{
"data": [
{
"entContent": {
"label": "PVS1",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* Use as defined by ClinGen SVI working group (Abou Tayoun et al., 2018[16](#pmid_30192042)) and as updated by the ClinGen SVI Splicing Subgroup (Walker et al., 2023[17](#pmid_37352859)).\n* Refer to GUCY2D-specific PVS1 Decision Tree, file attached.\n * PVS1: Predicted splice defects at +/- 1,2 in exons 2-20\n * PVS1: Single to multi-exon deletions, with or without predicted NMD. All exons are considered critical to protein function.\n * PVS1: Applied to variants in the initiation codon. The second in-frame methionine is located at residue 218 and use of this as a start codon would eliminate the leader sequence which targets the protein to the endoplasmic reticulum. There is no known study indicating that this methionine in GUCY2D can be used as start codon. Variants affecting Met1 can lead to a complete absence of the protein product. Additionally, there are multiple variants located upstream of p.Met218 that have been reported as a pathogenic in HGMD and ClinVar, evidence that this entire region of the protein is functionally important.\n * PVS1: Nonsense or frameshift mutations from p.Thr2 through p.Lys1068\n * PVS1: Duplications of exons proven in tandem\n * PVS1(RNA): RNA splicing data with evidence of alternative transcript production at complete levels, relative to normal allele.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* Use as defined by ClinGen SVI working group (Abou Tayoun et al., 2018[16](#pmid_30192042)) and as updated by the ClinGen SVI Splicing Subgroup (Walker et al., 2023[17](#pmid_37352859)).\n* Refer to GUCY2D-specific PVS1 Decision Tree, file attached.\n * PVS1\\_Strong: Nonsense or frameshift mutations from p.Pro1069 through p.Ser1103\n * PVS1\\_Strong: Duplications of exons presumed in tandem\n * PVS1(RNA)\\_Strong: RNA splicing data with evidence of alternative transcript production at near complete levels, relative to normal allele.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762135"
},
{
"entContent": {
"label": "BP4",
"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": "Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "For a missense variant use REVEL, requires a score of ≤0.183. In addition, highest SpliceAI delta score should also be below cutoff of 0.1.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "For a missense variant use REVEL, requires a score between 0.183 - 0.290. In addition, highest SpliceAI delta score should also be below cutoff of 0.1.\n\nFor a silent / intronic variant outside the designated splice region (conservatively at or beyond positions +7/-21) and synonymous (silent) exonic variants located outside of the first and the last 3 bases of the exon, BP4 can be met if the highest of the four delta scores within SpliceAI is below the cutoff of ≤0.1. See GUCY2D-specific PVS1 Decision Tree **part (a)** for SpliceAI flowchart.\n\n* Please note that BP7 can be met as well.",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762136"
},
{
"entContent": {
"label": "BP3",
"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": [
"Gene-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762137"
},
{
"entContent": {
"label": "PS1",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established Pathogenic variant regardless of nucleotide change.\n\n* Must have one comparison variant that reaches a Pathogenic classification using this rule specification.\n\nSame predicted splicing impact as a previously classified Pathogenic variant. \n\n* Used in conjunction with PP3 for variants located outside the splice donor/acceptor +/-1,2 dinucleotide positions that have a splice AI score ≥0.2 and have a comparable nucleotide variant at the **same position** that has been designated **Pathogenic**.\n* Used in conjunction with PVS1 for variants located at the splice donor/acceptor +/-1,2 dinucleotide positions and that have a comparable variant within the same splice donor/acceptor +/-1,2 dinucleotide that has been designated Pathogenic.\n\nSpecific combinations are found in GUCY2D-specific PVS1 Decision Tree **part (b)** (Table 2 from Walker 2023).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"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\n* Must have one comparison variant that reaches a Likely Pathogenic classification using this rule specification.\n\nSame predicted splicing impact as previously classified Likely Pathogenic variant.\n\n* Used in conjunction with PP3 for variants located outside the splice donor/acceptor +/-1,2 dinucleotide positions that have a splice AI score ≥0.2 and have a comparable nucleotide variant at the **same position** that has been designated **Likely Pathogenic**.\n* Used in conjunction with PVS1\\_(reduced strength) for variants located at the splice donor/acceptor +/-1,2 dinucleotide positions and have a comparable variant **within the same splice donor/acceptor motif** (but outside the +/-1,2 dinucleotide) that has been designated **Pathogenic**.\n\nSpecific combinations are found in GUCY2D-specific PVS1 Decision Tree **part (b)** (Table 2 from Walker 2023).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Used in conjunction with PP3 for variants located outside the splice donor/acceptor +/-1,2 dinucleotide positions that have a splice AI score ≥0.2 and have a comparable nucleotide variant within the **same motif** that has been designated **Likely Pathogenic**.\n* Used in conjunction with PVS1 or PVS1\\_(reduced strength) for variants located at the splice donor/acceptor +/-1,2 dinucleotide positions and have a comparable Likely Pathogenic or Pathogenic variant either within the same splice site donor/acceptor motif, outside the +/-1,2 dinucleotide, or at the +/-1,2 dinucleotide.\n\n Specific combinations are found in GUCY2D-specific PVS1 Decision Tree **part (b)** (Table 2 from Walker 2023).",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762138"
},
{
"entContent": {
"label": "PM6",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762139"
},
{
"entContent": {
"label": "PM3",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Points are calculated using Table 1 from [https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf) (or attached file “PM3 Tables”)\n\n* ≥4 points from Table 1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Points are calculated using Table 1 from [https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf) (or attached file “PM3 Tables”)\n\n* 2 to 3.75 points from Table 1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Points are calculated using Table 1 from [https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf) (or attached file “PM3 Tables”)\n\n* 1 to 1.75 points from Table 1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Points are calculated using Table 1 from [https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf) (or attached file “PM3 Tables”)\n\n* 0.5 to 0.75 points from Table 1",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762140"
