{ "data": [ { "codes": [ { "baseStrength": "Pathogenic", "id": "638433115", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433115", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433115", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433115", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433115", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433115", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433115", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433115", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "135637713", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637713", "label": "BP7", "strengthDescriptor": "Supporting", "text": "Variant is synonymous.\nCaveat: variant must also meet BP4 (i.e. no predicted impact on splicing)." }, { "baseStrength": "Pathogenic", "id": "135637712", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637712", "label": "PP3", "strengthDescriptor": "Supporting", "text": "REVEL score ≥0.75 (missense variants), or predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds)." }, { "baseStrength": "Benign", "id": "135637701", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637701", "label": "BP2", "strengthDescriptor": "Supporting", "text": "If a FH patient with a heterozygous phenotype has a pathogenic or likely pathogenic variant in LDLR (in trans), APOB or PCSK9, BP2 is applicable to any additional LDLR variants." }, { "baseStrength": "Pathogenic", "id": "135637714", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637714", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Any LDLR variant identified in an FH patient [diagnosis based on validated clinical criteria, e.g. Dutch Lipid Clinic Network (≥6), Simon Broome possible/definite), MEDPED], after alternative causes of high cholesterol are excluded.\nCaveat: variant must also meet PM2." }, { "baseStrength": "Pathogenic", "id": "135637711", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637711", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637711", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637711", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637711", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637711", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637711", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637711", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637710", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637710", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Variant has a PopMax FAF ≥0.005 (0.5%) in gnomAD." }, { "baseStrength": "Pathogenic", "id": "135637704", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637704", "label": "PS3", "strengthDescriptor": "Strong", "text": "Variant meets Level 1 pathogenic functional study criteria. See Table 3.\n(1) Study of the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding, and LDL internalization) performed in heterologous cells (with noendogenous LDLR) transfected with mutant plasmid. Assay result of <70% ofwild-type activity in either expression/biosynthesis, binding OR internalization." }, { "baseStrength": "Pathogenic", "id": "135637704", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637704", "label": "PS3", "strengthDescriptor": "Moderate", "text": "Variant meets Level 2 pathogenic functional study criteria. See Table 3.\n(1) Study of a) only part of the LDLR cycle following Level 1 methodology, or b) whole or part of the LDLR cycle in true homozygous patient cells. A variant with assay results of <70% of wild type activity in either LDLR expression/biosynthesis, LDL binding OR internalization.\n(2) RNA studies, using RNA extracted from heterozygous or true homozygous patient cells, where aberrant transcript is confirmed by sequencing and is quantified as >25% of total transcript from heterozygous cells or 50% of total transcript from homozygous cells.\n(3) Variants with two or more Level 3 functional studies (must be different assays); or any Level 3 functional study #1-4 performed by two or more independent labs with concordant results." }, { "baseStrength": "Pathogenic", "id": "135637704", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637704", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Variant meets Level 3 pathogenic functional study criteria. See Table 3.\n (1) Study of LDLR cycle (whole or part) in heterozygous patient cells, with assay results of <85% of wild-type activity in either LDLR expression/biosynthesis, LDL binding OR internalization.\n (2) Luciferase studies with transcription levels of <50% compared to wild-type (applicable to 5’UTR/promoter variants).\n (3) Minigene splicing assays with <10% wild-type transcript present where anaberrant transcript from the candidate variant is confirmed by sequencing.\n (4) High-throughput assays, which include alternative microscopy assays (e.g.,Thormaehlen et al., 2015), Multiplex Assays of Variant Effect (MAVE) (e.g.,Weile & Roth, 2018) and deep mutational scanning assays, can be considered here, only if assay has been validated with a minimum of four pathogenic and four benign variant controls in LDLR. Note: % activity thresholds will be defined by the FH VCEP as more data becomes available.\n (5) RNA studies, using RNA extracted from heterozygous or homozygous patient cells, with aberrant transcript confirmed by sequencing (but without transcript quantification)." }, { "baseStrength": "Pathogenic", "id": "135637702", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637702", "label": "PS2", "strengthDescriptor": "Strong", "text": "Variant is de novo in a patient with the disease and no family history. Follow SVI guidance for de novo occurrences: https://clinicalgenome.org/working-groups/sequence-variant-interpretation/" }, { "baseStrength": "Benign", "id": "135637695", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637695", "label": "BS3", "strengthDescriptor": "Strong", "text": "Variant meets Level 1 benign functional study criteria. See Table 3.\n(1) Study of the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding, and LDL internalization) performed in heterologous cells (with no endogenous LDLR) transfected with mutant plasmid. Assay result of >90% of wild-type activity in expression/biosynthesis, binding AND internalization.\nNote: studies of only part of the LDLR cycle are not eligible for BS3 or BS3_Supporting. " }, { "baseStrength": "Benign", "id": "135637695", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637695", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Variant meets Level 3 benign functional study criteria. See Table 3.\n(1) Study of whole LDLR cycle in a) true homozygous patient cells, with assay result of >90% of wild-type activity in biosynthesis, binding AND internalization; or in b) heterozygous patient cells with assay result of >95% of wild-type activity in biosynthesis, binding AND internalization.\n(2) Luciferase studies with transcription levels of >90% when compared to wild-type (applicable to 5’UTR/promoter variants).\n(3) RNA studies, using RNA extracted from heterozygous or homozygous patientcells, with a) aberrant transcripts quantification, where aberrant transcript is<10% of total transcript OR b) without transcript quantification where noaberrant transcript is confirmed by sequencing.\n(4) Minigene splicing assay where only wild-type transcript is present and confirmed by sequencing.\n(5) High-throughput assays as defined above; only applicable when assay canindicate the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding AND internalization) is unaffected." }, { "baseStrength": "Benign", "id": "135637709", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637709", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637709", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637709", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637709", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637709", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637709", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637709", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637707", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637707", "label": "PS4", "strengthDescriptor": "Strong", "text": "Variant is found in ≥10 unrelated FH cases (FH diagnosis met by validated clinical criteria).\nCaveat: variant must also meet PM2" }, { "baseStrength": "Pathogenic", "id": "135637707", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637707", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Variant is found in 6-9 unrelated FH cases (FH diagnosis made by validated clinical criteria).\nCaveat: variant must also meet PM2." }, { "baseStrength": "Pathogenic", "id": "135637707", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637707", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Variant is found in 2-5 unrelated FH cases (FH diagnosis made by validated clinical criteria).\nCaveat: variant must also meet PM2." }, { "baseStrength": "Benign", "id": "135637705", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637705", "label": "BP4", "strengthDescriptor": "Supporting", "text": "REVEL score ≤0.5 (missense variants), or no predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds)." }, { "baseStrength": "Pathogenic", "id": "135637700", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637700", "label": "PS1", "strengthDescriptor": "Strong", "text": "Missense variant at the same codon as a variant classified pathogenic (by these guidelines), and predicts the same amino acid change.\nCaveat: there is no in silico predicted splicing impact for either variant." }, { "baseStrength": "Benign", "id": "135637698", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637698", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in ≥2 index case families (unrelated), when data is available for ≥2 informative meioses in each family.\nCaveat: must be ≥1 unaffected relative (LDL-C <50th centile) who is positive for the variant." }, { "baseStrength": "Pathogenic", "id": "135637696", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637696", "label": "PM5", "strengthDescriptor": "Strong", "text": "Missense variant at a codon with ≥2 missense variants classified pathogenic (by these guidelines), and predicts a different amino acid change." }, { "baseStrength": "Pathogenic", "id": "135637696", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637696", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Missense variant at the same codon as a variant classified pathogenic (by these guidelines), and predicts a different amino acid change." }, { "baseStrength": "Benign", "id": "135637693", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637693", "label": "BS2", "strengthDescriptor": "Strong", "text": "Variant is identified in ≥3 heterozygous or ≥1 homozygous well-phenotyped, untreated, normolipidemic adults (unrelated)." }, { "baseStrength": "Benign", "id": "638433114", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433114", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433114", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433114", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433114", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433114", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433114", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433114", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135637699", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637699", "label": "PM6", "strengthDescriptor": "Moderate", "text": "See PS2 above." }, { "baseStrength": "Benign", "id": "135637697", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637697", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637697", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637697", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637697", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637697", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637697", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637697", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637694", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637694", "label": "PM4", "strengthDescriptor": "Moderate", "text": "In-frame deletion/insertions smaller than one whole exon, or in-frame whole-exon duplications not considered in any PVS1 criteria.\nCaveat: variant must also meet PM2." }, { "baseStrength": "Pathogenic", "id": "135637716", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637716", "label": "PM2", "strengthDescriptor": "Moderate", "text": "Variant has a PopMax MAF ≤0.0002 (0.02%) in gnomAD. Consider exceptions for known founder variants." }, { "baseStrength": "Pathogenic", "id": "135637715", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637715", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Missense variant located in exon 4, or a missense change in one of 60 highly conserved cysteine residues (listed in Supp. Table 4). Caveat: variant must also meet PM2." }, { "baseStrength": "Pathogenic", "id": "135637708", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637708", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "See PVS1 flow diagram (Figure 1)." }, { "baseStrength": "Pathogenic", "id": "135637708", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637708", "label": "PVS1", "strengthDescriptor": "Strong", "text": "See PVS1 flow diagram (Figure 1)." }, { "baseStrength": "Pathogenic", "id": "135637708", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637708", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "See PVS1 flow diagram (Figure 1)." }, { "baseStrength": "Pathogenic", "id": "135637706", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637706", "label": "PP1", "strengthDescriptor": "Strong", "text": "Variant segregates with phenotype in ≥6 informative meioses in ≥1 family. Must include ≥2 affected relatives (LDL-C >75th centile) with the variant." }, { "baseStrength": "Pathogenic", "id": "135637706", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637706", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Variant segregates with phenotype in 4-5 informative meioses in ≥1 family. Must include ≥2 affected relatives (LDL-C >75th centile) with the variant." }, { "baseStrength": "Pathogenic", "id": "135637706", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637706", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Variant segregates with phenotype in 2-3 informative meioses in ≥1 family. Must include ≥1 affected relative (LDL-C >75th centile) with the variant." }, { "baseStrength": "Benign", "id": "135637703", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637703", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637703", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637703", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637703", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637703", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637703", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637703", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637692", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637692", "label": "PM3", "strengthDescriptor": "Moderate", "text": "This criterion can be used for a candidate LDLR variant observed in an individual with a homozygous FH phenotype when there is only one other pathogenic or likely pathogenic variant in LDLR (in trans), APOB or PCSK9. Caveat: variant must also meet PM2." }, { "baseStrength": "Benign", "id": "135637691", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637691", "label": "BS1", "strengthDescriptor": "Strong", "text": "Variant has a PopMax FAF ≥0.002 (0.2%) in gnomAD." } ], "diseases": [ { "id": "MONDO:0007750", "iri": "https://genboree.org/cspec/Disease/id/135641990", "label": "hypercholesterolemia, familial, 1" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641793", "label": "LDLR" } ], "ruleSet": { "id": "135640393", "iri": "https://genboree.org/cspec/RuleSet/id/135640393" }, "svi": { "id": "GN013", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637573", "label": "ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "638432780", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432780", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432780", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432780", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432780", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432780", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432780", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432780", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432779", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432779", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432779", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432779", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432779", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432779", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432779", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432779", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135637792", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637792", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637792", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637792", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637792", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637792", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637792", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637792", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637790", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637790", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease" }, { "baseStrength": "Pathogenic", "id": "135637789", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637789", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Null Variant in gene with evidence supporting LOF as disease mechanism" }, { "baseStrength": "Benign", "id": "135637784", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637784", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637784", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637784", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637784", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637784", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637784", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637784", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637783", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637783", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo (paternity confirmed) in a patient with disease and no family history" }, { "baseStrength": "Pathogenic", "id": "135637780", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637780", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Confirmed de novo without confirmation of paternity" }, { "baseStrength": "Pathogenic", "id": "135637777", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637777", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Missense change at an amino acid residue where a different missense change previously established as pathogenic" }, { "baseStrength": "Benign", "id": "135637776", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637776", "label": "BS3", "strengthDescriptor": "Strong", "text": "Functional studies of mammalian knock-in models supportive of no damaging effect on protein function or splicing" }, { "baseStrength": "Benign", "id": "135637794", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637794", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A silent variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site -AND- the nucleotide is not highly conserved" }, { "baseStrength": "Pathogenic", "id": "135637785", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637785", "label": "PS3", "strengthDescriptor": "Strong", "text": "Functional studies of mammalian knock-in models supportive of a damaging effect on the gene or gene product" }, { "baseStrength": "Benign", "id": "135637772", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637772", "label": "BS1", "strengthDescriptor": "Strong", "text": "Allele frequency is >=0.02% based on the filtering allele frequency (FAF) in ExAC provided there is no conflicting information" }, { "baseStrength": "Pathogenic", "id": "135637797", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637797", "label": "PM2", "strengthDescriptor": "Moderate", "text": "Absent/extremely rare (<0.004%) from large population studies." }, { "baseStrength": "Pathogenic", "id": "135637795", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637795", "label": "PP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637795", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637795", "label": "PP4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637795", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637795", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637795", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637795", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637793", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637793", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product" }, { "baseStrength": "Benign", "id": "135637791", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637791", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Allele frequency is >= 0.1% based on the filtering allele frequency (FAF) in ExAC" }, { "baseStrength": "Pathogenic", "id": "135637787", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637787", "label": "PP1", "strengthDescriptor": "Strong", "text": "Variant segregates with >= 7 meioses" }, { "baseStrength": "Pathogenic", "id": "135637787", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637787", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Variant segragates in >=5 meioses" }, { "baseStrength": "Pathogenic", "id": "135637787", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637787", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Variant segragates in >=3 meioses" }, { "baseStrength": "Benign", "id": "135637779", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637779", "label": "BS4", "strengthDescriptor": "Strong", "text": "Non-segregation in affected members of a family" }, { "baseStrength": "Pathogenic", "id": "135637788", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637788", "label": "PS4", "strengthDescriptor": "Strong", "text": "Prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls -OR- Variant identified in ≥15 probands with consistent phenotypes" }, { "baseStrength": "Pathogenic", "id": "135637788", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637788", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Variant