyme activity (<20%) performed in a CLIA-approved (or equivalently-certified) laboratory in muscle, liver, and/or fibroblasts (for fibroblasts, must be seen in multiple unrelated probands and/or assayed in different individuals).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638272",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638272",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--k"
},
{
"entContent": {
"_uniqueProp": "015_BA1_mitochondrial",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"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": "",
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"id": "0085",
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"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).",
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}
]
},
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"entContent": {
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"text": "",
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"id": "0035",
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"text": "",
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"applicability": "Not applicable",
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"text": "",
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"modifier": "genbadmin",
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{
"entContent": {
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{
"applicability": "Not applicable",
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"strength": "Very Strong",
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"applicability": "Not applicable",
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"applicability": "Not applicable",
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{
"entContent": {
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{
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"text": "",
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{
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"id": "0019",
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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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"status": "not approved",
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"text": "",
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"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)",
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}
]
},
"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": "",
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"geneType": "mitochondrial",
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"applicability": "Not applicable",
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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",
"instructionsToUse": "",
"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": "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",
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]
},
"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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"geneType": "mitochondrial",
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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"
},
{
"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).",
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"evidenceCategory": "Population Data",
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"tRNA",
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],
"geneType": "mitochondrial",
"label": "PS4",
"ns": "015",
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"specificationType": [],
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"applicability": "Not applicable",
"id": "0243",
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"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"
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{
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"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"
}
]
},
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"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",
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"evidenceCategory": "Computational And Predictive Data",
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"geneType": "mitochondrial",
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"ns": "015",
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"id": "0215",
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"status": "not approved",
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"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
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{
"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)",
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}
]
},
"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": {
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"additionalComments": "",
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"evidenceCategory": "Allelic Data",
"geneClass": [
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"geneType": "mitochondrial",
"label": "BP2",
"ns": "015",
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"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"
},
{
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"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": {
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"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"geneClass": [
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],
"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"
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{
"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": "638433340",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433340",
"modified": "2022-01-19T20:31:33.889Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--i"
},
{
"entContent": {
"_uniqueProp": "016_PP5_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": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"FOXG1"
],
"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": "638433313",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433313",
"modified": "2022-01-19T20:31:33.731Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--R"
},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
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],
"evidenceCategory": "Population Data",
"gene": [
"UBE3A"
],
"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": "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",
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"text": "",
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{
"applicability": "Not applicable",
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"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": "",
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
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"text": "",
"type": "EvidenceLineStrength"
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]
},
"entType": "CriteriaCode",
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"modified": "2022-01-19T20:33:35.555Z",
"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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{
"applicability": "Not applicable",
"id": "0015",
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"strength": "Very Strong",
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"text": "",
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{
"applicability": "Not applicable",
"id": "0028",
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"status": "not approved",
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"text": "",
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{
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"status": "approved",
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"strengthSepioID": "SEPIO:0000216",
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},
{
"applicability": "Not applicable",
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"text": "",
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]
},
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"modifier": "genbadmin",
"rev": "_inf5Ap2--l"
},
{
"entContent": {
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{
"applicability": "Not applicable",
"id": "0049",
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"text": "",
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{
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
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{
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},
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"modifier": "genbadmin",
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},
{
"entContent": {
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"text": "",
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{
"applicability": "Not applicable",
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{
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"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
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{
"applicability": "Not applicable",
"id": "0100",
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"text": "",
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{
"applicability": "Not applicable",
"id": "0085",
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"strength": "Supporting",
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"text": "",
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]
},
"entType": "CriteriaCode",
"ldhId": "135638415",
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"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ape--l"
},
{
"entContent": {
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{
"applicability": "Not applicable",
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"text": "",
"type": "EvidenceLineStrength"
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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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"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