},
{
"entContent": {
"label": "BA1",
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Use gnomAD Grpmax FAF if available, cutoff of >0.016\n\n* Use large population databases (i.e. 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"
}
]
},
"ldhId": "100762141"
},
{
"entContent": {
"label": "PS2",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (**both** maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* Use ClinGen SVI's recommendation for assigning weight to the PS2/PM6 codes (See PS2-Table 1 within PS2/PM6 file). \n* Total of 4 or more points required for Very Strong level",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (**both** maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* Use ClinGen SVI's recommendation for assigning weight to the PS2/PM6 codes (See PS2-Table 1 within PS2/PM6 file). \n* Total of 2.00 - 3.75 points required for Strong level",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "De novo (**both** maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* Use ClinGen SVI's recommendation for assigning weight to the PS2/PM6 codes (See PS2-Table 1 within PS2/PM6 file). \n* Total of 1.00 - 1.75 points required for Moderate level",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "De novo (**both** maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* Use ClinGen SVI's recommendation for assigning weight to the PS2/PM6 codes (See Table 1 within PS2/PM6 file). \n* Total of 0.50 - 0.75 points required for Supporting level",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762142"
},
{
"entContent": {
"label": "PS4",
"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": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762143"
},
{
"entContent": {
"label": "PM1",
"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": "Met by active site residues that bind the GTP substrate or the Mg2+ ion; Phe883, Asp885, Thr890, Leu905, Glu925, Ile927, Asp929, Met932, Arg976, Arg995, Cys997, Leu998, Phe999, Gly1000, Val1003, Asn1004, Arg1008, and Glu1010 [13](#pmid_9391039).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Met by variants not explicitly listed above, encoding missense substitutions between positions p.873-951. This region forms part of the guanylate cyclase catalytic domain and exhibits intolerance to missense variation [14](#pmid_31704230).\n* Met by variants in the 6 bp CRX binding site located at position 17:8002593-8002598 (hg38) [18](#pmid_36084042)",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762144"
},
{
"entContent": {
"label": "BS2",
"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",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant is present in ≥ 3 homozygotes without any features of the phenotype. This rule applies to individuals found in the literature who have been well-phenotyped and are unaffected by age 40. Alternatively, this strength can be applied if the variant is present in ≥ 6 homozygotes in gnomAD v.4.1.0 or later.",
"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": "Variant is present in ≥ 3 homozygotes in gnomAD v.4.1.0 or later.",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762145"
},
{
"entContent": {
"label": "PP4",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* 8 phenotype points or more are required to use this code at the moderate strength for a single proband (see points list below).\n* Additionally, at least one **specific** criterion must be met (see below).\n* Do not include a proband with a suspected diagnosis of more than one retinal dystrophy.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* 4-7.5 phenotype points are required to use this code (see points list below).\n* Do not include a proband with a suspected diagnosis of more than one retinal dystrophy.",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762146"
},
{
"entContent": {
"label": "PM2",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n\n* Used if the gnomAD total allele frequency is ≤ 4.0 x 10-4.",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762147"
},
{
"entContent": {
"label": "BP6",
"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"
}
]
},
"ldhId": "100762149"
},
{
"entContent": {
"label": "BP5",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762150"
},
{
"entContent": {
"label": "BP1",
"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"
}
]
},
"ldhId": "100762151"
},
{
"entContent": {
"label": "PM4",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n\n* Protein length change of ≥2 amino acids that leads to loss of at least one conserved residue (PhyloP>2.0) or insertion of new amino acids adjacent to at least one conserved residue (PhyloP>2.0).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n\n* Protein length change of 1 amino acid that leads to loss of at least one conserved residue (PhyloP>2.0) or insertion of new amino acid adjacent to at least one conserved residue (PhyloP>2.0).",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762152"
},
{
"entContent": {
"label": "PP3",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* For a missense variant use REVEL, requires a score of ≥ 0.774.\n* Splice variants use PP3 only at Supporting level.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* For a missense variant use REVEL, requires a score of 0.644 - 0.773.\n* For a variant in an untranslated region use CADD, requires a score of ≥ 20.0\n* For a predicted splicing variant use SpliceAI with max distance set to 500 bp. Highest delta score from SpliceAI must be ≥ 0.2 to use this code. See GUCY2D-specific PVS1 Decision Tree **part (a)** for SpliceAI flowchart.",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762153"
},
{
"entContent": {
"label": "PP5",
"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"
}
]
},
"ldhId": "100762154"
},
{
"entContent": {
"label": "PP1",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members and evidence that this variant and another GUCY2D variant are _in trans_.\n\n* Requires segregation in one proband plus ≥3 similarly affected relatives",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members and evidence that this variant and another GUCY2D variant are _in trans_.\n\n* Requires segregation in one proband plus 2 similarly affected relatives",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members and evidence that this variant and another GUCY2D variant are _in trans_.\n\n* Requires segregation in one proband plus 1 similarly affected relative",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762155"
},
{
"entContent": {
"label": "PS3",