identified in >=6 probands with consistent phenotypes" }, { "baseStrength": "Pathogenic", "id": "135637788", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637788", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Variant identified in >=2 probands with consistent phenotypes" }, { "baseStrength": "Pathogenic", "id": "135637781", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637781", "label": "PS1", "strengthDescriptor": "Strong", "text": "Different nucleotide change (same amino acid) as a previously established pathogenic variant" }, { "baseStrength": "Pathogenic", "id": "135637796", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637796", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Hotspot/est. functional domain (amino acids 181-937) without benign variation" }, { "baseStrength": "Benign", "id": "135637786", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637786", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Multiple lines of computational evidence suggest no impact on gene or gene product" }, { "baseStrength": "Benign", "id": "135637782", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637782", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Observed as comp het (in trans) or double het in genes with overlapping function (e.g. sarcomere genes) without increased disease severity -OR- Observed in cis with a pathogenic variant in any inheritance pattern" }, { "baseStrength": "Benign", "id": "135637778", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637778", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637778", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637778", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637778", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637778", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637778", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637778", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637775", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637775", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions of any size in a non-repeat region or stop-loss variants" }, { "baseStrength": "Benign", "id": "135637774", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637774", "label": "BS2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637774", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637774", "label": "BS2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637774", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637774", "label": "BS2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637774", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637774", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637773", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637773", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637773", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637773", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637773", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637773", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637773", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637773", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable" } ], "diseases": [], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641799", "label": "MYH7" } ], "ruleSet": { "id": "135640453", "iri": "https://genboree.org/cspec/RuleSet/id/135640453" }, "svi": { "id": "GN002", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637574", "label": "ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "135638193", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638193", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Absent in population\n\n* Databases present at \\<0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population.  If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be \\<0.00002 (0.002%)." }, { "baseStrength": "Pathogenic", "id": "135638192", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638192", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168 (NP_ 000305.3)" }, { "baseStrength": "Pathogenic", "id": "135638191", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638191", "label": "PP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: PTEN EP Commentary: Phenotype specificity has been incorporated into the rule specifications for PS4 Use 2." }, { "baseStrength": "Pathogenic", "id": "135638191", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638191", "label": "PP4", "strengthDescriptor": "Strong", "text": "Not Applicable: PTEN EP Commentary: Phenotype specificity has been incorporated into the rule specifications for PS4 Use 2." }, { "baseStrength": "Pathogenic", "id": "135638191", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638191", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Not Applicable: PTEN EP Commentary: Phenotype specificity has been incorporated into the rule specifications for PS4 Use 2." }, { "baseStrength": "Pathogenic", "id": "135638191", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638191", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Not Applicable: PTEN EP Commentary: Phenotype specificity has been incorporated into the rule specifications for PS4 Use 2." }, { "baseStrength": "Benign", "id": "135638186", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638186", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease. Other gene/disorder must be considered highly penetrant AND patient’s personal/family history must demonstrate no overlap between other gene and PTEN." }, { "baseStrength": "Pathogenic", "id": "135638183", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638183", "label": "PP1", "strengthDescriptor": "Strong", "text": "Co-segregation with disease in multiple affected family members, with ≥7 meioses observed across at least two families." }, { "baseStrength": "Pathogenic", "id": "135638183", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638183", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed." }, { "baseStrength": "Pathogenic", "id": "135638183", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638183", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed." }, { "baseStrength": "Benign", "id": "135638175", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638175", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected members of two or more families." }, { "baseStrength": "Benign", "id": "135638175", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638175", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Lack of segregation in affected members of one family." }, { "baseStrength": "Pathogenic", "id": "638432815", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432815", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432815", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432815", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432815", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432815", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432815", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432815", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432814", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432814", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432814", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432814", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432814", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432814", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432814", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432814", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135638181", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638181", "label": "PS3", "strengthDescriptor": "Strong", "text": "Well-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect on the gene or gene product.\n\n* RNA, mini-gene, or other assay shows impact on splicing" }, { "baseStrength": "Pathogenic", "id": "135638181", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638181", "label": "PS3", "strengthDescriptor": "Moderate", "text": "Well-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect on the gene or gene product.\n\n* Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350." }, { "baseStrength": "Pathogenic", "id": "135638181", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638181", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Phosphatase activity \\<50% of wild-type or abnormal _in vitro_ cellular assay or transgenic model with phenotype different from wild type that does not meet PS3\\_moderate." }, { "baseStrength": "Pathogenic", "id": "135638179", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638179", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history." }, { "baseStrength": "Pathogenic", "id": "135638179", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638179", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history." }, { "baseStrength": "Pathogenic", "id": "135638177", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638177", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant." }, { "baseStrength": "Pathogenic", "id": "135638176", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638176", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history." }, { "baseStrength": "Pathogenic", "id": "135638176", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638176", "label": "PM6", "strengthDescriptor": "Strong", "text": "Two probands with presumed _de novo_ occurrence (maternity/ paternity not confirmed) with the disease and no family history.\n\n* May also be used for a proband with presumed de novo occurrence for an individual with a highly specific phenotype (meets criteria to count towards PS4)" }, { "baseStrength": "Pathogenic", "id": "135638176", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638176", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Assumed _de novo,_ but without confirmation of paternity and maternity, in proband with the disease and no family history." }, { "baseStrength": "Benign", "id": "135638170", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638170", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in the homozygous state in a healthy or PHTS-unaffected individual. One observation if homozygous status confirmed, two if not confirmed. To be applied at supporting evidence level if BS1 is also applied." }, { "baseStrength": "Benign", "id": "135638170", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638170", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Two homozygous observations with no clinical data provided, or meets criteria for BS2 but BS1 is also applied." }, { "baseStrength": "Benign", "id": "135638168", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638168", "label": "BS1", "strengthDescriptor": "Strong", "text": "gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%)" }, { "baseStrength": "Benign", "id": "135638168", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638168", "label": "BS1", "strengthDescriptor": "Supporting", "text": "Allele frequency from 0.0000043 (0.00043%) up to 0.000043 (0.0043%)." }, { "baseStrength": "Benign", "id": "638432814", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432814", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432814", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432814", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432814", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432814", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432814", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432814", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432815", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432815", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432815", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432815", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432815", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432815", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432815", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432815", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "135638187", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638187", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "gnomAD Filtering allele frequency >0.00056 (0.056%)" }, { "baseStrength": "Benign", "id": "135638182", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638182", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Multiple lines of computational evidence suggest no impact on gene or gene product. \n\n* Splicing variants: Concordance of SpliceAl and VarSeak\n* Missense variants: REVEL scores \\< 0.5" }, { "baseStrength": "Benign", "id": "135638180", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638180", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This rule is not applicable to PTEN." }, { "baseStrength": "Benign", "id": "135638180", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638180", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: This rule is not applicable to PTEN." }, { "baseStrength": "Benign", "id": "135638180", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638180", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: This rule is not applicable to PTEN." }, { "baseStrength": "Benign", "id": "135638180", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638180", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: This rule is not applicable to PTEN." }, { "baseStrength": "Benign", "id": "135638174", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638174", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This rule is not applicable to PTEN." }, { "baseStrength": "Benign", "id": "135638174", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638174", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: This rule is not applicable to PTEN." }, { "baseStrength": "Benign", "id": "135638174", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638174", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: This rule is not applicable to PTEN." }, { "baseStrength": "Benign", "id": "135638174", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638174", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: This rule is not applicable to PTEN." }, { "baseStrength": "Pathogenic", "id": "135638171", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638171", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif (see PM1), and variants causing protein extension." }, { "baseStrength": "Benign", "id": "135638190", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638190", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice." }, { "baseStrength": "Pathogenic", "id": "135638189", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638189", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.\n\n* Splicing variants: Concordance of SpliceAl and VarSeak\n* Missense variants: REVEL score > 0.7" }, { "baseStrength": "Pathogenic", "id": "135638184", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638184", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Probands with specificity score ≥16 (see text)." }, { "baseStrength": "Pathogenic", "id": "135638184", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638184", "label": "PS4", "strengthDescriptor": "Strong", "text": "Probands with specificity score 4-15.5 (see text) OR The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls." }, { "baseStrength": "Pathogenic", "id": "135638184", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638184", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Probands with specificity score of 2-3.5 (see text)." }, { "baseStrength": "Pathogenic", "id": "135638184", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638184", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Phenotype specific for disease with single genetic etiology. Proband(s) with specificity score of 1-1.5 (see text)." }, { "baseStrength": "Benign", "id": "135638178", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638178", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants." }, { "baseStrength": "Pathogenic", "id": "135638173", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638173", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before. In addition, variant being interrogated must have BLOSUM62 score equal to or less than the known variant." }, { "baseStrength": "Pathogenic", "id": "135638169", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638169", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This rule is not applicable to PTEN." }, { "baseStrength": "Pathogenic", "id": "135638169", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638169", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: This rule is not applicable to PTEN." }, { "baseStrength": "Pathogenic", "id": "135638169", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638169", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: This rule is not applicable to PTEN." }, { "baseStrength": "Pathogenic", "id": "135638169", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638169", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: This rule is not applicable to PTEN." }, { "baseStrength": "Benign", "id": "638432814", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432814", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432814", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432814", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432814", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432814", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432814", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432814", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135638188", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638188", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease." }, { "baseStrength": "Pathogenic", "id": "135638185", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638185", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Use PTEN PVS1 decision tree." }, { "baseStrength": "Pathogenic", "id": "135638185", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638185", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Use PTEN PVS1 decision tree." }, { "baseStrength": "Pathogenic", "id": "135638185", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638185", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Use PTEN PVS1 decision tree." }, { "baseStrength": "Benign", "id": "135638172", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638172", "label": "BS3", "strengthDescriptor": "Strong", "text": "Well-established _in vitro_ or _in vivo_ functional studies shows no damaging effect on protein function. To be applied to intronic or synonymous variants, RNA, mini-gene or other splicing assay demonstrating no splicing impact." }, { "baseStrength": "Benign", "id": "135638172", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638172", "label": "BS3", "strengthDescriptor": "Supporting", "text": "_In vitro_ or _in vivo_ functional study or studies showing no damaging effect on protein function.\n\n* Phosphatase activity >0 per Mighell et al. 2018, PMID: 29706350." } ], "diseases": [], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641805", "label": "PTEN" } ], "ruleSet": { "id": "135640513", "iri": "https://genboree.org/cspec/RuleSet/id/135640513" }, "svi": { "id": "GN003", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637575", "label": "ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.1.0" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "135638355", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638355", "label": "PM2", "strengthDescriptor": "Moderate", "text": "The variant must be completely absent from all population databases." }, { "baseStrength": "Pathogenic", "id": "135638354", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638354", "label": "PM1", "strengthDescriptor": "Moderate", "text": "See supplemental material for approved functional domains and residues. This evidence rule can also be applied for the same analogous residue positions/regions in highly analogous groupings below:\nGroup 1: HRAS, NRAS, KRAS\nGroup 2: MAP2K1, MAP2K2\nGroup 3: SOS1, SOS2" }, { "baseStrength": "Pathogenic", "id": "135638353", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638353", "label": "PP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not applicable to the RASopathies. See PS4 criterion for proband counting options." }, { "baseStrength": "Pathogenic", "id": "135638353", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638353", "label": "PP4", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not applicable to the RASopathies. See PS4 criterion for proband counting options." }, { "baseStrength": "Pathogenic", "id": "135638353", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638353", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not applicable to the RASopathies. See PS4 criterion for proband counting options." }, { "baseStrength": "Pathogenic", "id": "135638353", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638353", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not applicable to the RASopathies. See PS4 criterion for proband counting options." }, { "baseStrength": "Benign", "id": "135638348", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638348", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease." }, { "baseStrength": "Pathogenic", "id": "135638347", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638347", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: LOF and/or haploinsufficiency has not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype, therefore in general this rule is not applicable. Note that PTPN11 is currently the only gene with a confirmed association to another non-RASopathy disorder due to LOF alleles. Variants in PTPN11 with predicted LOF should not be evaluated by these RASopathy specific criteria, but should defer to non-adjusted criteria. Given that some historical LOF variants (e.g. canonical splice sites) could potentially result in a gain of function, users should assess using these criteria and non-adjusted criteria to identify the highest likelihood of pathogenicity for all associated diseases. We recommend that the ClinGen Dosage Sensitivity Map Status (http://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/index.shtml) be reviewed for any new apparently LOF disease associations prior to classification assessment." }, { "baseStrength": "Pathogenic", "id": "135638347", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638347", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Not Applicable: LOF and/or haploinsufficiency has not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype, therefore in general this rule is