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"status": "not approved",
"strength": "Moderate",
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"text": "",
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{
"applicability": "Not applicable",
"id": "0027",
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"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
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"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638412",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--f"
},
{
"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",
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"instructionsToUse": "",
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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",
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"strength": "Very Strong",
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{
"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.",
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},
{
"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": "638433420",
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"modified": "2022-01-19T20:31:34.350Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--a"
},
{
"entContent": {
"_uniqueProp": "016_PP5_nuclear_SLC9A6",
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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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"strengthDescriptor": [
{
"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"
}
]
},
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"ldhId": "638433367",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433367",
"modified": "2022-01-19T20:31:34.054Z",
"modifier": "genbadmin",
"rev": "_inf5Apm--j"
},
{
"entContent": {
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"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
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],
"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"
}
],
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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",
"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",
"rev": "_inf5Apy--P"
},
{
"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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],
"instructionsToUse": "",
"label": "PP5",
"ns": "016",
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"references": [
{
"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",
"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": "638433286",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/638433286",
"modified": "2022-01-19T20:31:33.578Z",
"modifier": "genbadmin",
"rev": "_inf5Apy--Y"
},
{
"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",
"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": [
{
"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": [
"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": "135638554",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638554",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_inf5Api--K"
},
{
"entContent": {
"_uniqueProp": "016_BP3_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"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": "135638553",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/135638553",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_inf5Ap2--g"
},
{
"entContent": {
"_uniqueProp": "016_BP2_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007113"
],
"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": {
"_uniqueProp": "016_PM5_nuclear_UBE3A",
"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": [
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],
"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": {
"_uniqueProp": "016_PP5_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": "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",
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"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",
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"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
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},
{
"entContent": {
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"additionalComments": "",
"baseStrength": "Benign",
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"evidenceCategory": "Population Data",
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"strengthDescriptor": [
{
"applicability": "Not applicable",
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"strengthSepioID": "SEPIO:0000325",
"text": "",
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{
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"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
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],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
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{
"applicability": "Not applicable",
"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"
}
]
},
"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": {
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"additionalComments": "",
"baseStrength": "Benign",
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"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BP3",
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"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": [
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],
"geneType": "nuclear",
"label": "BP2",
"ns": "016",
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"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"
},
{
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"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",
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"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": [
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],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
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],
"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": [
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],
"evidenceCategory": "Population Data",
"gene": [
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],
"geneType": "nuclear",
"label": "BS1",
"ns": "016",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
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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": "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": {
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"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
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],
"evidenceCategory": "Population Data",
"gene": [
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],
"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": [
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],
"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": {
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"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
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],
"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": [
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],
"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": {
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"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
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],
"evidenceCategory": "Functional Data",
"gene": [
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],
"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",
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"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---"
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"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
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],
"geneType": "nuclear",
"instructionsToUse": null,
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"sepioID": "SEPIO-CG:99029",
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"Pilot Rules In Prep": {
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}
},
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"text": "",
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"text": "",
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"strengthSepioID": "SEPIO:0000329",
"text": "",
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"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
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"defaultStrength": "Pathogenic Moderate",
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"gene": [
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"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",
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"Pilot Rules In Prep": {
"completed": true
}
},
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"text": "",
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"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
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"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
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"id": "0011",
"instructionsToUse": "",
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"text": "",
"type": "EvidenceLineStrength"
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"instructionsToUse": "",
"specificationType": [
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"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",
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"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
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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",
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"evidenceCategory": "Other Database",
"gene": [
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"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"
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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"
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{