"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": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect. \n\nSee attached table for acceptable functional studies. \n\nEligible results include _Gucy2e−/−Gucy2f−/−_ knockout mice subretinally injected with adeno-associated virus-packaged constructs encoding a GUCY2D variant (Boye et al., 2016,[10](#pmid_27881908)) or mice with knock-in of a _GUCY2D_ variant (not yet available in the published literature). Results should include flat or nearly flat scotopic and photopic electroretinogram responses in comparison to wild-type injected control, absent or near-absent guanylate cyclase activity in comparison to wild-type injected control, and/or absent or near absent GUCY2D expression at the protein level despite approximately wild-type expression at the RNA level.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect. Not applicable for splicing effects (replaced by PVS1\\_Strength (RNA))\n\nSee attached table for acceptable functional studies.\n\nFor studies reporting guanylate cyclase activity, cutoff is ≤10% of wild-type control.",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762157"
},
{
"entContent": {
"label": "BP2",
"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 cis with a Pathogenic variant.\n\n* Use code if the variant of interest is _in cis_ with a Pathogenic or Likely Pathogenic variant. The other variant must meet a Likely Pathogenic or Pathogenic classification using these rule specifications.",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762158"
},
{
"entContent": {
"label": "PM5",
"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": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n\n* Must have one comparison variant that reaches a Pathogenic classification using this rule specification.\n* SpliceAI scores for both variants should be in the same category (\\<0.1, between 0.1 and 0.2, >0.2)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n\n* Must have one comparison variant that reaches a Likely Pathogenic classification using this rule specification.\n* SpliceAI scores for both variants should be in the same category (\\<0.1, between 0.1 and 0.2, >0.2)",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762159"
},
{
"entContent": {
"label": "BP7",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "BP7\\_Strong (RNA) Used to designate capture of splicing data (not BS3). See GUCY2D-specific PVS1 Decision Tree, file attached, for weighting and combining with other codes.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use not only for synonymous variants but also for intronic variants located outside of the donor/acceptor +/- 1,2 dinucleotide positions. \n\nIf SpliceAI score ≤0.1, apply BP4 followed by assessment of BP7. See GUCY2D-specific PVS1 Decision Tree **part (a)** for SpliceAI flowchart.\n\n* Positions **excluded** from BP7:\n * Synonymous substitutions at the first base of an exon\n * Synonymous substitutions in the last 3 bases of an exon\n * +1 through +7 of donor sequence\n * \\-1 through -21 of acceptor sequence",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762160"
},
{
"entContent": {
"label": "BS1",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disorder. Use gnomAD Grpmax FAF if available.\n\n* Allele frequency of 0.0016 - 0.016",
"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"
}
]
},
"ldhId": "100762161"
},
{
"entContent": {
"label": "BS4",
"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": [
"Clarification"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n\n* One or both variants are absent in a similarly affected family member.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762162"
},
{
"entContent": {
"label": "PP2",
"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"
}
]
},
"ldhId": "100762163"
},
{
"entContent": {
"label": "BS3",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Not applicable for splicing effects (replaced by BP7\\_Strong (RNA)).\n\nFor studies reporting guanylate cyclase activity, cutoff is >50% of wild-type control. Studies included; Peshenko et al., 2020[1](#pmid_33109612), Feng et al., 2020, Jacobson et al., 2021[2](#pmid_33997691), Jacobson et al., 2020[3](#pmid_36274938), Tucker et al., 2004[4](#pmid_15123990), Jacobson et al., 2013[5](#pmid_23035049), and Peshenko et al., 2015[7](#pmid_26100624)\n\nSee attached table of Approved PS3 Functional Assays for a list of acceptable functional studies including those that:\n\n* Report failure of GUCY2D to localize to the cell surface : Zulliger et al., 2015[6](#pmid_25477517).\n* Report failure of GUCY2D to bind RD3: Zulliger et al., 2015[6](#pmid_25477517). \n* Report failure of GCAP1, GCAP2, or RD3 to co-localize with GUCY2D at the cell surface: Peshenko et al., 2020[1](#pmid_33109612), Jacobson et al., 2020[3](#pmid_36274938), and Peshenko et al., 2015[7](#pmid_26100624).",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "100762164"
},
{
"entContent": {
"label": "BP6",
"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"
}
]
},
"ldhId": "1100975048"
},
{
"entContent": {
"label": "BP3",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0074",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975049"
},
{
"entContent": {
"label": "PS3",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 8,
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Applicable for beta-oxidation activity assays OR immunofluorescence assays showing absence or mislocalization of protein OR immunoblotting assay showing absence or reduced protein levels.\n* Note: for variants meeting PS1, functional studies on a different variant (different nucleotide change, same amino acid change) may be applicable to the variant being curated. PS3\\_supporting may be used in addition to PS1.\n* There are not many benign variants to curate for functional evidence at this time. We would favor using PS3\\_moderate in the event that more variants with functional evidence are classified as benign by the Peroxisomal Disorders VCEP.",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975050"
},
{
"entContent": {
"label": "PVS1",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Applicable",
"defaultPoint": 8,
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "The Perox VCEP will utilize SVI’s PVS1 recommendation for determining applicable PVS1 strength level (Abou Tayoun et al 2018; PMID: 30192042). Refer to the modified PVS1 decision tree attached.\n\nPVS1 RNA is applicable for splicing defects demonstrated by RNA studies on patient mRNA or when a variant expressed in human/mammalian host cells. Strength level may be decided based on the assay as well as the abundance of normal splice products as recommended by Walker et al, 2023.\n\nExons 1 and 9 are in-frame. Exon skipping consequences for splice site variants are listed in the attached table.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0020",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0026",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975051"
},
{
"entContent": {
"label": "PM3",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 8,
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 4,
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"This requires testing of parents (or offspring) to determine phase."