not applicable. Note that PTPN11 is currently the only gene with a confirmed association to another non-RASopathy disorder due to LOF alleles. Variants in PTPN11 with predicted LOF should not be evaluated by these RASopathy specific criteria, but should defer to non-adjusted criteria. Given that some historical LOF variants (e.g. canonical splice sites) could potentially result in a gain of function, users should assess using these criteria and non-adjusted criteria to identify the highest likelihood of pathogenicity for all associated diseases. We recommend that the ClinGen Dosage Sensitivity Map Status (http://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/index.shtml) be reviewed for any new apparently LOF disease associations prior to classification assessment." }, { "baseStrength": "Pathogenic", "id": "135638347", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638347", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Not Applicable: LOF and/or haploinsufficiency has not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype, therefore in general this rule is not applicable. Note that PTPN11 is currently the only gene with a confirmed association to another non-RASopathy disorder due to LOF alleles. Variants in PTPN11 with predicted LOF should not be evaluated by these RASopathy specific criteria, but should defer to non-adjusted criteria. Given that some historical LOF variants (e.g. canonical splice sites) could potentially result in a gain of function, users should assess using these criteria and non-adjusted criteria to identify the highest likelihood of pathogenicity for all associated diseases. We recommend that the ClinGen Dosage Sensitivity Map Status (http://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/index.shtml) be reviewed for any new apparently LOF disease associations prior to classification assessment." }, { "baseStrength": "Pathogenic", "id": "135638347", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638347", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "Not Applicable: LOF and/or haploinsufficiency has not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype, therefore in general this rule is not applicable. Note that PTPN11 is currently the only gene with a confirmed association to another non-RASopathy disorder due to LOF alleles. Variants in PTPN11 with predicted LOF should not be evaluated by these RASopathy specific criteria, but should defer to non-adjusted criteria. Given that some historical LOF variants (e.g. canonical splice sites) could potentially result in a gain of function, users should assess using these criteria and non-adjusted criteria to identify the highest likelihood of pathogenicity for all associated diseases. We recommend that the ClinGen Dosage Sensitivity Map Status (http://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/index.shtml) be reviewed for any new apparently LOF disease associations prior to classification assessment." }, { "baseStrength": "Pathogenic", "id": "135638343", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638343", "label": "PS3", "strengthDescriptor": "Strong", "text": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval." }, { "baseStrength": "Pathogenic", "id": "135638335", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638335", "label": "PM5", "strengthDescriptor": "Strong", "text": "Previously established variant must be established as pathogenic per these criteria. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes. This evidence rule can also be used for pathogenic missense variants seen in the same analogous residue position in highly analogous groupings below:\nGroup 1: HRAS, NRAS, KRAS\nGroup 2: MAP2K1, MAP2K2 Group 3: SOS1, SOS2\nThis rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a “mutational hot-spot”. For example, Gly12 in HRAS is listed as a hot-spot for PM1 usage. In these situations, only PM1 should be used when combining criteria for final variant classification in order to avoid premature designation of a likely pathogenic classification in the absence of other evidence for pathogenicity.\n≥2 different pathogenic missense changes seen before at same residue of missense change." }, { "baseStrength": "Pathogenic", "id": "135638335", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638335", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Previously established variant must be established as pathogenic per these criteria. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes. This evidence rule can also be used for pathogenic missense variants seen in the same analogous residue position in highly analogous groupings below:\nGroup 1: HRAS, NRAS, KRAS\nGroup 2: MAP2K1, MAP2K2 Group 3: SOS1, SOS2\nThis rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a “mutational hot-spot”. For example, Gly12 in HRAS is listed as a hot-spot for PM1 usage. In these situations, only PM1 should be used when combining criteria for final variant classification in order to avoid premature designation of a likely pathogenic classification in the absence of other evidence for pathogenicity." }, { "baseStrength": "Pathogenic", "id": "135638333", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638333", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." }, { "baseStrength": "Benign", "id": "135638330", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638330", "label": "BS1", "strengthDescriptor": "Strong", "text": "An allele frequency ≥0.025% was approved. See supplemental material for additional frequency information." }, { "baseStrength": "Pathogenic", "id": "135638351", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638351", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product." }, { "baseStrength": "Pathogenic", "id": "135638346", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638346", "label": "PS4", "strengthDescriptor": "Strong", "text": "≥5 independent occurrences." }, { "baseStrength": "Pathogenic", "id": "135638346", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638346", "label": "PS4", "strengthDescriptor": "Moderate", "text": "≥3 independent occurrences." }, { "baseStrength": "Pathogenic", "id": "135638346", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638346", "label": "PS4", "strengthDescriptor": "Supporting", "text": "≥1 independent occurrences." }, { "baseStrength": "Pathogenic", "id": "135638345", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638345", "label": "PP1", "strengthDescriptor": "Strong", "text": "Usage of PP1 requires at least three informative meioses. Segregation in more than one family is recommended.\n≥7 informative meioses." }, { "baseStrength": "Pathogenic", "id": "135638345", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638345", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Usage of PP1 requires at least three informative meioses. Segregation in more than one family is recommended.\n≥5 informative meioses." }, { "baseStrength": "Pathogenic", "id": "135638345", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638345", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Usage of PP1 requires at least three informative meioses. Segregation in more than one family is recommended." }, { "baseStrength": "Pathogenic", "id": "135638338", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638338", "label": "PM6", "strengthDescriptor": "Strong", "text": "≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events." }, { "baseStrength": "Pathogenic", "id": "135638338", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638338", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Confirmed de novo without confirmation of paternity and maternity." }, { "baseStrength": "Benign", "id": "135638342", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638342", "label": "BP3", "strengthDescriptor": "Supporting", "text": "In frame-deletions/insertions in a repetitive region without a known function." }, { "baseStrength": "Benign", "id": "135638340", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638340", "label": "BP2", "strengthDescriptor": "Supporting", "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." }, { "baseStrength": "Benign", "id": "135638336", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638336", "label": "BP1", "strengthDescriptor": "Supporting", "text": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants." }, { "baseStrength": "Benign", "id": "135638332", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638332", "label": "BS2", "strengthDescriptor": "Strong", "text": "Due to variable expressivity and severity, extensive clinical workup for RASopathy spectrum features is warranted, thus general population data should not be used for this criterion. Clinical laboratories are encouraged to accumulate more than 3 instances of well phenotyped family members before applying this strong criterion." }, { "baseStrength": "Pathogenic", "id": "135638350", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638350", "label": "PP2", "strengthDescriptor": "Supporting", "text": "PP2 is applicable to all RASopathy genes described and curated herein." }, { "baseStrength": "Benign", "id": "135638349", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638349", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "An allele frequency ≥0.05% was approved. See supplemental material for additional frequency information." }, { "baseStrength": "Benign", "id": "135638344", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638344", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant." }, { "baseStrength": "Benign", "id": "135638337", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638337", "label": "BS4", "strengthDescriptor": "Strong", "text": "Requires only one informative meiosis and does not require an additional piece of supporting evidence to classify variant as likely benign." }, { "baseStrength": "Benign", "id": "135638334", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638334", "label": "BS3", "strengthDescriptor": "Strong", "text": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval." }, { "baseStrength": "Pathogenic", "id": "638432845", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432845", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432845", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432845", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432845", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432845", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432845", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432845", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432844", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432844", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432844", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432844", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432844", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432844", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432844", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432844", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "135638352", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638352", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\nThis rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4." }, { "baseStrength": "Pathogenic", "id": "135638341", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638341", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events." }, { "baseStrength": "Pathogenic", "id": "135638341", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638341", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo (paternity confirmed) in a patient with the disease and no family history." }, { "baseStrength": "Pathogenic", "id": "135638339", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638339", "label": "PS1", "strengthDescriptor": "Strong", "text": "Previously established variant must be established as pathogenic per these criteria for germline RASopathy variants. This evidence rule can also be applied for the any observed analogous residue positions/regions throughout the gene in highly analogous groupings below:\nGroup 1: HRAS, NRAS, KRAS\n Group 2: MAP2K1, MAP2K2\nGroup 3: SOS1, SOS2" }, { "baseStrength": "Pathogenic", "id": "135638331", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638331", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not applicable to the RASopathies." }, { "baseStrength": "Pathogenic", "id": "135638331", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638331", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not applicable to the RASopathies." }, { "baseStrength": "Pathogenic", "id": "135638331", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638331", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not applicable to the RASopathies." }, { "baseStrength": "Pathogenic", "id": "135638331", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638331", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not applicable to the RASopathies." } ], "diseases": [], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641811", "label": "SHOC2" }, { "iri": "https://genboree.org/cspec/Gene/id/135641812", "label": "NRAS" }, { "iri": "https://genboree.org/cspec/Gene/id/135641813", "label": "RAF1" }, { "iri": "https://genboree.org/cspec/Gene/id/135641814", "label": "SOS1" }, { "iri": "https://genboree.org/cspec/Gene/id/135641815", "label": "SOS2" }, { "iri": "https://genboree.org/cspec/Gene/id/135641816", "label": "PTPN11" }, { "iri": "https://genboree.org/cspec/Gene/id/135641817", "label": "KRAS" }, { "iri": "https://genboree.org/cspec/Gene/id/135641818", "label": "MAP2K1" }, { "iri": "https://genboree.org/cspec/Gene/id/135641819", "label": "HRAS" }, { "iri": "https://genboree.org/cspec/Gene/id/135641820", "label": "RIT1" }, { "iri": "https://genboree.org/cspec/Gene/id/135641821", "label": "MAP2K2" }, { "iri": "https://genboree.org/cspec/Gene/id/135641822", "label": "BRAF" } ], "ruleSet": { "id": "135640573", "iri": "https://genboree.org/cspec/RuleSet/id/135640573" }, "svi": { "id": "GN004", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637576", "label": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1" } }, { "codes": [ { "baseStrength": "Benign", "id": "638432874", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432874", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432874", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432874", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432874", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432874", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432874", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432874", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "135638892", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638892", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Observed in trans with a dominant variant/observed in cis with a pathogenic variant (use with caution).\nUse with caution. For genes that are associated with both dominant and recessive hearing loss, consider whether an earlier onset/more severe phenotype could be present if variant is identified in trans with a dominant variant." }, { "baseStrength": "Pathogenic", "id": "135638885", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638885", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length change due to an in-frame deletion or insertion that are not located in repetitive regions.\n* No changes. Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group." }, { "baseStrength": "Benign", "id": "135638882", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638882", "label": "BS1", "strengthDescriptor": "Strong", "text": "MAF of ≥0.003 (0.3%) for autosomal recessive; MAF of ≥0.0002 (0.02%) for autosomal dominant. Likely benign, provided there is no conflicting evidence." }, { "baseStrength": "Benign", "id": "135638882", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638882", "label": "BS1", "strengthDescriptor": "Supporting", "text": "MAF of ≥0.0007 (0.07%) for autosomal recessive. No BS1_Supporting criteria for autosomal dominant." }, { "baseStrength": "Pathogenic", "id": "135638906", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638906", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Mutational hot spot or well-studied functional domain without benign variation (KCNQ4 pore-forming region).\n* KCNQ4 (NM_004700.4) gene - missense variants located within amino acids 271-292 can be awarded PM1. This region is the pore-forming intramembrane region where many variants that cause autosomal dominant hearing loss are located (Naito et al. 2013, PMID: 23717403; https://www.uniprot.org/uniprot/P56696). There are only two missense variants in this region in gnomAD, each with only single allele (http://gnomad.broadinstitute.org/; rs763326539: 1/33578 Latino chromosomes; rs55737429: 1/111720 European chromosomes)." }, { "baseStrength": "Benign", "id": "135638904", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638904", "label": "BP7", "strengthDescriptor": "Supporting", "text": "Silent variant with no predicted impact to splicing.\nNo changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group." }, { "baseStrength": "Benign", "id": "135638900", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638900", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant in an autosomal dominant gene found in a patient with an alternate explanation.\n* Autosomal recessive: Do not use. An individual could be carrier of pathogenic variant and have an alternate cause. Therefore, BP5 shouldn’t be used as evidence for benign in this case.\n* Autosomal dominant: Can use BP5 as outlined by Richards 2015.\n\n * Caveat: consider whether multiple pathogenic autosomal dominant variants could cause a more severe phenotype or whether multigenic inheritance is known to occur (example: Bardet-Biedl syndrome)." }, { "baseStrength": "Pathogenic", "id": "135638895", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638895", "label": "PS3", "strengthDescriptor": "Strong", "text": "Knock-in mouse model demonstrates the phenotype." }, { "baseStrength": "Pathogenic", "id": "135638895", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638895", "label": "PS3", "strengthDescriptor": "Moderate", "text": "Validated functional studies show a deleterious effect (predefined list): GJB2: electrical coupling assays, dye transfer assays → PS3_Moderate\n* Dye Transfer Assays: Expect results that compare the fluorescence of a variant-transfected cell to\nboth a negative control (or H2O injected control) and a wildtype-transfected cell. PS3_Moderate\nwould be applied if the variant results in no dye transfer or significantly different dye transfer when\ncompared to the wildtype.\n* Electrical Coupling Assays: Expect results comparing the current of the variant-transfected cells to both a negative control (i.e. H2O injected control) and a wildtype-transfected cell. PS3_Moderate would be applied if the variant results in significantly different current compared to the wildtype, and the current is comparable to background levels/negative control." }, { "baseStrength": "Pathogenic", "id": "135638895", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638895", "label": "PS3", "strengthDescriptor": "Supporting", "text": "SLC26A4: Radio isotope and fluorescence assays → PS3_Supporting\n* Radio Isotope Assays: PS3_Supporting would be applied when cells transfected with mutant SLC26A4 show a statistically significant decreased efflux of iodide compared to wildtype pendrin.\n* Fluorescence Assays: PS3_Supporting would be applied when a cell transfected with the mutant SLC26A4 shows a statistically significant difference in fluorescence (ΔFmax %) compared to the wildtype protein, and when the fluorescence is not significantly different from that of an empty vector control.\nCOCH: Localization, secretion, and dimerization studies performed using immunofluorescence and\nWestern blotting techniques →PS3_Supporting\n* Localization: PS3_Supporting would be applied if the mutant cochlin protein does not aggregate into extracellular deposits or in the perinuclear region, comparable to the localization of wildtype cochlin.\n* Secretion: PS3_Supporting would be applied if cochlin protein containing the variant does not show secretion from transfected cells, but aggregates in cell regions such as the ER, Golgi and nucleus or is degraded.\n* Dimerization: In a non-reducing environment, wildtype cochlin migrate quickly and appear smaller than in the reduced state because the structure is maintained by disulfide bonds. PS3_Supporting would be applied if the cochlin protein containing the variant forms more, or less, stable disulfide bonds when compared to the wildtype in non-reducing conditions.\n* If not listed above, OK to use PS3_Supporting for other genes/functional analyses if\n * The assay has been validated by a known pathogenic and benign variant AND \n * There is plausible reason that the function the assay is testing relates to the phenotype AND\n * The assay conditions are likely to mimic the physiological environment." }, { "baseStrength": "Benign", "id": "135638894", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638894", "label": "BP3", "strengthDescriptor": "Supporting", "text": "In-frame indels in repeat region without known function.\nNo changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group." }, { "baseStrength": "Benign", "id": "135638888", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638888", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135638888", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638888", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135638888", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638888", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135638888", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638888", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135638887", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638887", "label": "PM5", "strengthDescriptor": "Strong", "text": "Missense change at same codon as two different pathogenic missense variants.\n* Located at an amino acid residue with known pathogenic variation (at least 2 other variants at the same site meet pathogenic criteria for based on independent data)\n* Caveat: Assess whether the variants in question could have an impact at the DNA level, such as through splicing impacts." }, { "baseStrength": "Pathogenic", "id": "135638887", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638887", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Missense change at same codon as another pathogenic missense variant.\nNo changes. Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group." }, { "baseStrength": "Benign", "id": "135638884", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638884", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observation of variant (biallelic with known pathogenic variant for recessive) in controls inconsistent with disease penetrance.\n* Advise caution when using this rule, since most of hearing loss is autosomal recessive, and autosomal dominant hearing loss could display reduced penetrance or variable expression.\n* However, if biallelic observations in controls are inconsistent with disease penetrance, this may be applicable." }, { "baseStrength": "Pathogenic", "id": "638432875", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432875", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432875", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432875", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432875", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432875", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432875", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432875", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135638905", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638905", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Patient's phenotype highly specific for gene or fully sequenced gene set (see specifications in Table 7)." }, { "baseStrength": "Pathogenic", "id": "135638899", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638899", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Null variant in a gene with established LOF as a disease mechanism; see PVS1_Strong, PVS1_Moderate, PVS1_Supporting for reduced evidence applications." }, { "baseStrength": "Pathogenic", "id": "135638899", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638899", "label": "PVS1", "strengthDescriptor": "Strong", "text": "See PVS1 flow chart for PVS1_Strong variants in gene where LOF is a known mechanism of disease.\n* PVS1 should also be considered for the following genes with variants assessed in the Hearing Loss Variant Pilot: GJB2, CDH23, USH2A, SLC26A4, MYO6, MYO7A, TECTA, KCNQ4.\n* For other genes, LOF must be an established disease mechanism, and the gene/disease association must be Strong or Definitive clinical validity level as outlined in Strande et al. 2017 (PMID: 28552198).\n* If above criteria is met, follow PVS1 flowchart as recommended by the SVI." }, { "baseStrength": "Pathogenic", "id": "135638899", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638899", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "See PVS1 flowchart for PVS1_Moderate variants in gene where LOF is a known mechanism of disease." }, { "baseStrength": "Pathogenic", "id": "135638899", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638899", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "See PVS1 flowchart for PVS1_Supporting variants in gene where LOF is a known mechanism of disease." }, { "baseStrength": "Pathogenic", "id": "135638897", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638897", "label": "PP1", "strengthDescriptor": "Strong", "text": "Segregation in three affected relatives for recessive and five affected relatives for dominant." }, { "baseStrength": "Pathogenic", "id": "135638897", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638897", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Segregation in two affected relatives for recessive and 4 affected relatives for dominant." }, { "baseStrength": "Pathogenic", "id": "135638897", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638897", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Segregation in one affected relative for recessive and two affected relatives for dominant." }, { "baseStrength": "Benign", "id": "135638896", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638896", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Computational evidence suggests no impact; REVEL score ≤0.15 or no impact to splicing in MaxEntScan." }, { "baseStrength": "Pathogenic", "id": "135638891", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638891", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as an established pathogenic variant; OR\nsplice variants at same nucleotide and with similar impact prediction as previously reported pathogenic variant.\n* Established variant must meet criteria for pathogenicity by the HL specifications\n * Can also use PS1 for splice variants located in the splice consensus sequence, at the same nucleotide position as a previously reported pathogenic variant\n * Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T\n* No additional hearing loss specifications for missense variants. Follow recommendations as outlined in Richard 2015 and/or the Sequence Variant Interpretation working group within ClinGen.\n\n* Caveat (from ACMG/AMP guidelines): Assess the possibility that the variant may act directly through the DNA change (e.g. through splicing disruption as assessed by at least computational analysis) instead of through the amino acid change)" }, { "baseStrength": "Pathogenic", "id": "135638907", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638907", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Absent/Rare in population databases (absent or ≤0.00007 (0.007%) for autosomal recessive, ≤0.00002 (0.002%) for autosomal dominant).\n* Background: Rarity or absence in the general population is not robust evidence for pathogenicity, particularly for autosomal recessive disorders. However, the ACMG/AMP Guidelines were devised in such a way that absence or rarity were considered moderate evidence towards pathogenicity, and the framework requires multiple pieces of evidence to classify a variant as likely pathogenic or pathogenic." }, { "baseStrength": "Benign", "id": "135638889", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638889", "label": "BS4", "strengthDescriptor": "Strong", "text": "Non-segregation with disease.\n* Phenotype+/genotype-\n * Strong evidence for benign.\n * Be cautious when using this as the possibility for phenocopy is high. The hearing loss phenotype should be consistent within the family to consider it a non-segregation, though intra-familial variability has been reported. Factors to consider are:\n * Age of onset (ie. congenital/early childhood vs. adult onset).\n * Hearing loss prevalence increases significantly with age. A congenital hearing loss in a child and a late onset hearing loss in a grandparent would not be a consistent phenotype.\n * Severity (ie - mild vs. profound).\n * Minor differences may exist among family members.\n * Keep in mind that progression in older individuals may account for a discrepancy between individuals.\n * Sex -based differences (infertility, genes on X chromosomes)\n * Audiogram shape.\n * May not be completely consistent among family members even with same etiology.\n* Genotype+/phenotype-\n * Confounding variables to applying this rule: Age-related/sex-related penetrance, variable expressivity, etc.\n * If the gene is associated with later onset and individual with the non-segregation is beyond the expected age that the hearing loss would occur, consider applying BS4_Supporting\n * Recommend only using for fully penetrant genes (typically genes associated with AR hearing loss).\n * Must be confident that patient is truly unaffected and a hearing loss is not missed or subclinical. Be cautious if only phenotyping was newborn hearing screening. Diagnostic audiometric testing (auditory brainstem response (ABR) or audiogram should be required).\n * Any evidence for reduced penetrance, do not use BS4" }, { "baseStrength": "Benign", "id": "135638886", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638886", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Functional study shows no deleterious effect (predefined list).\n* Recommend that functional evidence is not used as strong evidence, due to the absence of well-established functional studies for hearing loss genes.\n* Guidance on functional evidence at supporting level is as follows (see functional spreadsheets attached):\n * GJB2: electrical coupling assays, dye transfer assays → BS3_Supporting\n * Dye Transfer Assays: Expect results that compare the fluorescence of a variant-transfected cell to both a negative control (or H2O injected control) and a wildtype-transfected cell. BS2_Supporting can be applied if the variant results in dye transfer comparable to the wildtype.\n * Electrical Coupling Assays: Expect results comparing the current of the variant-transfected cells to both a negative control (or H2O injected control) and a wildtype-transfected cell. BS2_Supporting would be applied if the variant results in a current comparable to the wildtype.\n * SLC26A4: Radio isotope and fluorescence assays → BS3_Supporting\n * Radio Isotope Assays: BS3_Supporting would be applied if the variant results in iodide efflux levels comparable to the wildtype.\n * Fluorescence assay: BS3_Supporting would be applied if the variant results in fluorescence comparable to the wildtype\n * COCH: Localization, secretion, and dimerization studies performed using immunofluorescence and Western blotting techniques → BS3_Supporting\n * Localization: BS3_Supporting would be applied if the variant results in extracellular deposits comparable to the wildtype.\n * Secretion: BS3_Supporting would be applied if the variant results in secretion comparable to the wildtype.\n * Dimerization: In a non-reducing environment, wildtype cochlin migrate quickly and appear smaller than in the reduced state because the structure is maintained by disulfide bonds. BS3_Supporting would be applied if the variant results in molecular weight and size comparable to the wildtype.\n* If not listed above, OK to use BS3_Supporting for other genes/functional analyses if\n * The assay has been validated by a known pathogenic and benign variant AND\n * There is plausible reason that the function the assay is testing relates to the phenotype AND\n * The assay conditions are likely to mimic the physiological environment." }, { "baseStrength": "Pathogenic", "id": "135638883", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638883", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "4 points awarded from tables 7a and 7b\nExample: Detected in trans in ≥4 probands with a pathogenic variant (recessive)." }, { "baseStrength": "Pathogenic", "id": "135638883", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638883", "label": "PM3", "strengthDescriptor": "Strong", "text": "2 points awarded from tables 7a and 7b\nExample: Detected in trans in 2 probands with a pathogenic variant (recessive)." }, { "baseStrength": "Pathogenic", "id": "135638883", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638883", "label": "PM3", "strengthDescriptor": "Moderate", "text": "1 point awarded from tables 7a and 7b.\nExample: Detected in trans with a pathogenic variant (recessive)." }, { "baseStrength": "Pathogenic", "id": "135638883", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638883", "label": "PM3", "strengthDescriptor": "Supporting", "text": "0.5 points awarded from tables 7a and 7b\nExamples: Two variants that meet PM2_Supporting detected in trans; OR\na homozygous variant meeting PM2_Supporting.\n" }, { "baseStrength": "Pathogenic", "id": "135638903", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638903", "label": "PP3", "strengthDescriptor": "Supporting", "text": "REVEL score ≥0.7, or predicted impact to splicing using MaxEntScan.\n* Use REVEL and MAXENTSCAN.\n * For missense variants, award PP3 if REVEL score is ≥0.7.\n * If splicing is predicted to be impacted, either creation of a cryptic splice site, or disruption of a native splice site, award PP3.\n* For splice variants (except for canonical -/+1 or 2), use MAXENTSCAN.\n * For -/+ 1 or 2 splice variants, do not use PP3 if you are using PVS1." }, { "baseStrength": "Pathogenic", "id": "135638902", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638902", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Advise against using this rule because there are few such genes that this would apply to, particularly genes associated to autosomal recessive hearing loss." }, { "baseStrength": "Pathogenic", "id": "135638902", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638902", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Advise against using this rule because there are few such genes that this would apply to, particularly genes associated to autosomal recessive hearing loss." }, { "baseStrength": "Pathogenic", "id": "135638902", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638902", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Advise against using this rule because there are few such genes that this would apply to, particularly genes associated to autosomal recessive hearing loss." }, { "baseStrength": "Pathogenic", "id": "135638902", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638902", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Advise against using this rule because there are few such genes that this would apply to, particularly genes associated to autosomal recessive hearing loss." }, { "baseStrength": "Benign", "id": "135638901", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638901", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "MAF of ≥0.005 (0.5%) for autosomal recessive; MAF of ≥0.001 (0.1%) for autosomal dominant." }, { "baseStrength": "Pathogenic", "id": "135638898", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638898", "label": "PS4", "strengthDescriptor": "Strong", "text": "Fisher Exact or Chi-Squared analysis shows statistical increase in cases over controls, OR\nAutosomal dominant: ≥15 probands with variant, and variant meets PM2_Supporting." }, { "baseStrength": "Pathogenic", "id": "135638898", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638898", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Autosomal dominant: ≥6 probands with variant, and variant meets PM2_Supporting." }, { "baseStrength": "Pathogenic", "id": "135638898", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638898", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Autosomal dominant: ≥2 probands with variant, and variant meets PM2_Supporting." }, { "baseStrength": "Pathogenic", "id": "135638893", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638893", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "4 points per tables 5a and 5b:\nExamples: 2 proven de novo occurrences; OR 1 proven + 2 assumed de novo occurrences; OR\n4 assumed de novo occurrences." }, { "baseStrength": "Pathogenic", "id": "135638893", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638893", "label": "PS2", "strengthDescriptor": "Strong", "text": "2 points per tables 5a and 5b:\nExamples: 1 proven de novo occurrence; OR 2 assumed de novo occurrences." }, { "baseStrength": "Pathogenic", "id": "135638893", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638893", "label": "PS2", "strengthDescriptor": "Moderate", "text": "1 point per tables 5a and 5b:\nExamples: 1 proven de novo occurrence (phenotype consistent but not specific to gene); OR\n1 assumed de novo occurrence; OR 2 assumed de novo occurrences (phenotype/gene not specific)." }, { "baseStrength": "Pathogenic", "id": "135638893", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638893", "label": "PS2", "strengthDescriptor": "Supporting", "text": "0.5 points per tables 5a and 5b:\nExample: 1 assumed de novo occurrence (phenotype/gene not specific)." }, { "baseStrength": "Pathogenic", "id": "135638890", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638890", "label": "PM6", "strengthDescriptor": "Moderate", "text": "See PS2 above" } ], "diseases": [ { "id": "MONDO:0019501", "iri": "https://genboree.org/cspec/Disease/id/135642102", "label": "Usher syndrome" }, { "id": "MONDO:0019497", "iri": "https://genboree.org/cspec/Disease/id/135642106", "label": "nonsyndromic genetic hearing loss" }, { "id": "MONDO:0019497", "iri": "https://genboree.org/cspec/Disease/id/135642106", "label": "nonsyndromic genetic hearing loss" }, { "id": "MONDO:0019497", "iri": "https://genboree.org/cspec/Disease/id/135642106", "label": "nonsyndromic genetic hearing loss" }, { "id": "MONDO:0019497", "iri": "https://genboree.org/cspec/Disease/id/135642106", "label": "nonsyndromic genetic hearing loss" }, { "id": "MONDO:0019497", "iri": "https://genboree.org/cspec/Disease/id/135642106", "label": "nonsyndromic genetic hearing loss" }, { "id": "MONDO:0019501", "iri": "https://genboree.org/cspec/Disease/id/135642102", "label": "Usher syndrome" }, { "id": "MONDO:0019497", "iri": "https://genboree.org/cspec/Disease/id/135642106", "label": "nonsyndromic genetic hearing loss" }, { "id": "MONDO:0010134", "iri": "https://genboree.org/cspec/Disease/id/135642098", "label": "Pendred syndrome" }, { "id": "MONDO:0019497", "iri": "https://genboree.org/cspec/Disease/id/135642106", "label": "nonsyndromic genetic hearing loss" }, { "id": "MONDO:0019501", "iri": "https://genboree.org/cspec/Disease/id/135642102", "label": "Usher syndrome" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641858", "label": "CDH23" }, { "iri": "https://genboree.org/cspec/Gene/id/135641857", "label": "COCH" }, { "iri": "https://genboree.org/cspec/Gene/id/135641856", "label": "GJB2" }, { "iri": "https://genboree.org/cspec/Gene/id/135641851", "label": "KCNQ4" }, { "iri": "https://genboree.org/cspec/Gene/id/135641855", "label": "MYO6" }, { "iri": "https://genboree.org/cspec/Gene/id/135641853", "label": "MYO7A" }, { "iri": "https://genboree.org/cspec/Gene/id/135641852", "label": "SLC26A4" }, { "iri": "https://genboree.org/cspec/Gene/id/135641850", "label": "TECTA" }, { "iri": "https://genboree.org/cspec/Gene/id/135641854", "label": "USH2A" } ], "ruleSet": { "id": "135640633", "iri": "https://genboree.org/cspec/RuleSet/id/135640633" }, "svi": { "id": "GN005", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637577", "label": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2,\nKCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "135638983", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638983", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135638983", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638983", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135638983", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638983", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135638983", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638983", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135638981", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638981", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease" }, { "baseStrength": "Pathogenic", "id": "135638979", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638979", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not applicable for PAH. For proband counting, use PM3 criterion." }, { "baseStrength": "Pathogenic", "id": "135638979", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638979", "label": "PS4", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not applicable for PAH. For proband counting, use PM3 criterion." }, { "baseStrength": "Pathogenic", "id": "135638979", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638979", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not applicable for PAH. For proband counting, use PM3 criterion." }, { "baseStrength": "Pathogenic", "id": "135638979", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638979", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not applicable for PAH. For proband counting, use PM3 criterion." }, { "baseStrength": "Pathogenic", "id": "135638971", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638971", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135638971", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638971", "label": "PM6", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135638971", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638971", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135638971", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638971", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135638968", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638968", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." }, { "baseStrength": "Benign", "id": "135638963", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638963", "label": "BS1", "strengthDescriptor": "Strong", "text": "Allele frequency greater than expected for disease (>0.002, 0.2%)" }, { "baseStrength": "Benign", "id": "135638985", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638985", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved." }, { "baseStrength": "Pathogenic", "id": "135638978", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638978", "label": "PP1", "strengthDescriptor": "Strong", "text": "Co-segregation with disease in multiple affected family members:\n * 3 affected segregations + 0 unaffected segregations OR\n * 2 affected segregations + 3 unaffected segregations" }, { "baseStrength": "Pathogenic", "id": "135638978", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638978", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Co-segregation with disease in multiple affected family members\n * 2 affected segregations + 0 unaffected segregations" }, { "baseStrength": "Pathogenic", "id": "135638978", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638978", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Co-segregation with disease in multiple affected family members\n * 1 affected family member + 3 unaffected segregations" }, { "baseStrength": "Pathogenic", "id": "135638974", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638974", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo (paternity confirmed) in a patient with the disease and no family history." }, { "baseStrength": "Benign", "id": "135638982", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638982", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Allele frequency above 0.015 (1.5%)" }, { "baseStrength": "Pathogenic", "id": "135638976", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638976", "label": "PS3", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect\n * PAH enzyme activity assay demonstrating enzyme activity <50%\n * RT-PCR evidence of missplicing for non-canonical intronic variants" }, { "baseStrength": "Benign", "id": "135638969", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638969", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135638969", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638969", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135638969", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638969", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135638969", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638969", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135638964", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638964", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "For recessive disorders, detected in trans with a pathogenic variant.