"applicability": "Not applicable",
"instructionsToUse": "",
"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",
"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": "638433451",
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"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRi----"
},
{
"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": "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": [
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"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
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{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
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],
"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": "",
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"strength": "Moderate",
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"text": "",
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{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
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"modified": "2025-10-10T18:20:25.930Z",
"modifier": "cjodarski",
"rev": "_ka7YRgy---"
},
{
"entContent": {
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"additionalComments": null,
"applicability": "Applicable",
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"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
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"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": [
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"id": "0087",
"instructionsToUse": "",
"specificationType": [
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],
"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": [
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"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
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"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"
],
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"id": "0019",
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"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": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "018",
"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": "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",
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"text": "",
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"id": "008",
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"text": "No change.",
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"applicability": "Not Applicable for this VCEP",
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},
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"applicability": "Not Applicable for this VCEP",
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{
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"id": "0027",
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"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
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"label": "PM2",
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"id": "0044",
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"text": "",
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{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
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"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
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{
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"id": "0011",
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"text": "",
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{
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"id": "0030",
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"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
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}
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},
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"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
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{
"entContent": {
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"additionalComments": null,
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"instructionsToUse": "**Document 1. (PS3)**\n\n**Functional Assay Validation** \n\nPMID: 31892348\n\n1. The 4 classes of assays (phosphorylation, DEPTOR binding, cell survivability, cell proliferation) are considered “broadly accepted historically” for these genes. \n2. Any publication within the spreadsheet can be used as evidence for a supporting level of evidence (PS3).\n3. Any paper must have validation controls (positive and negative) in order to be used as evidence for a level above supporting. Positive validation controls are defined as variants classified as pathogenic/likely pathogenic (P/LP) independent of the PS3 criterion. Negative validation controls are defined as variants classified as benign/likely benign independent of the BS3 criterion\n * 8-34 variants are required for moderate evidence.\n * 35+ variants are required for strong evidence.\n4. For a publication to be used for any strength of evidence above supporting, it must also meet the minimum criteria below, depending on the type of evidence:\n\n**Supplemental Table 1**\n\n**Evidence from Phosphorylation/Deptor Binding/Cell Survivability Assay:**\n\n (Assay Controls) \n\n* Basic Positive Control – WT necessary \n* Basic Negative Control – Empty vector or blank transfection can be used. \n* Biological Replicates – not necessary \n* Technical Replicates – yes, documented in at least triplicate (You can contact the researcher and ask if it is not specifically mentioned in the publication.)\n\n**Evidence of Cell Proliferation:**\n\n* Basic Positive Control - WT necessary \n* Basic Negative Control – Empty vector or blank transfection can be used. \n* Biological Replicates – Necessary for animal studies (e.g., each mouse is a replicate, need at least 2) \n* Technical Replicates – Necessary, multiple samples measured from the same animal or experiment done in triplicate (at least 3)",
"label": "PS3",
"ns": "018",
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"applicability": "Not Applicable for this VCEP",
"id": "0242",
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"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
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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.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0039",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Follow recommendations set forth by the SVI in conjunction with specifications added by the BMVCEP for quality metrics and minimum validation controls required (PMID: 31892348). Animal models are considered in a different manner. Award PS4_Moderate if the animal model generated with the variant of interest expressed in non-neural tissues show an increased cancer burden.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0045",
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"type": "EvidenceLineStrength"
}
]
},
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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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}
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},
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{
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"text": "",
"type": "EvidenceLineStrength"
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{
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"specificationType": "Disease-specific",
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"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0086",
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"type": "EvidenceLineStrength"
}
]
},
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{
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"type": "EvidenceLineStrength"
},
{
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
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"text": "",
"type": "EvidenceLineStrength"
},
{
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0022",
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"text": "",
"type": "EvidenceLineStrength"
}
]
},
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"modified": "2022-01-19T20:33:35.978Z",
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}
],
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"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"
},
{
"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"
},
{
"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"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003699",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003699",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2Ma2---"
},
{
"entContent": {
"_uniqueProp": "019_PP4_nuclear_MYOC",
"additionalComments": "The phenotype associated with MYOC variants is not highly specific and there is genetic heterogeneity.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "019",
"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": "Not applicable",
"defaultPoint": 2,
"id": "0018",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0063",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003697",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003697",
"modified": "2025-11-06T00:01:50.954Z",
"modifier": "esouzeau",
"rev": "_kjX2McC---"
},
{
"entContent": {
"_uniqueProp": "019_PP5_nuclear_MYOC",
"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": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "019",
"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": "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",
"evidenceCategory": "Other Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "019",
"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": "635003707",
"ldhIri": "https://cspec.genome.network/cspec/CriteriaCode/id/635003707",
"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": "",
"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": "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