]
},
"applicability": "Not applicable",
"defaultPoint": 2,
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975052"
},
{
"entContent": {
"label": "BS2",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"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\n* This code is applicable when >10 hemizygous healthy adult (>40y) males are observed",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -1,
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975053"
},
{
"entContent": {
"label": "PM5",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"defaultPoint": 2,
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\n* Splicing abnormalities (using VCEP-specified prediction algorithms or evidence from literature) should be excluded for all missense variants\n* PM5 will be applied at moderate strength for 1 pathogenic variant with no benign variation at the residue\n* The other variant(s) used for evidence should also have been curated using the Perox VCEP rule specifications and must reach a pathogenic/likely pathogenic classification without PM5",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* PM5\\_Supporting can be applied for 1 likely pathogenic variant with no benign variation at the residue.\n* The other variant(s) used for evidence should also have been curated using the Perox VCEP rule specifications and must reach a pathogenic/likely pathogenic classification without PM5",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975054"
},
{
"entContent": {
"label": "BP2",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -4,
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"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.\n\n* Use when variant is found to be is cis with another pathogenic variant\n* The “in-cis” variant should also be curated by the Perox VCEP to apply rule.",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975055"
},
{
"entContent": {
"label": "PS1",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* Splicing abnormalities (using VCEP-specified prediction algorithms or evidence from literature) should be excluded for all missense variants\n* PS1 will be applied at the strong level for 1 previously established pathogenic variant \n* PS1 can also be applied at the strong level for 1 previously established pathogenic canonical splice site variant (at the same position)\n* The other variant(s) used for evidence should also have been curated using Perox VCEP rule specifications and reach a pathogenic/likely pathogenic classification without using PS1.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Splicing abnormalities (using VCEP-specified prediction algorithms or evidence from literature) should be excluded for all missense variants\n* PS1 will be applied at the moderate level for 1 previously established likely pathogenic variant \n* PS1 can also be applied at the moderate level for 1 previously established likely pathogenic canonical splice site variant (at the same position)\n* The other variant(s) used for evidence should also have been curated using Perox VCEP rule specifications and reach a pathogenic/likely pathogenic classification without using PS1.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975056"
},
{
"entContent": {
"label": "BP5",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0073",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0217",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975057"
},
{
"entContent": {
"label": "PP2",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975058"
},
{
"entContent": {
"label": "BS4",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family. Caveat: 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.\n\n* Use as is when there is a lack of segregation in 1 affected male in the family in addition to the proband",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -1,
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975059"
},
{
"entContent": {
"label": "PS4",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 8,
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "* Applicable when multiple unrelated probands are reported with the same variant. All probands counted should meet at least PP4\\_supporting phenotype criteria. When multiple unrelated individuals are reported with the variant, use the proband that would meet the highest strength level for PP4 and count the remaining ones (at least meeting PP4\\_supporting strength) towards PS4.\n* PS4\\_Very Strong applicable for ≥ 16 probands\n* Note: We caution against applying PS4 for >4 cases (meeting phenotype criteria D/E and F) with the same variant identified solely on newborn screening.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* Applicable when multiple unrelated probands are reported with the same variant. All probands counted should meet at least PP4\\_supporting phenotype criteria. When multiple unrelated individuals are reported with the variant, use the proband that would meet the highest strength level for PP4 and count the remaining ones (at least meeting PP4\\_supporting strength) towards PS4.\n* PS4 applicable for 4 -15 probands\n* Note: We caution against applying PS4 for >4 cases (meeting phenotype criteria D/E and F) with the same variant identified solely on newborn screening.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Applicable when multiple unrelated probands are reported with the same variant. All probands counted should meet at least PP4\\_supporting phenotype criteria. When multiple unrelated individuals are reported with the variant, use the proband that would meet the highest strength level for PP4 and count the remaining ones (at least meeting PP4\\_supporting strength) towards PS4.\n* PS4\\_Moderate for 2-3 probands\n* Note: We caution against applying PS4 for >4 cases (meeting phenotype criteria D/E and F) with the same variant identified solely on newborn screening.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Applicable when multiple unrelated probands are reported with the same variant. All probands counted should meet at least PP4\\_supporting phenotype criteria. When multiple unrelated individuals are reported with the variant, use the proband that would meet the highest strength level for PP4 and count the remaining ones (at least meeting PP4\\_supporting strength) towards PS4.\n* PS4\\_Supporting for 1 proband\n* Note: We caution against applying PS4 for >4 cases (meeting phenotype criteria D/E and F) with the same variant identified solely on newborn screening.",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975060"
},
{
"entContent": {
"label": "PS2",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 8,