\n * 4 compound heterozygotes with 3 P/LP variants OR\n * 2 compound heterozygotes with 2 P/LP variants AND 4 homozygotes OR\n * 3 compound heterozygotes with 2 P/LP variants AND 2 homozygotes" }, { "baseStrength": "Pathogenic", "id": "135638964", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638964", "label": "PM3", "strengthDescriptor": "Strong", "text": "For recessive disorders, detected in trans with a pathogenic variant.\n * Compound heterozygous with 2 P/LP variants OR\n * Compound heterozygous with 1 P/LP variant AND 2 homozygotes" }, { "baseStrength": "Pathogenic", "id": "135638964", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638964", "label": "PM3", "strengthDescriptor": "Moderate", "text": "For recessive disorders, detected in trans with a pathogenic variant." }, { "baseStrength": "Pathogenic", "id": "135638964", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638964", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Detected in trans with another variant:\n * 2 compound heterozygotes (with VUS in trans)\n * 2 homozygotes (allele drop out excluded)" }, { "baseStrength": "Pathogenic", "id": "638432905", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432905", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432905", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432905", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432905", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432905", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432905", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432905", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432904", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432904", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432904", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432904", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432904", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432904", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432904", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432904", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135638988", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638988", "label": "PM2", "strengthDescriptor": "Moderate", "text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n * Threshold: <0.0002 (0.02%)." }, { "baseStrength": "Pathogenic", "id": "135638987", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638987", "label": "PM1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135638987", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638987", "label": "PM1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135638987", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638987", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135638987", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638987", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135638986", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638986", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Plasma Phe >120 µmol/L and exclusion of a defect of BH4 cofactor metabolism." }, { "baseStrength": "Pathogenic", "id": "135638986", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638986", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Phenotype specific for disease with single genetic etiology." }, { "baseStrength": "Pathogenic", "id": "135638984", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638984", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product" }, { "baseStrength": "Pathogenic", "id": "135638980", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638980", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Null variant in a gene where loss of function is a known mechanism of disease." }, { "baseStrength": "Benign", "id": "135638977", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638977", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Multiple lines of computational evidence suggest no impact on gene or gene product" }, { "baseStrength": "Benign", "id": "135638973", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638973", "label": "BP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135638973", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638973", "label": "BP2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135638973", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638973", "label": "BP2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135638973", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638973", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135638967", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638967", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function\n * Enzyme activity >85%" }, { "baseStrength": "Benign", "id": "135638965", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638965", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in the homozygous state in a healthy adult" }, { "baseStrength": "Benign", "id": "135638975", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638975", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135638975", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638975", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135638975", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638975", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135638975", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638975", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135638972", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638972", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." }, { "baseStrength": "Benign", "id": "135638970", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638970", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected members of a family." }, { "baseStrength": "Pathogenic", "id": "135638966", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638966", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." } ], "diseases": [ { "id": "MONDO:0009861", "iri": "https://genboree.org/cspec/Disease/id/135642146", "label": "phenylketonuria" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641880", "label": "PAH" } ], "ruleSet": { "id": "135640693", "iri": "https://genboree.org/cspec/RuleSet/id/135640693" }, "svi": { "id": "GN006", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637578", "label": "ClinGen PAH Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1" } }, { "codes": [ { "baseStrength": "Benign", "id": "135639062", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639062", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Per original ACMG/AMP guidelines." }, { "baseStrength": "Pathogenic", "id": "135639069", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639069", "label": "PM2", "strengthDescriptor": "Supporting", "text": "≤ One out of 100,000 alleles in gnomAD cohort; if present in ≥2 individuals within a subpopulation, must be present in ≤ One out of 50,000 alleles." }, { "baseStrength": "Pathogenic", "id": "135639068", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639068", "label": "PM1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Pathogenic", "id": "135639068", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639068", "label": "PM1", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Pathogenic", "id": "135639068", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639068", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Pathogenic", "id": "135639068", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639068", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Benign", "id": "135639066", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639066", "label": "BP7", "strengthDescriptor": "Supporting", "text": "Synonymous and intronic variants at or beyond +7 to -21 locations." }, { "baseStrength": "Pathogenic", "id": "135639064", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639064", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Pathogenic", "id": "135639064", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639064", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Pathogenic", "id": "135639064", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639064", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Pathogenic", "id": "135639064", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639064", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Pathogenic", "id": "135639053", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639053", "label": "PS1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Pathogenic", "id": "135639053", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639053", "label": "PS1", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Pathogenic", "id": "135639053", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639053", "label": "PS1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Pathogenic", "id": "135639053", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639053", "label": "PS1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Pathogenic", "id": "135639047", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639047", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Only apply to stop-loss variants\nVariant example: CDH1 c.2647T>C (p.Ter883Glnext*29)." }, { "baseStrength": "Benign", "id": "135639044", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639044", "label": "BS1", "strengthDescriptor": "Strong", "text": "MAF cutoff of 0.1%." }, { "baseStrength": "Pathogenic", "id": "638432935", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432935", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432935", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432935", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432935", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432935", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432935", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432935", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432934", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432934", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432934", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432934", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432934", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432934", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432934", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432934", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135639061", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639061", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Per modified CDH1 PVS1 decision tree." }, { "baseStrength": "Pathogenic", "id": "135639061", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639061", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Per modified CDH1 PVS1 decision tree.\nOther CDH1 caveats:\n * Use PVS1_Strong as the default strength of evidence for canonical splice site variants and follow the site-specific recommendations in the splicing table. \n * CDH1 Exonic deletions or tandem duplications of in-frame exons (exon 4,5,8,9,12,13,15).\n" }, { "baseStrength": "Pathogenic", "id": "135639061", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639061", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Per modified CDH1 PVS1 decision tree.\nOther CDH1 caveats:\n * G to non-G variants disrupting the last nucleotide of an exon.\n * Canonical splice sites predicted or demonstrated experimentally to result in in-frame partial skipping/insertion (e.g., Exon 3 donor site)." }, { "baseStrength": "Pathogenic", "id": "135639055", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639055", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "≥Two patients meet the HDGC individual phenotype criteria w/ parental confirmation." }, { "baseStrength": "Pathogenic", "id": "135639055", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639055", "label": "PS2", "strengthDescriptor": "Strong", "text": "One patient meets the HDGC individual phenotype criteria w/ parental confirmation." }, { "baseStrength": "Pathogenic", "id": "135639052", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639052", "label": "PM6", "strengthDescriptor": "Very Strong", "text": ">Four patients meet the HDGC individual phenotype criteria w/o parental confirmation." }, { "baseStrength": "Pathogenic", "id": "135639052", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639052", "label": "PM6", "strengthDescriptor": "Strong", "text": "≥Two patients meet the HDGC individual phenotype criteria w/o parental confirmation." }, { "baseStrength": "Pathogenic", "id": "135639052", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639052", "label": "PM6", "strengthDescriptor": "Moderate", "text": "One patient meets the HDGC individual phenotype criteria w/o parental confirmation" }, { "baseStrength": "Benign", "id": "135639051", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639051", "label": "BS4", "strengthDescriptor": "Strong", "text": "Per original ACMG/AMP guidelines." }, { "baseStrength": "Benign", "id": "135639063", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639063", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "MAF cutoff of 0.2%." }, { "baseStrength": "Pathogenic", "id": "135639060", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639060", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "≥Sixteen families meet HDGC criteria." }, { "baseStrength": "Pathogenic", "id": "135639060", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639060", "label": "PS4", "strengthDescriptor": "Strong", "text": "Four - Fifteen families meet HDGC criteria." }, { "baseStrength": "Pathogenic", "id": "135639060", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639060", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Two or three families meet HDGC criteria." }, { "baseStrength": "Pathogenic", "id": "135639060", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639060", "label": "PS4", "strengthDescriptor": "Supporting", "text": "One family meets HDGC criteria." }, { "baseStrength": "Pathogenic", "id": "135639059", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639059", "label": "PP1", "strengthDescriptor": "Strong", "text": "≥Seven informative meioses across ≥2 families." }, { "baseStrength": "Pathogenic", "id": "135639059", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639059", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Five-six informative meioses across ≥1 family." }, { "baseStrength": "Pathogenic", "id": "135639059", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639059", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Three-four informative meioses across ≥1 family." }, { "baseStrength": "Benign", "id": "135639058", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639058", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Splicing predictions only. At least three in silico splicing predictors in agreement (SpliceAI, MaxEntScan, SSF, GeneSplicer, HSF, TraP, varSEAK)." }, { "baseStrength": "Benign", "id": "135639054", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639054", "label": "BP2", "strengthDescriptor": "Strong", "text": "Variant observed in trans w/known pathogenic variant (phase confirmed) OR observed in the homozygous state in individual w/o personal &/or family history of DGC, LBC, or SRC tumors." }, { "baseStrength": "Benign", "id": "135639054", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639054", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Variant is observed in cis (or phase is unknown) w/ a pathogenic variant\nOR observed in the homozygous state in gnomAD." }, { "baseStrength": "Benign", "id": "135639050", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639050", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Benign", "id": "135639050", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639050", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Benign", "id": "135639050", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639050", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Benign", "id": "135639050", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639050", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Benign", "id": "135639046", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639046", "label": "BS2", "strengthDescriptor": "Strong", "text": "Variant seen in ≥10 individuals w/o GC, DGC, gSRC tumors, or LBC & whose families do not suggest HDGC." }, { "baseStrength": "Benign", "id": "135639046", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639046", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Variant seen in ≥3 individuals w/o GC, DGC, SRC tumors, or LBC & whose families do not suggest HDGC." }, { "baseStrength": "Pathogenic", "id": "135639045", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639045", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Pathogenic", "id": "135639045", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639045", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Pathogenic", "id": "135639045", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639045", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Pathogenic", "id": "135639045", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639045", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Pathogenic", "id": "135639067", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639067", "label": "PP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Pathogenic", "id": "135639067", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639067", "label": "PP4", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Pathogenic", "id": "135639067", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639067", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Pathogenic", "id": "135639067", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639067", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Pathogenic", "id": "135639065", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639065", "label": "PP3", "strengthDescriptor": "Moderate", "text": "Variants affecting the same splice site as a well-characterized variant with similar or worse in silico/ RNA predictions." }, { "baseStrength": "Pathogenic", "id": "135639065", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639065", "label": "PP3", "strengthDescriptor": "Supporting", "text": "At least three in silico splicing predictors in agreement (SpliceAI, MaxEntScan, SSF, GeneSplicer, HSF, TraP, varSEAK)." }, { "baseStrength": "Pathogenic", "id": "135639057", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639057", "label": "PS3", "strengthDescriptor": "Strong", "text": "RNA assay demonstrating abnormal out-of-frame transcripts." }, { "baseStrength": "Pathogenic", "id": "135639057", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639057", "label": "PS3", "strengthDescriptor": "Moderate", "text": "RNA assay demonstrating abnormal in-frame transcript." }, { "baseStrength": "Benign", "id": "135639056", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639056", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Benign", "id": "135639056", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639056", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Benign", "id": "135639056", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639056", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Benign", "id": "135639056", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639056", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for CDH1." }, { "baseStrength": "Pathogenic", "id": "135639049", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639049", "label": "PM5", "strengthDescriptor": "Supporting", "text": "PM5_supporting is applicable to nonsense and frameshift variants that are predicted/proved to undergo NMD or located upstream of the last known pathogenic truncating variant. Site-specific recommendations for the application of PM5_Supporting for canonical splicing variants." }, { "baseStrength": "Benign", "id": "135639048", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639048", "label": "BS3", "strengthDescriptor": "Strong", "text": "Functional RNA studies demonstrating no impact on transcript composition." } ], "diseases": [ { "id": "MONDO:0007648", "iri": "https://genboree.org/cspec/Disease/id/135642152", "label": "hereditary diffuse gastric adenocarcinoma" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641886", "label": "CDH1" } ], "ruleSet": { "id": "135640753", "iri": "https://genboree.org/cspec/RuleSet/id/135640753" }, "svi": { "id": "GN007", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637579", "label": "ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH1 Version 3.2.0" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "135639148", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639148", "label": "PP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: The FPD/AML phenotype is rather unspecific and can be caused by a number of other inherited predisposition syndromes, somatic mutations or environmental factors that are insufficient to meet the original ACMG/AMP rule PP4." }, { "baseStrength": "Pathogenic", "id": "135639148", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639148", "label": "PP4", "strengthDescriptor": "Strong", "text": "Not Applicable: The FPD/AML phenotype is rather unspecific and can be caused by a number of other inherited predisposition syndromes, somatic mutations or environmental factors that are insufficient to meet the original ACMG/AMP rule PP4." }, { "baseStrength": "Pathogenic", "id": "135639148", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639148", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Not Applicable: The FPD/AML phenotype is rather unspecific and can be caused by a number of other inherited predisposition syndromes, somatic mutations or environmental factors that are insufficient to meet the original ACMG/AMP rule PP4." }, { "baseStrength": "Pathogenic", "id": "135639148", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639148", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Not Applicable: The FPD/AML phenotype is rather unspecific and can be caused by a number of other inherited predisposition syndromes, somatic mutations or environmental factors that are insufficient to meet the original ACMG/AMP rule PP4." }, { "baseStrength": "Benign", "id": "135639143", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639143", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: BP5 is not applicable. In rare circumstances, a patient can carry two pathogenic variants in genes predisposing to hematologic malignancies." }, { "baseStrength": "Benign", "id": "135639143", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639143", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable: BP5 is not applicable. In rare circumstances, a patient can carry two pathogenic variants in genes predisposing to hematologic malignancies." }, { "baseStrength": "Benign", "id": "135639143", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639143", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: BP5 is not applicable. In rare circumstances, a patient can carry two pathogenic variants in genes predisposing to hematologic malignancies." }, { "baseStrength": "Benign", "id": "135639143", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639143", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: BP5 is not applicable. In rare circumstances, a patient can carry two pathogenic variants in genes predisposing to hematologic malignancies." }, { "baseStrength": "Benign", "id": "135639139", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639139", "label": "BP4", "strengthDescriptor": "Supporting", "text": "For missense variants: REVEL score <0.50 AND SpliceAI ≤ 0.20.