"id": "0016",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.\n\n* Confirmed maternity and paternity by WES Trio or paternity and maternity testing for affected females. Confirmation of maternity is sufficient in the case of affected males. \n* Use SVI-recommended point system at 2nd tier, “phenotype consistent with gene but not highly specific”, for probands meeting PP4 and at the 1st tier, “phenotype highly specific for gene”, for probands meeting PP4\\_Moderate\n* See attached table.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "004",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "0043",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975061"
},
{
"entContent": {
"label": "PP1",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* Segregations can be counted across families. All individuals counted for segregation must be genotype positive AND phenotype positive. In the absence of a pedigree available to determine relationships, segregations among related individuals can be counted conservatively (assuming closest relationships).\n* PP1\\_Strong: 3 affected segregations (in addition to proband)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Segregations can be counted across families. All individuals counted for segregation must be genotype positive AND phenotype positive. In the absence of a pedigree available to determine relationships, segregations among related individuals can be counted conservatively (assuming closest relationships).\n* PP1\\_Moderate: 2 affected segregation (in addition to proband)",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"May be used as stronger evidence with increasing segregation data"
]
},
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Segregations can be counted across families. All individuals counted for segregation must be genotype positive AND phenotype positive. In the absence of a pedigree available to determine relationships, segregations among related individuals can be counted conservatively (assuming closest relationships).\n* PP1\\_supporting: 1 affected segregation (in addition to proband)",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975062"
},
{
"entContent": {
"label": "BP7",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -4,
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Can be applied to synonymous variants meeting BP4 criteria OR intronic variants meeting BP4 criteria and are beyond the Walker et. al. (PMID 37352859) defined splice region of +7/-21\n\n* Conservation does not have to be considered for this code to apply",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975063"
},
{
"entContent": {
"label": "BA1",
"strengthDescriptor": [
{
"applicability": "Applicable",
"defaultPoint": "Not Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Use a Total Grpmax filtering allele frequency (FAF) cutoff of ≥0.017% (0.00017) from the most resent version of gnomAD. This frequency was calculated using the Whiffen-Ware calculator with a prevalence estimated at 1 in 5000 (actual prevalence in hemizygotes and heterozygotes is reported to be 1 in 16800, GeneReviews, Bezman et al 2001; however, a more conservative BA1 was designated based on a value 1 order of magnitude higher than the BS1 cut-off), penetrance at 60% (based on penetrance in heterozygotes by expert judgment, maximum allelic contribution and maximum genetic contribution at 100%).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975064"
},
{
"entContent": {
"label": "BS3",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -4,
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"status": "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": "* BS3\\_Supporting is applicable for beta-oxidation activity assay in ALD fibroblasts transfected with variant, showing >57% activity of WT (PMID: 34946879)",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975065"
},
{
"entContent": {
"label": "BP4",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -4,
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants, use REVEL with a score of ≤ 0.5 AND SpliceAI with a score \\< 0.1\n* For variants with splicing impact (exonic and intronic variants, not applicable for UTR variants), use SpliceAI with a score \\< 0.1",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975066"
},
{
"entContent": {
"label": "BS1",
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Use a Total Grpmax filtering allele frequency (FAF) cutoff of ≥0.0017% (0.000017) from the most recent version of gnomAD. This frequency was calculated using the Whiffen-Ware calculator with a prevalence estimated at 1 in 50000 (upper limit of prevalence range in hemizygotes; GeneReviews), penetrance at 60% (based on penetrance in heterozygotes by expert judgment, maximum allelic contribution and maximum genetic contribution at 100%).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -1,
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975067"
},
{
"entContent": {
"label": "PM1",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.\n\n* PM1 applied at moderate strength for variants within the Walker A (aa 507-520; c.1519-c.1560) and B (aa 617-641; c.1849-c.1923) domains",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975068"
},
{
"entContent": {
"label": "PP5",
"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"
}
]
},
"ldhId": "1100975069"
},
{
"entContent": {
"label": "PP4",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Use PP4 table to determine the appropriate PP4 strength level \n* When multiple unrelated individuals are reported with the variant, use the proband that would meet the highest strength level for PP4 and count the remaining ones (at least meeting PP4\\_supporting strength) toward PS4.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Use PP4 table to determine the appropriate PP4 strength level \n* When multiple unrelated individuals are reported with the variant, use the proband that would meet the highest strength level for PP4 and count the remaining ones (at least meeting PP4\\_supporting strength) toward PS4.",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975070"
},
{
"entContent": {
"label": "PP3",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* For missense variants, use REVEL with a score of >0.85 \n* For variants with a splicing impact (loss of canonical splice sites AND creation of cryptic sites), use SpliceAI with a score of ≥ 0.5",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975071"
},
{
"entContent": {
"label": "PM6",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 8,
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of paternity and maternity.\n\n* See PS2 specification; Use SVI-recommended point system at 2nd tier for probands meeting PP4 and at the 1st tier for probands meeting PP4\\_Moderate",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975072"
},
{
"entContent": {
"label": "BP1",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0075",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0205",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975073"
},
{
"entContent": {
"label": "PM2",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Population data for insertions/deletions may be poorly called by next-generation sequencing."
]
},
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0011",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* PM2\\_Supporting can be applied if the variant is absent in hemizygotes AND has a maximum allele frequency of \\<0.00017% (0.0000017) in heterozygotes in the latest version of gnomAD. Use the highest population MAF from a non-bottleneck population from the latest version of gnomAD.",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975074"
},
{
"entContent": {
"label": "PM4",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "009",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1100975075"
},
{
"entContent": {
"label": "PP1",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use general recommendations from Oza AM et al, 2018, PMID: 30311386, sufficient affected and unaffected segregations have been counted to reach likelihood of 32:1.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Using general recommendations from Oza AM et al., 2018, PMID: 30311386, sufficient affected and unaffected segregations have been counted to reach likelihood of 16:1.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"May be used as stronger evidence with increasing segregation data"
]
},
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Using general recommendations from Oza AM et al., 2018, (PMID: 30311386), sufficient affected and unaffected segregations have been counted to reach likelihood of 4:1.",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823435"
},
{
"entContent": {
"label": "PP3",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* For missense variants use REVEL with a score ≥0.7 \n* In-frame in/dels, Provean (“deleterious”) and MutationTaster (“Disease-causing”) must agree\n* For non-canonical splicing variants use SpliceAI with a score ≥0.2, look for cryptic splice sites.",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823436"
},
{
"entContent": {
"label": "BP1",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823437"
},
{
"entContent": {
"label": "PM6",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Paternity and maternity must be confirmed. Patient must meet PP4.\n\nBecause there has only ever been one reported de novo occurrence of a _GALT_ variant and de novo occurrence is not expected to significantly contribute to disease, the VCEP will use PM6 and not PS2. PM6 will not be upgraded with number of occurrences.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823438"
},
{
"entContent": {
"label": "BA1",
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Use a minor allele frequency cutoff of ≥0.01 (1%) (use PopMax FAF in gnomAD). This frequency was calculated using the Whiffen-Ware calculator with a prevalence estimated at 1 in 10,000, penetrance at 100%, maximum allelic contribution and maximum genetic contribution at 100%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823439"
},
{
"entContent": {
"label": "PVS1",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "* The Galactosemia VCEP will utilize SVI’s PVS1 recommendation for determining applicable PVS1 strength level (Abou Tayoun et al 2018; PMID: 30192042). Refer to the modified PVS1 decision tree attached.\n* Exons 6, 7, and 9 are in-frame. Exon skipping consequences for splice site variants are listed in the attachment as well.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Refer to PVS1 decision tree attached.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Refer to PVS1 decision tree attached.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823440"
},
{
"entContent": {
"label": "PM1",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "PM1 applied at moderate strength for variants that occur in the active site from Phe171 to Gln188",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823441"
},
{
"entContent": {
"label": "PP5",
"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"
}
]
},
"ldhId": "1151823442"
},
{
"entContent": {
"label": "PP2",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823443"
},
{
"entContent": {
"label": "BS3",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0072",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* Can only be used at the supporting level \n* Functional assay in non-patient material \n* BS3\\_Supporting is applicable for greater than 50% enzyme activity in a model system (cannot apply at strong level)",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823444"
},
{
"entContent": {
"label": "PS1",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* Splicing abnormalities (using VCEP-specified prediction algorithms or evidence from literature) should be excluded for all missense variants\n* PS1 will be applied at the strong level for 1 previously established pathogenic missense variant or use Table 2 in Walker et al., PMID: 37352859 for splicing variant\n* The other variant(s) used for evidence should also have been curated using GALT VCEP rule specifications and reach a pathogenic/likely pathogenic classification without using PS1.\n* Same predicted impact on splicing as previously classified variant (refer to table 2 in Walker et al., 2023, PMID: 37352859).\n * PS1 can by applied at varying strengths (strong, moderate, supporting) in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/-1,2, dinculeotide position). Specific combinations are outlined in table 2 Walker et al., 2023, PMID: 37352859.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Same predicted impact on splicing as previously classified variant (refer to table 2 in Walker et al., 2023, PMID: 37352859).\n * PS1 can by applied at varying strengths (strong, moderate, supporting) in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/-1,2, dinculeotide position). Specific combinations are outlined in table 2 Walker et al., 2023, PMID: 37352859.\n* PS1\\_Moderate will apply for 1 previously established likely pathogenic variant or use Table 2 in Walker et al., 2023, PMID: 37352859 for splicing variant",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Same predicted impact on splicing as previously classified variant (refer to table 2 in Walker et al., 2023, PMID: 37352859).\n * PS1 can by applied at varying strengths (strong, moderate, supporting) in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/-1,2, dinculeotide position). Specific combinations are outlined in table 2 Walker et al., 2023, PMID: 37352859.\n* PS1\\_Supporting will apply for splicing variants only, used Table 2 in Walker et al., 2023, PMID: 37352859",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823445"
},
{
"entContent": {
"label": "BP3",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823446"
},
{
"entContent": {
"label": "BP5",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823447"
},
{
"entContent": {
"label": "PM3",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Variant under investigation meets PM2, identified individuals meet PP4, and at least 4 PM3 points have been reached.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Variant under investigation meets PM2, identified individuals meet PP4, and at least 2 PM3 points have been reached.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"This requires testing of parents (or offspring) to determine phase."