\nFor synonymous and Intronic variants: SpliceAI ≤ 0.20." }, { "baseStrength": "Benign", "id": "135639129", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639129", "label": "BS3", "strengthDescriptor": "Strong", "text": "Transactivation assays demonstrating normal transactivation (80- 115% of wt) AND data from a secondary assay demonstrating normal function." }, { "baseStrength": "Benign", "id": "135639129", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639129", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Transactivation assays demonstrating normal transactivation (80- 115% of wt)." }, { "baseStrength": "Pathogenic", "id": "135639150", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639150", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Variant must be completely absent from all population databases." }, { "baseStrength": "Pathogenic", "id": "135639136", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639136", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Phenotypic specificity category: “Phenotype consistent with gene but not highly specific and high genetic heterogeneity”. For each proven de novo case give 0.5 points, for each assumed de novo case give 0.25 point.\nModerate = 1.0 points total." }, { "baseStrength": "Pathogenic", "id": "135639136", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639136", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Phenotypic specificity category: “Phenotype consistent with gene but not highly specific and high genetic heterogeneity”. For each proven de novo case give 0.5 points, for each assumed de novo case give 0.25 point.\nSupporting = 0.5 points total." }, { "baseStrength": "Pathogenic", "id": "135639149", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639149", "label": "PM1", "strengthDescriptor": "Moderate", "text": " Variant affecting one of the following amino acid residues within he RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204." }, { "baseStrength": "Pathogenic", "id": "135639149", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639149", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Variant affecting one of the other amino acid residues 89-204 within the RHD." }, { "baseStrength": "Benign", "id": "135639147", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639147", "label": "BP7", "strengthDescriptor": "Supporting", "text": "BP7 is applicable for synonymous and intronic which SpliceAI ≤ 0.20 AND evolutionary conservation prediction algorithms predict the site as not conserved phyloP100 way (GRCh38/hg38) ≤2.0)." }, { "baseStrength": "Pathogenic", "id": "135639145", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639145", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: The recommended cutoff for PP2 by the SVI is a missense constraint z score of 3.09 which was not met by RUNX1 (2.48 on ExAC and 2.08 on gnomAD). In addition, there are 9 benign/likely benign missense RUNX1 variants in ClinVar." }, { "baseStrength": "Pathogenic", "id": "135639145", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639145", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: The recommended cutoff for PP2 by the SVI is a missense constraint z score of 3.09 which was not met by RUNX1 (2.48 on ExAC and 2.08 on gnomAD). In addition, there are 9 benign/likely benign missense RUNX1 variants in ClinVar." }, { "baseStrength": "Pathogenic", "id": "135639145", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639145", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: The recommended cutoff for PP2 by the SVI is a missense constraint z score of 3.09 which was not met by RUNX1 (2.48 on ExAC and 2.08 on gnomAD). In addition, there are 9 benign/likely benign missense RUNX1 variants in ClinVar." }, { "baseStrength": "Pathogenic", "id": "135639145", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639145", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: The recommended cutoff for PP2 by the SVI is a missense constraint z score of 3.09 which was not met by RUNX1 (2.48 on ExAC and 2.08 on gnomAD). In addition, there are 9 benign/likely benign missense RUNX1 variants in ClinVar." }, { "baseStrength": "Benign", "id": "135639144", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639144", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Minor allele frequency between 0.0015 (0.15%) in any general continental population dataset with ≥ 2,000 alleles tested and variant present in ≥ 5 alleles." }, { "baseStrength": "Pathogenic", "id": "135639141", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639141", "label": "PS4", "strengthDescriptor": "Strong", "text": "≥ 4 probands meeting at least one of the RUNX1-phenotypic criteria." }, { "baseStrength": "Pathogenic", "id": "135639141", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639141", "label": "PS4", "strengthDescriptor": "Moderate", "text": "2-3 probands meeting at least one of the RUNX1-phenotypic criteria." }, { "baseStrength": "Pathogenic", "id": "135639141", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639141", "label": "PS4", "strengthDescriptor": "Supporting", "text": "1 proband meeting at least one of the RUNX1-phenotypic criteria." }, { "baseStrength": "Pathogenic", "id": "135639138", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639138", "label": "PS3", "strengthDescriptor": "Strong", "text": "Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well established pathogenic variants such as R201Q or R166Q) AND data from a secondary assay demonstrating altered function. Not applicable if variant meets PVS1. If variant meets PVS1_strong, either apply PS3_moderate or upgrade to PVS1." }, { "baseStrength": "Pathogenic", "id": "135639138", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639138", "label": "PS3", "strengthDescriptor": "Moderate", "text": "Transactivation assays demonstrating altered transactivation (<20% of wt and/or reduced to levels similar to well established pathogenic variants such as R201Q or R166Q) OR ≥ 2 secondary assays demonstrating altered function." }, { "baseStrength": "Pathogenic", "id": "135639138", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639138", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Transactivation assays demonstrating enhanced transactivation (>115% of wt)." }, { "baseStrength": "Pathogenic", "id": "135639134", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639134", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. " }, { "baseStrength": "Pathogenic", "id": "135639134", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639134", "label": "PS1", "strengthDescriptor": "Moderate", "text": "Same amino acid change as a previously established likely pathogenic variant regardless of nucleotide change." }, { "baseStrength": "Benign", "id": "135639132", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639132", "label": "BS4", "strengthDescriptor": "Strong", "text": "Applied when seen in ≥ 2 informative meioses." }, { "baseStrength": "Pathogenic", "id": "135639126", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639126", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: FPD/AML is inherited in an autosomal dominant manner, thus PM3 is not applicable." }, { "baseStrength": "Pathogenic", "id": "135639126", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639126", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: FPD/AML is inherited in an autosomal dominant manner, thus PM3 is not applicable." }, { "baseStrength": "Pathogenic", "id": "135639126", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639126", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: FPD/AML is inherited in an autosomal dominant manner, thus PM3 is not applicable." }, { "baseStrength": "Pathogenic", "id": "135639126", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639126", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: FPD/AML is inherited in an autosomal dominant manner, thus PM3 is not applicable." }, { "baseStrength": "Benign", "id": "638432964", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432964", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432964", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432964", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432964", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432964", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432964", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432964", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135639146", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639146", "label": "PP3", "strengthDescriptor": "Supporting", "text": "For missense variants: REVEL score ≥ 0.88.\nFor missense, synonymous and intronic (intron 4-8) variants: SpliceAI ≥ 0.38, including the creation of cryptic novel splice sites." }, { "baseStrength": "Pathogenic", "id": "135639142", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639142", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects." }, { "baseStrength": "Pathogenic", "id": "135639142", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639142", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects." }, { "baseStrength": "Pathogenic", "id": "135639142", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639142", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects." }, { "baseStrength": "Pathogenic", "id": "135639140", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639140", "label": "PP1", "strengthDescriptor": "Strong", "text": "≥ 7 meioses observed within one or across multiple families." }, { "baseStrength": "Pathogenic", "id": "135639140", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639140", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Co-segregation with disease in multiple affected family members. 5 or 6 meioses observed within one or across multiple families." }, { "baseStrength": "Pathogenic", "id": "135639140", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639140", "label": "PP1", "strengthDescriptor": "Supporting", "text": "3 or 4 meioses observed within one or across multiple families." }, { "baseStrength": "Benign", "id": "135639135", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639135", "label": "BP2", "strengthDescriptor": "Supporting", "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." }, { "baseStrength": "Pathogenic", "id": "135639130", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639130", "label": "PM5", "strengthDescriptor": "Strong", "text": "Missense change at an AA residue where ≥ 2 different missense changes which have been determined to be pathogenic before. Not applicable in combination with PM1." }, { "baseStrength": "Pathogenic", "id": "135639130", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639130", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Missense change at an amino acid residue where a different missense change which has been determined to be pathogenic before." }, { "baseStrength": "Pathogenic", "id": "135639130", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639130", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Missense change at an amino acid residue where a different missense change which has been determined to be likely pathogenic before. PM5_supporting is also applied to nonsense/frameshift variants that are downstream of c.98 (in transcript NM_001754.4)." }, { "baseStrength": "Pathogenic", "id": "135639128", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639128", "label": "PM4", "strengthDescriptor": "Moderate", "text": "In-frame deletion/insertion impacting at least one of the following amino acid residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204." }, { "baseStrength": "Pathogenic", "id": "135639128", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639128", "label": "PM4", "strengthDescriptor": "Supporting", "text": "In-frame deletion/insertion impacting at least one of the other amino acid residues 89-204 within the RHD." }, { "baseStrength": "Benign", "id": "135639127", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639127", "label": "BS2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: BS2 is not applicable since FPD/AML patients display incomplete penetrance and the average age of onset of hematologic malignancies is 33." }, { "baseStrength": "Benign", "id": "135639127", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639127", "label": "BS2", "strengthDescriptor": "Strong", "text": "Not Applicable: BS2 is not applicable since FPD/AML patients display incomplete penetrance and the average age of onset of hematologic malignancies is 33." }, { "baseStrength": "Benign", "id": "135639127", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639127", "label": "BS2", "strengthDescriptor": "Moderate", "text": "Not Applicable: BS2 is not applicable since FPD/AML patients display incomplete penetrance and the average age of onset of hematologic malignancies is 33." }, { "baseStrength": "Benign", "id": "135639127", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639127", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Not Applicable: BS2 is not applicable since FPD/AML patients display incomplete penetrance and the average age of onset of hematologic malignancies is 33." }, { "baseStrength": "Benign", "id": "135639125", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639125", "label": "BS1", "strengthDescriptor": "Strong", "text": "Minor allele frequency between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental population dataset with ≥ 2,000 alleles tested and variant present in ≥ 5 alleles." }, { "baseStrength": "Pathogenic", "id": "638432965", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432965", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432965", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432965", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432965", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432965", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432965", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432965", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "135639137", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639137", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: RUNX1 does not contain a repetitive region without known function. BP3 is therefore deemed not applicable." }, { "baseStrength": "Benign", "id": "135639137", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639137", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: RUNX1 does not contain a repetitive region without known function. BP3 is therefore deemed not applicable." }, { "baseStrength": "Benign", "id": "135639137", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639137", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: RUNX1 does not contain a repetitive region without known function. BP3 is therefore deemed not applicable." }, { "baseStrength": "Benign", "id": "135639137", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639137", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: RUNX1 does not contain a repetitive region without known function. BP3 is therefore deemed not applicable." }, { "baseStrength": "Pathogenic", "id": "135639133", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639133", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Phenotypic specificity category: “Phenotype consistent with gene but not highly specific and high genetic heterogeneity” For each proven de novo case give 0.5 points, for each assumed de novo case give 0.25 point.\nModerate = 1.0 points total." }, { "baseStrength": "Benign", "id": "135639131", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639131", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: BP1 is not applicable for RUNX1, because both truncating and missense variants cause FPD/AML." }, { "baseStrength": "Benign", "id": "135639131", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639131", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: BP1 is not applicable for RUNX1, because both truncating and missense variants cause FPD/AML." }, { "baseStrength": "Benign", "id": "135639131", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639131", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: BP1 is not applicable for RUNX1, because both truncating and missense variants cause FPD/AML." }, { "baseStrength": "Benign", "id": "135639131", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639131", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: BP1 is not applicable for RUNX1, because both truncating and missense variants cause FPD/AML." } ], "diseases": [ { "id": "MONDO:0011071", "iri": "https://genboree.org/cspec/Disease/id/135642158", "label": "hereditary thrombocytopenia and hematologic cancer predisposition syndrome" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641893", "label": "RUNX1" } ], "ruleSet": { "id": "135640813", "iri": "https://genboree.org/cspec/RuleSet/id/135640813" }, "svi": { "id": "GN008", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637580", "label": "ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "135639230", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639230", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Missense variants within the following codons using transcript NM\\_00546.4: 175, 245, 248, 249, 273, 282. This code weight can also be used for germline missense variants seen in cancerhotspots.org with ≥ 10 somatic occurrences for the same amino acid change." }, { "baseStrength": "Pathogenic", "id": "135639230", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639230", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Missense variants seen in cancerhotspots.org with 2-9 somatic occurrences for the same amino acid change." }, { "baseStrength": "Pathogenic", "id": "135639231", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639231", "label": "PM2", "strengthDescriptor": "Supporting", "text": "This rule should be applied at supporting level. Variant should have an allele frequency of less than 0.00003 (0.003%) in gnomAD or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be \\<0.00004 (0.004%). Subpopulations influenced by founder effects (such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”) should be ignored. If the variant being assessed does not meet any population rule codes (PM2, BA1, BS1), curators should recalculate the total allele frequency based on the number of alleles between 0.35-0.65 to assess whether PM2 may be met after excluding the low AB alleles which are likely to represent clonal hematopoiesis of indeterminant potential (CHIP) contamination in the database.\n\nIn general, the most recent version of gnomAD with a non-cancer dataset should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if there is a reason to believe they would provide superior information for a particular variant type or have a large sample size, or better representation for certain subpopulations." }, { "baseStrength": "Pathogenic", "id": "135639217", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639217", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "≥ 8 points" }, { "baseStrength": "Pathogenic", "id": "135639217", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639217", "label": "PS2", "strengthDescriptor": "Strong", "text": "4-7 points" }, { "baseStrength": "Pathogenic", "id": "135639217", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639217", "label": "PS2", "strengthDescriptor": "Moderate", "text": "2-3 points" }, { "baseStrength": "Pathogenic", "id": "135639217", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639217", "label": "PS2", "strengthDescriptor": "Supporting", "text": "1 point" }, { "baseStrength": "Pathogenic", "id": "135639209", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639209", "label": "PM4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Pathogenic", "id": "135639209", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639209", "label": "PM4", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Pathogenic", "id": "135639209", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639209", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Pathogenic", "id": "135639209", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639209", "label": "PM4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Pathogenic", "id": "135639215", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639215", "label": "PS1", "strengthDescriptor": "Strong", "text": "Can be applied to variants asserted as Pathogenic following the _TP53_ VCEP’s specifications." }, { "baseStrength": "Pathogenic", "id": "135639215", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639215", "label": "PS1", "strengthDescriptor": "Moderate", "text": "Can be applied to variants asserted as Likely Pathogenic following the _TP53_ VCEP’s specifications." }, { "baseStrength": "Benign", "id": "135639216", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639216", "label": "BP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Benign", "id": "135639216", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639216", "label": "BP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Benign", "id": "135639216", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639216", "label": "BP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Benign", "id": "135639216", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639216", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Benign", "id": "135639220", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639220", "label": "BP4", "strengthDescriptor": "Moderate", "text": "**Missense variants** _(See flowchart for application of PP3 and BP4 rules for missense variants):_\n\nBayesDel ≤ -0.008 irrespective of aGVGD score (except C65, in this case do not apply BP4\\_Moderate) AND no predicted differences in splicing (SpliceAI \\< 0.2)" }, { "baseStrength": "Benign", "id": "135639220", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639220", "label": "BP4", "strengthDescriptor": "Supporting", "text": "**Missense variants** _(See flowchart for application of PP3 and BP4 rules for missense variants):_\n\nBayesDel \\< 0.16 and > -0.008 irrespective of aGVGD score (except C65, this case do not apply BP4) AND no predicted differences in splicing (SpliceAI \\< 0.2)\n\n**Single amino acid inframe deletions** _(See single aa BayesDel spreadsheet):_\n\nBayesDel score \\< 0.16 AND no predicted splicing impact (Splice AI \\< 0.2)\n\n**Silent or Intronic Variants (outside ± 1,2 positions):**\n\nSpliceAI ≤ 0.1" }, { "baseStrength": "Pathogenic", "id": "135639221", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639221", "label": "PP1", "strengthDescriptor": "Strong", "text": "Cosegregation must be observed in ≥ 7 meioses across > 1 family" }, { "baseStrength": "Pathogenic", "id": "135639221", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639221", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Cosegregation must be observed in 5-6 meioses in/across 1 or more families" }, { "baseStrength": "Pathogenic", "id": "135639221", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639221", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Cosegregation must be observed in 3-4 meioses in/across 1 or more families" }, { "baseStrength": "Benign", "id": "135639225", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639225", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Filtering allele frequency (FAF) of ≥ 0.001 or 0.1% in gnomAD continental subpopulations of a single genetic ancestry group (excluding subpopulations influenced by founder effects, such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”). Sub-population must have ≥2,000 alleles tested and a minimum of 2 alleles present. Caution should be exerted if the majority of alleles have an allele balance below 0.35.  