]
},
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant under investigation meets PM2, identified individual(s) meet PP4, and at least 1 PM3 point has been reached.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Variant under investigation meets PM2, identified individual(s) meet PP4, and at least 0.5 PM3 points have been reached.",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823448"
},
{
"entContent": {
"label": "BS4",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Individual considered unaffected RBC GALT enzyme activity ≥25% with the caveat of no bone marrow transfusions in individual.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823449"
},
{
"entContent": {
"label": "PM2",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Population data for insertions/deletions may be poorly called by next-generation sequencing."
]
},
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Can only be used at the supporting level \n* Use the PopMax filtering allele frequency (FAF) from gnomAD.\n* Use if variant is present at ≤ 0.0005 or 0.05% \n * One order of magnitude below BS1\n* A curated list of _GALT_ variants known to be pathogenic despite not fulfilling the PM2 criterion has been developed (see PM2 exception list)",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823450"
},
{
"entContent": {
"label": "PS2",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Not applicable",
"id": "0051",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823451"
},
{
"entContent": {
"label": "PP4",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* RBC GALT enzyme activity \\<10%\n* In order to apply PP4 at the moderate level, newborn screen alone would not count, must have confirmatory testing. \n* For PP4 to be applied at moderate level, full _GALT_ gene sequencing (exons and exon/intron boundaries) rather than _GALT_ panel testing must have been carried out.\n* Variants must meet PM2\\_Supporting for PP4 to apply at any strength.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* RBC GALT enzyme activity \\<10%\n* In order to apply PP4 at the supporting level, newborn screen alone would not count, must have confirmatory testing.",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823452"
},
{
"entContent": {
"label": "BS1",
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Use a minor allele frequency cutoff of ≥0.005 (0.5%) (use PopMax FAF in gnomAD). This frequency was calculated using the Whiffen-Ware calculator with a prevalence estimated at 1 in 10,000, penetrance at 100%, maximum allelic contribution of 50% and maximum genetic contribution at 100%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823453"
},
{
"entContent": {
"label": "PS3",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Not Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Applicable for up to 20% enzyme activity in a model system",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823454"
},
{
"entContent": {
"label": "BS2",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This code is applicable when individual is confirmed to be unaffected by GALT activity levels",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823455"
},
{
"entContent": {
"label": "BP2",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* Observed in cis with a likely pathogenic or pathogenic variant OR observed in trans with a pathogenic variant in an unaffected individual with RBC GALT enzyme activity in the carrier range\n* Pathogenicity of first variant must be determined using VCEP guidelines. \n* Full gene sequencing including promoter region must have been completed to apply BP2",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823456"
},
{
"entContent": {
"label": "PM4",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823457"
},
{
"entContent": {
"label": "BP4",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score of \\<0.15 \n* In-frame in/dels, Provean (“neutral”) and MutationTaster (“polymorphism”) must agree\n\nFor non-canonical splicing variants use SpliceAI with a score of \\<0.1, do not use if there is evidence of a cryptic splice site",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823458"
},
{
"entContent": {
"label": "BP6",
"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"
}
]
},
"ldhId": "1151823459"
},
{
"entContent": {
"label": "BP7",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* Use “as is”, but no conservation requirement \n* BP4 must be applied for BP7 to be used, the codes can be combined \n* Do not use for silent variants in the first nucleotide or last 3 nucleotides of the exon\n* Can also be used for intronic variants at or beyond positions +7/-21 with no predicted effect on splicing.",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823460"
},
{
"entContent": {
"label": "PM5",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Splicing abnormalities (using VCEP-specified prediction algorithms or evidence from literature) should be excluded for all missense variants\n* PM5 will be applied at moderate strength for 1 pathogenic variant with no benign variation at the residue\n* The other variant(s) used for evidence should also have been curated using the GALT VCEP rule specifications and must reach a pathogenic/likely pathogenic classification without PM5.\n* Grantham should be used to compare the variants. The new variant must be equal or worse than the known pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* PM5\\_Supporting can be applied for 1 likely pathogenic variant with no benign variation at the residue.\n* The other variant(s) used for evidence should also have been curated using the GALT VCEP rule specifications and must reach a pathogenic/likely pathogenic classification without PM5\n* Grantham should be used to compare the variants. The new variant must be equal or worse than the known pathogenic variant.",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823461"
},
{
"entContent": {
"label": "PS4",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Not applicable",
"id": "0053",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0057",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0032",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "1151823462"
},
{
"entContent": {
"label": "BP5",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "115438191"
},
{
"entContent": {
"label": "PS4",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0053",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See instructions below for scoring heterozygous individuals only. Moderate strength applicable for score of 2+ points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "See instructions below for scoring heterozygous individuals only. Supporting strength applicable for scores ranging from 1-1.75",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "115438192"
},
{
"entContent": {
"label": "PS1",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use as originally specified, but the comparison variant must reach a pathogenic classification using the these rule specifications in order to apply code.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use as originally specified, but the comparison variant must reach a likely pathogenic classification using the these rule specifications in order to apply code.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "115438193"
},
{
"entContent": {
"label": "BS4",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant not tracking in an affected family member.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "115438194"
},
{
"entContent": {
"label": "BP1",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "115438195"
},
{
"entContent": {
"label": "BS1",
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "gnomAD MAF of greater than or equal to 0.0007 but less than 0.001.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "115438196"
},
{
"entContent": {
"label": "PP4",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Must meet both criteria: \n\n1. Proband with platelet aggregation study absent for ristocetin and present for all other agonists OR flow cytometry or Western blot less than 10% expression of GPIba \n2. Proband must have full sequencing of all three BSS genes (_GP1BA, GP1BB_ and _GP9_) and deletion/duplication analysis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Proband with platelet aggregation study absent for ristocetin and present for all other agonists, OR \n* Flow cytometry or Western blot less than 10% expression of GPIba.",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "115438197"
},
{
"entContent": {
"label": "BP7",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use SpliceAI to rule out possible splicing defect (score = 0.2 or less) and reference PhyloP (score = 1.5 or less) to assess conservation.",
"type": "EvidenceLineStrength"
}
]
},
"ldhId": "115438198"
},
{
"entContent": {
"label": "PS3",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "In a transgenic animal model, must demonstrate minimal to no function.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Functional assays measuring quantity of GP9 expression on cell surface measured by flow cytometry analysis of GPIb and GPIX when there is absent or near absent expression, >75% reduction (see spreadsheet for more detail).",
"type": "EvidenceLineStrength"
}
]
},
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},
{
"entContent": {
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{
"applicability": "Not applicable",
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"text": "",
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{
"applicability": "Not applicable",
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"text": "",
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"applicability": "Not Applicable",
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"applicability": "Applicable",
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],
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"strengthSepioID": "SEPIO:0000216",
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"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
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],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
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"type": "EvidenceLineStrength"
}
]
},
"ldhId": "115438200"
},
{
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"applicability": "Not applicable",
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"text": "",
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{
"applicability": "Not applicable",
"id": "0225",
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"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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"applicability": "Applicable",
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"strengthSepioID": "SEPIO:0000328",
"text": "Must demonstrate normal aggregometry in a transgenic mouse model",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
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"text": "",
"type": "EvidenceLineStrength"
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"applicability": "Applicable",
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],
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"strengthSepioID": "SEPIO:0000327",
"text": "In a heterologous cell line, must demonstrate BOTH normal expression and normal protein function as compared to wildtype.",
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]
},
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},
{
"entContent": {
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{
"applicability": "Not applicable",
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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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]
},
"ldhId": "115438202"
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{
"entContent": {
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"applicability": "Not applicable",
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"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
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{
"applicability": "Not applicable",
"id": "0044",
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"text": "",
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{
"applicability": "Not applicable",
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"strengthSepioID": "SEPIO:0000330",
"text": "",
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{
"applicability": "Not Applicable",
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"text": "",
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{
"applicability": "Applicable",
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]
},
"ldhId": "115438203"
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{
"entContent": {
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"applicability": "Not applicable",
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"text": "",
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{
"applicability": "Not Applicable",
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"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
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"instructionsToUse": "",
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],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "REVEL score of ≥0.773 based on recommendations of Pejaver et al., 2022 (PMID: 36413997).",
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{
"applicability": "Applicable",
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"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "REVEL score of ≥0.644 (to \\<0.773), based on recommendations of Pejaver et al., 2022 (PMID: 36413997),\n\nOR suggested splicing affect using SpliceAI greater than or equal to 0.5.",
"type": "EvidenceLineStrength"
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]
},
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{
"entContent": {
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"applicability": "Not applicable",
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{
"applicability": "Not applicable",
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{
"applicability": "Not applicable",
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{
"applicability": "Not applicable",
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{
"applicability": "Not applicable",
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}
]
},
"ldhId": "115438205"
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{
"entContent": {
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{
"applicability": "Not applicable",
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{
"applicability": "Not applicable",
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{
"applicability": "Not applicable",
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"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
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}
]
},
"ldhId": "115438207"
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],
"metadata": {
"rendered": {
"by": "https://cspec.genome.network/cspec/srvc",
"when": "2026-04-29T09:19:49.754Z"
}
},
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}