To set the stand-alone benign FAF cutoff, we used the FAF cutoff established for BS1 (0.0003) and increased this cutoff by one order of magnitude to come to a value of 0.001. \n\n In general, the most recent version of gnomAD with a non-cancer dataset should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if there is a reason to believe they would provide superior information for a particular variant type or have a large sample size, or better representation for certain subpopulations." }, { "baseStrength": "Benign", "id": "135639228", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639228", "label": "BP7", "strengthDescriptor": "Strong", "text": "A (synonymous) silent or intronic variant for which RNA splicing assay data demonstrates no splicing aberration, as per recommendations from Walker et al., 2023 (PMID: 37352859). BP7 cannot be applied if BP4 is not met." }, { "baseStrength": "Benign", "id": "135639228", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639228", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) outside of the core splice motif (last three nucleotides and first nucleotide of the exon) or intronic variant at or beyond +7 to -21 positions for which SpliceAI predicts no impact to the splice consensus nor the creation of a new splice site (BP4 is met, SpliceAI ≤ 0.1). No requirement to assess for nucleotide conservation for rule application as per evidence and recommendations in Walker et al., 2023  (PMID: 37352859). BP7 cannot be applied if BP4 is not met." }, { "baseStrength": "Benign", "id": "135639206", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639206", "label": "BS1", "strengthDescriptor": "Strong", "text": "Filtering allele frequency (FAF) of ≥ 0.0003 but \\< 0.001 in gnomAD continental subpopulations of a single genetic ancestry group (excluding subpopulations influenced by founder effects, such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”). Sub-population must have ≥2,000 alleles tested and a minimum of 2 alleles present. Caution should be exerted if the majority of alleles have an allele balance below 0.35. To set the strong benign FAF cutoff, we used a Whiffin-Ware calculation using prevalence of 1 in 5,000 (Lalloo, et al., 2006 PMID: 16644204). Genetic and allelic heterogeneity were set at 100% and penetrance at 30%. \n\nIn general, the most recent version of gnomAD with a non-cancer dataset should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if there is a reason to believe they would provide superior information for a particular variant type or have a large sample size, or better representation for certain subpopulations." }, { "baseStrength": "Benign", "id": "638432994", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432994", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432994", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432994", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432994", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432994", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432994", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432994", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135639226", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639226", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Pathogenic", "id": "135639226", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639226", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Pathogenic", "id": "135639226", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639226", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Pathogenic", "id": "135639226", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639226", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Benign", "id": "135639210", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639210", "label": "BS3", "strengthDescriptor": "Strong", "text": "Functional on Kato et al. data **AND** no loss of function (LOF) on Giacomelli et al. data **AND/OR** no evidence of LOF on another assay (e.g. Kotler or a second assay)" }, { "baseStrength": "Benign", "id": "135639210", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639210", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Partially functional on Kato et al. data **AND** no evidence of loss of function (LOF) on Giacomelli et al. data **AND** no evidence of LOF on another assay (e.g. Kotler or other assay showing preserved function) **AND** normal or no data on Kawaguchi et al. data. Do not apply BS3\\_Supporting if any assay evidence is conflicting. If no Kato et al. data is available: no evidence of LOF on Kotler et al. data **AND** no evidence of LOF (or no data available) on Giacomelli et al. data. \n\nBS3\\_Supporting may also be applied to small deletions with available Kotler et al. data that demonstrate no evidence of LOF." }, { "baseStrength": "Pathogenic", "id": "135639223", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639223", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Per the PVS1 workflow guidance provided in Tayoun et al. 2018 (PMID: 30192042) the following will apply:\n\n* Initiation codon:\n * PVS1 may be applied to initiation codon variants\n* Nonsense or frameshift variants:\n * PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD) for nonsense variants upstream of p.Lys351 and for frameshift induced premature termination codon (PTC) upstream of p.Lys351\n * PVS1\\_Strong applies to variants not predicted to undergo NMD (nonsense variants downstream of p.Leu350 or frameshift induced PTC in exon 11 or in the 3’ most 50 nucleotides of exon 10) in variants located in the p.Lys351 to p.Ala 355 range\n * PVS1\\_Moderate applies to variants not predicted to undergo NMD (nonsense variants downstream of p.Leu350 or frameshift induced PTC in exon 11 or in the 3’ most 50 nucleotides of exon 10) in variants located in the p.Gly356 to p.Asp393 range\n * PVS1\\_Moderate may also be applied to frameshift induced PTC downstream of the natural stop codon\n* Canonical splice variants (+/- 1,2 intronic positions): \n * PVS1 applies to predicted splicing alterations that are PTC resulting in NMD (or in-frame but targeting critical domains or residues)\n * PVS1 applies to predicted splicing alterations that target the start codon (Exon 2 donor)\n * PVS1\\_Moderate applied to splicing alterations that are predicted to shorten (\\<10% of the protein removed) or expand a _TP53_ C-terminal end of unknown function (E10 donor or E11 acceptor)\n* Deletions\n * Full gene deletions: PVS1\n * Single- to multi-exon deletions that target the initiation codon, preserving the potential rescue ATG (p.Met40) in exon 4: PVS1\n * Single- to multi-exon deletions that target the initiation codon and the potential rescue ATG (p.Met40) in exon 4: PVS1\n * Single- to multi-exon deletion that disrupts the reading frame and is predicted to undergo NMD (nonsense or frameshift induced PTC upstream of p.Lys351): PVS1\n * Single- to multi-exon deletion that disrupts the reading frame and is **NOT** predicted to undergo NMD (nonsense or frameshift inducted PTC downstream of p.Leu350): PVS1\n * Single- to multi-exon deletion including the last exon where the truncated/altered region is critical to protein function (any multi-exon combination targeting exon 11): PVS1\n * If the role of the region in protein function is unknown, if the variant removed \\< 10% of the protein (deletion of exon 11): PVS1\\_Moderate\n * Single- to multi-exon deletion that preserves the reading frame where the truncated/altered region is critical to protein function: PVS1\n* Duplications (≥1 exon in size and must be completely contained within the _TP53_ gene)\n * Proven in tandem. Reading frame is disrupted and NMD predicted to occur (nonsense upstream of p.Lys351 or frameshift-induced PTC upstream of p.Lys351): PVS1\n * Presumed in tandem. Reading frame presumed disrupted and NMD predicted to occur (nonsense upstream of p.Lys351 or frameshift-induced PTC upstream of p.Lys351): PVS1\\_Strong\n\nFor variants inducing aberrant transcripts identified via mRNA assay, apply as PVS1\\_Variable Weight (RNA) following recommendations from Walker et al., 2023 (PMID: 37352859), downgrading one strength level if the assay data indicates leakiness.\n\n_Caveats_: PS3 should not be applied at any strength if PVS1 is applied at full strength. PP3 should not be used in combination with PVS1.\n\nFor the purposes of unified curation, the TP53 domains/important motifs by amino acid range are defined as:\n\n**TAD1**: aa 17-25\n\n**TAD2**: aa 48-56\n\n**Proline residues**: aa 64-92\n\n**DNA binding domain**: aa 100-292\n\n**Hinge domain**: aa 293-324\n\n**Oligomerization domain**: aa 325-356\n\n**C-terminal domain (Basic domain)**: aa 368-387\n\nA disease-specific PVS1 decision tree incorporating the above bullets as well as a supplemental file for _TP53_ PVS1 Splicing Worksheet is also included as an additional curation tool and has more granular details." }, { "baseStrength": "Benign", "id": "135639213", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639213", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected family members (i.e. family members diagnosed with LFS-associated cancers as described in Table of LFS Cancers and Points for PS2 and PP1 Code Application)." }, { "baseStrength": "Benign", "id": "135639224", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639224", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Benign", "id": "135639224", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639224", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Benign", "id": "135639224", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639224", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Benign", "id": "135639224", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639224", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Pathogenic", "id": "135639222", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639222", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "≥ 8 points" }, { "baseStrength": "Pathogenic", "id": "135639222", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639222", "label": "PS4", "strengthDescriptor": "Strong", "text": "≥ 4-7.5 points" }, { "baseStrength": "Pathogenic", "id": "135639222", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639222", "label": "PS4", "strengthDescriptor": "Moderate", "text": "2-3.5 points" }, { "baseStrength": "Pathogenic", "id": "135639222", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639222", "label": "PS4", "strengthDescriptor": "Supporting", "text": "1-1.5 points" }, { "baseStrength": "Pathogenic", "id": "135639229", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639229", "label": "PP4", "strengthDescriptor": "Moderate", "text": "At least 2 independent observations of the variant with VAF 5-25%." }, { "baseStrength": "Pathogenic", "id": "135639229", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639229", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Observation of the variant with VAF at or below 35%." }, { "baseStrength": "Benign", "id": "135639212", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639212", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This rule code does not apply to these genes, as truncating variants account for only a portion of disease causing variants." }, { "baseStrength": "Benign", "id": "135639212", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639212", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: This rule code does not apply to these genes, as truncating variants account for only a portion of disease causing variants." }, { "baseStrength": "Benign", "id": "135639212", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639212", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: This rule code does not apply to these genes, as truncating variants account for only a portion of disease causing variants." }, { "baseStrength": "Benign", "id": "135639212", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639212", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: This rule code does not apply to these genes, as truncating variants account for only a portion of disease causing variants." }, { "baseStrength": "Pathogenic", "id": "135639214", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639214", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Combined with PS2. Use PS2 instead of PM6." }, { "baseStrength": "Pathogenic", "id": "135639214", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639214", "label": "PM6", "strengthDescriptor": "Strong", "text": "Not Applicable: Combined with PS2. Use PS2 instead of PM6." }, { "baseStrength": "Pathogenic", "id": "135639214", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639214", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Not Applicable: Combined with PS2. Use PS2 instead of PM6." }, { "baseStrength": "Pathogenic", "id": "135639214", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639214", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Not Applicable: Combined with PS2. Use PS2 instead of PM6." }, { "baseStrength": "Pathogenic", "id": "135639219", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639219", "label": "PS3", "strengthDescriptor": "Strong", "text": "Non-functional on Kato et al. data **AND** loss of function (LOF) on Giacomelli et al. data **AND/OR** LOF on another assay (e.g. Kotler or a second assay showing low function)" }, { "baseStrength": "Pathogenic", "id": "135639219", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639219", "label": "PS3", "strengthDescriptor": "Moderate", "text": "Partially functional on Kato et al. data **AND** loss of function (LOF) on Giacomelli et al. data **AND/OR** LOF on another assay  (e.g. Kotler or a second assay showing low function). Do not apply PS3\\_Moderate if any assay evidence is conflicting." }, { "baseStrength": "Pathogenic", "id": "135639219", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639219", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Non-functional on Kato et.al data **AND** abnormal on Kawaguchi et al. data regardless of other assays. If no Kato et al. data is available: LOF on Kotler et al. data **AND** LOF (or no data available) on Giacomelli et al. data.\n\nPS3\\_Supporting may also be applied to small deletions with available Kotler et al. data that demonstrates LOF." }, { "baseStrength": "Pathogenic", "id": "135639227", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639227", "label": "PP3", "strengthDescriptor": "Moderate", "text": "**Missense variants** _(See flowchart for application of PP3 and BP4 rules for missense variants)_\n\naGVGD Class C65 and BayesDel score ≥ 0.16" }, { "baseStrength": "Pathogenic", "id": "135639227", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639227", "label": "PP3", "strengthDescriptor": "Supporting", "text": "**Missense variants** _(See flowchart for application of PP3 and BP4 rules for missense variants)_\n\naGVGD class C25-C55 and BayesDel score ≥ 0.16\n\n**Single amino acid inframe deletions** _(See single aa BayesDel spreadsheet)_\n\nBayesDel score ≥ 0.16\n\n**Exonic (including silent variants and apparent “missense” variants or “single amino acid inframe deletions” for which there is a predicted splice effect) or Intronic Splice Variants (excluding ± 1,2 positions):**\n\nSpliceAI ≥ 0.2" }, { "baseStrength": "Benign", "id": "638432994", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432994", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432994", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432994", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432994", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432994", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432994", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432994", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432995", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432995", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432995", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432995", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432995", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432995", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432995", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432995", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135639207", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639207", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This rule does not apply to TP53/Li-Fraumeni syndrome." }, { "baseStrength": "Pathogenic", "id": "135639207", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639207", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: This rule does not apply to TP53/Li-Fraumeni syndrome." }, { "baseStrength": "Pathogenic", "id": "135639207", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639207", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: This rule does not apply to TP53/Li-Fraumeni syndrome." }, { "baseStrength": "Pathogenic", "id": "135639207", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639207", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: This rule does not apply to TP53/Li-Fraumeni syndrome." }, { "baseStrength": "Benign", "id": "135639208", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639208", "label": "BS2", "strengthDescriptor": "Strong", "text": "≥ 8 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total." }, { "baseStrength": "Benign", "id": "135639208", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639208", "label": "BS2", "strengthDescriptor": "Moderate", "text": "4-7 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total." }, { "baseStrength": "Benign", "id": "135639208", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639208", "label": "BS2", "strengthDescriptor": "Supporting", "text": "2-3 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total." }, { "baseStrength": "Pathogenic", "id": "135639211", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639211", "label": "PM5", "strengthDescriptor": "Strong", "text": "Missense variant at an amino acid residue where ≥2 different missense variants previously determined to be pathogenic according to the _TP53_ VCEP’s specifications have been seen before." }, { "baseStrength": "Pathogenic", "id": "135639211", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639211", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Missense variant at an amino acid residue where 1 different missense variant previously determined to be pathogenic according to the _TP53_ VCEP’s specifications has been seen before." }, { "baseStrength": "Pathogenic", "id": "135639211", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639211", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Missense variant at an amino acid residue where 1 different missense variant previously determined to be likely pathogenic according to the _TP53_ VCEP’s specifications has been seen before. The previously seen likely pathogenic variant must have clinical data that demonstrates pathogenicity (i.e. PS2, PS4, PP1) in order for it to count towards PM5\\_Supporting code application." }, { "baseStrength": "Benign", "id": "135639218", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639218", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Benign", "id": "135639218", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639218", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Benign", "id": "135639218", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639218", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Benign", "id": "135639218", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639218", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable" } ], "diseases": [ { "id": "MONDO:0018875", "iri": "https://genboree.org/cspec/Disease/id/135642164", "label": "Li-Fraumeni syndrome" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641899", "label": "TP53" } ], "ruleSet": { "id": "135640873", "iri": "https://genboree.org/cspec/RuleSet/id/135640873" }, "svi": { "id": "GN009", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637581", "label": "ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.0.0" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "135639311", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639311", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation.\n * Missense substitution or in frame deletion of residues important in the active site architecture and substrate binding of GAA:- D282, W376, D404, L405, I441, W481, W516, D518, M519, R600, W613, D616, W618, F649, L650, H674." }, { "baseStrength": "Pathogenic", "id": "135639310", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639310", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Phenotype specific for disease with single genetic etiology.\n * Points-based system. See main specifications document" }, { "baseStrength": "Pathogenic", "id": "135639310", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639310", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Phenotype specific for disease with single genetic etiology.\n * Points-based system. See main specifications document" }, { "baseStrength": "Pathogenic", "id": "135639307", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639307", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply; there are benign and pathogenic missense variants in GAA." }, { "baseStrength": "Pathogenic", "id": "135639307", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639307", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply; there are benign and pathogenic missense variants in GAA." }, { "baseStrength": "Pathogenic", "id": "135639307", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639307", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply; there are benign and pathogenic missense variants in GAA." }, { "baseStrength": "Pathogenic", "id": "135639307", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639307", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply; there are benign and pathogenic missense variants in GAA." }, { "baseStrength": "Benign", "id": "135639306", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639306", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Common in population databases.\n * Highest minor allele frequency >0.01 (>1%) in any continental population in gnomAD with >2000 alleles." }, { "baseStrength": "Pathogenic", "id": "135639303", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639303", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: There are no case-control studies for Pompe disease. As this is a recessive disorder, the prevalence of the variant in affected individuals may not be increased compared to controls (who could be heterozygous carriers). The number of patients with the variant will be addressed by the PM3 evidence code." }, { "baseStrength": "Pathogenic", "id": "135639303", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639303", "label": "PS4", "strengthDescriptor": "Strong", "text": "Not Applicable: There are no case-control studies for Pompe disease. As this is a recessive disorder, the prevalence of the variant in affected individuals may not be increased compared to controls (who could be heterozygous carriers). The number of patients with the variant will be addressed by the PM3 evidence code." }, { "baseStrength": "Pathogenic", "id": "135639303", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639303", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Not Applicable: There are no case-control studies for Pompe disease. As this is a recessive disorder, the prevalence of the variant in affected individuals may not be increased compared to controls (who could be heterozygous carriers). The number of patients with the variant will be addressed by the PM3 evidence code." }, { "baseStrength": "Pathogenic", "id": "135639303", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639303", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Not Applicable: There are no case-control studies for Pompe disease. As this is a recessive disorder, the prevalence of the variant in affected individuals may not be increased compared to controls (who could be heterozygous carriers). The number of patients with the variant will be addressed by the PM3 evidence code." }, { "baseStrength": "Benign", "id": "135639297", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639297", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Observed in cis with a pathogenic variant." }, { "baseStrength": "Benign", "id": "135639287", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639287", "label": "BS1", "strengthDescriptor": "Strong", "text": "Allele frequency greater than expected for disease.\n * Highest minor allele frequency >0.005 (>0.5%) in any continental population in gnomAD with >2000 alleles." }, { "baseStrength": "Pathogenic", "id": "638433025", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433025", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433025", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433025", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433025", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433025", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433025", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433025", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "135639309", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639309", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved." }, { "baseStrength": "Pathogenic", "id": "135639304", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639304", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Null variant in a gene where loss of function is a known mechanism of disease or in frame loss of an exon that contains residues involved in the active site of GAA.\n * Any nonsense, frameshift, or splice variant creating a premature stop codon before codon 916.\n * In frame deletions of an entire exon containing critical active site/substrate binding residues (exons 8 and 10), or for which another variant removing the exon is known to be pathogenic (exons 2 and 18)." }, { "baseStrength": "Pathogenic", "id": "135639304", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639304", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n * In frame loss of an exon which is part of the catalytic barrel domain and contains pathogenic/likely pathogenic nontruncating variants (exons 6 and 9).\n * Initiator codon variant." }, { "baseStrength": "Pathogenic", "id": "135639304", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639304", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n * Premature termination codon in the 3’ end of GAA (3’ to codon 916), not predicted to be detected by nonsense-mediated decay.\n * Predicted exon-skipping due to canonical splice variant or exon deletion resulting in an in frame deletion of <10% of the gene product (exons 17, 19, and 20)." }, { "baseStrength": "Pathogenic", "id": "135639296", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639296", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." }, { "baseStrength": "Pathogenic", "id": "135639295", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639295", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: See explanation for PS2." }, { "baseStrength": "Pathogenic", "id": "135639295", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639295", "label": "PM6", "strengthDescriptor": "Strong", "text": "Not Applicable: See explanation for PS2." }, { "baseStrength": "Pathogenic", "id": "135639295", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639295", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Not Applicable: See explanation for PS2." }, { "baseStrength": "Pathogenic", "id": "135639295", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639295", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Not Applicable: See explanation for PS2." }, { "baseStrength": "Pathogenic", "id": "135639290", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639290", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a nonrepeat region or stop-loss variants.\n * In frame deletion/insertions of two or more amino acids but less than one exon." }, { "baseStrength": "Pathogenic", "id": "135639290", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639290", "label": "PM4", "strengthDescriptor": "Supporting", "text": "Protein length changes due to in-frame deletions/insertions in a nonrepeat region or stop-loss variants.\n * In frame deletion/insertions of one amino acid." }, { "baseStrength": "Benign", "id": "638433024", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433024", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433024", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433024", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433024", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433024", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433024", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433024", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135639308", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639308", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.\n * REVEL score >0.7 for missense variants.\n * In frame deletion or insertion predicted deleterious by 2 out of 3 tools (PROVEAN, MutationTaster, MutPred-InDel).\n * Predicted impact on splicing by SpliceAI (score >0.5)." }, { "baseStrength": "Pathogenic", "id": "135639300", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639300", "label": "PS3", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n * RT-PCR evidence of mis-splicing for non-canonical intronic variants with no evidence of normal splice products. " }, { "baseStrength": "Pathogenic", "id": "135639300", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639300", "label": "PS3", "strengthDescriptor": "Moderate", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n * <5% wild type GAA activity when the variant is expressed in a heterologous cell type and evidence of abnormal GAA synthesis and/or processing.\n * RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products." }, { "baseStrength": "Pathogenic", "id": "135639300", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639300", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n * <30% wild type GAA activity when the variant is expressed in a heterologous cell type.\n * RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products." }, { "baseStrength": "Pathogenic", "id": "135639302", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639302", "label": "PP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Sib-ships large enough to meet this criterion are extremely rare. In addition, because GAA is the only gene involved in Pompe disease, all patients are expected to be bi-allelic, regardless of whether the pathogenic variants can be, or have been, detected. A variant under assessment may not be the true pathogenic variant but instead in linkage disequilibrium with an unidentified pathogenic variant. For this reason, this criterion does not facilitate assessment of pathogenicity." }, { "baseStrength": "Pathogenic", "id": "135639302", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639302", "label": "PP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Sib-ships large enough to meet this criterion are extremely rare. In addition, because GAA is the only gene involved in Pompe disease, all patients are expected to be bi-allelic, regardless of whether the pathogenic variants can be, or have been, detected. A variant under assessment may not be the true pathogenic variant but instead in linkage disequilibrium with an unidentified pathogenic variant. For this reason, this criterion does not facilitate assessment of pathogenicity." }, { "baseStrength": "Pathogenic", "id": "135639302", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639302", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Sib-ships large enough to meet this criterion are extremely rare. In addition, because GAA is the only gene involved in Pompe disease, all patients are expected to be bi-allelic, regardless of whether the pathogenic variants can be, or have been, detected. A variant under assessment may not be the true pathogenic variant but instead in linkage disequilibrium with an unidentified pathogenic variant. For this reason, this criterion does not facilitate assessment of pathogenicity." }, { "baseStrength": "Pathogenic", "id": "135639302", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639302", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Sib-ships large enough to meet this criterion are extremely rare. In addition, because GAA is the only gene involved in Pompe disease, all patients are expected to be bi-allelic, regardless of whether the pathogenic variants can be, or have been, detected. A variant under assessment may not be the true pathogenic variant but instead in linkage disequilibrium with an unidentified pathogenic variant. For this reason, this criterion does not facilitate assessment of pathogenicity." }, { "baseStrength": "Benign", "id": "135639301", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639301", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Multiple lines of computational evidence suggest no impact on gene or gene product.\n * REVEL score <0.5 for missense variants.\n * In frame deletion or insertion predicted benign by PROVEAN, MutationTaster, and MutPred-InDel.\n * No predicted impact on splicing by SpliceAI (score <0.2)" }, { "baseStrength": "Pathogenic", "id": "135639298", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639298", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: De novo variants are rarely reported in GAA (PMIDs 7981676, 27142047). The occurrence of de novo variants in GAA is not a mechanism of disease for Pompe disease, and the observation that a variant in GAA has arisen de novo does not support its causality. Any de novo variants will be assessed based on the variant type, functional evidence, and in trans data as described in these guidelines." }, { "baseStrength": "Pathogenic", "id": "135639298", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639298", "label": "PS2", "strengthDescriptor": "Strong", "text": "Not Applicable: De novo variants are rarely reported in GAA (PMIDs 7981676, 27142047). The occurrence of de novo variants in GAA is not a mechanism of disease for Pompe disease, and the observation that a variant in GAA has arisen de novo does not support its causality. Any de novo variants will be assessed based on the variant type, functional evidence, and in trans data as described in these guidelines." }, { "baseStrength": "Pathogenic", "id": "135639298", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639298", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Not Applicable: De novo variants are rarely reported in GAA (PMIDs 7981676, 27142047). The occurrence of de novo variants in GAA is not a mechanism of disease for Pompe disease, and the observation that a variant in GAA has arisen de novo does not support its causality. Any de novo variants will be assessed based on the variant type, functional evidence, and in trans data as described in these guidelines." }, { "baseStrength": "Pathogenic", "id": "135639298", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639298", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Not Applicable: De novo variants are rarely reported in GAA (PMIDs 7981676, 27142047). The occurrence of de novo variants in GAA is not a mechanism of disease for Pompe disease, and the observation that a variant in GAA has arisen de novo does not support its causality. Any de novo variants will be assessed based on the variant type, functional evidence, and in trans data as described in these guidelines." }, { "baseStrength": "Benign", "id": "135639293", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639293", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply. All types of variants cause Pompe disease." }, { "baseStrength": "Benign", "id": "135639293", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639293", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply. All types of variants cause Pompe disease." }, { "baseStrength": "Benign", "id": "135639293", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639293", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply. All types of variants cause Pompe disease." }, { "baseStrength": "Benign", "id": "135639293", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639293", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply. All types of variants cause Pompe disease." }, { "baseStrength": "Pathogenic", "id": "135639292", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639292", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." }, { "baseStrength": "Pathogenic", "id": "135639292", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639292", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Missense change at an amino acid residue where a different missense change determined to be 'likely pathogenic' has been seen before." }, { "baseStrength": "Benign", "id": "135639291", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639291", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n * >50% activity when the variant is expressed in a heterologous cell type, or >30% activity if there is also evidence of normal synthesis and processing." }, { "baseStrength": "Pathogenic", "id": "135639288", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639288", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Detected in trans with a pathogenic variant. Points-based system. See main specifications document." }, { "baseStrength": "Pathogenic", "id": "135639288", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639288", "label": "PM3", "strengthDescriptor": "Strong", "text": "Detected in trans with a pathogenic variant. Points-based system. See main specifications document." }, { "baseStrength": "Pathogenic", "id": "135639288", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639288", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Detected in trans with a pathogenic variant. Points-based system. See main specifications document." }, { "baseStrength": "Pathogenic", "id": "135639288", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639288", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Detected in trans with a pathogenic variant. Points-based system. See main specifications document." }, { "baseStrength": "Pathogenic", "id": "135639312", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639312", "label": "PM2", "strengthDescriptor": "Moderate", "text": "Low frequency in population databases.\n * Minor allele frequency <0.1% (0.001) in all continental populations with >2000 alleles in gnomAD." }, { "baseStrength": "Benign", "id": "135639305", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639305", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: * An individual could be a carrier of a pathogenic variant in GAA and have another disorder.\n* There is no known alternate molecular basis for deficiency of GAA activity, other than variants in GAA." }, { "baseStrength": "Benign", "id": "135639305", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639305", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable: * An individual could be a carrier of a pathogenic variant in GAA and have another disorder.\n* There is no known alternate molecular basis for deficiency of GAA activity, other than variants in GAA." }, { "baseStrength": "Benign", "id": "135639305", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639305", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: * An individual could be a carrier of a pathogenic variant in GAA and have another disorder.\n* There is no known alternate molecular basis for deficiency of GAA activity, other than variants in GAA." }, { "baseStrength": "Benign", "id": "135639305", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639305", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: * An individual could be a carrier of a pathogenic variant in GAA and have another disorder.\n* There is no known alternate molecular basis for deficiency of GAA activity, other than variants in GAA." }, { "baseStrength": "Benign", "id": "135639299", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639299", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: There are no known repetitive regions without known function in GAA." }, { "baseStrength": "Benign", "id": "135639299", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639299", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: There are no known repetitive regions without known function in GAA." }, { "baseStrength": "Benign", "id": "135639299", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639299", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: There are no known repetitive regions without known function in GAA." }, { "baseStrength": "Benign", "id": "135639299", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639299", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: There are no known repetitive regions without known function in GAA." }, { "baseStrength": "Benign", "id": "135639294", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639294", "label": "BS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135639294", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639294", "label": "BS4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135639294", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639294", "label": "BS4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135639294", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639294", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135639289", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639289", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in the homozygous state in a healthy adult.\n * Homozygous individual of any age with normal GAA activity." } ], "diseases": [ { "id": "MONDO:0009290", "iri": "https://genboree.org/cspec/Disease/id/135642171", "label": "glycogen storage disease II" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641911", "label": "GAA" } ], "ruleSet": { "id": "135640933", "iri": "https://genboree.org/cspec/RuleSet/id/135640933" }, "svi": { "id": "GN010", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637582", "label": "ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "135639393", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639393", "label": "PM2", "strengthDescriptor": "Moderate", "text": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium" }, { "baseStrength": "Pathogenic", "id": "135639393", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639393", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Prevalence <1/10,000 (<0.0001) alleles in gnomAD." }, { "baseStrength": "Benign", "id": "135639387", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639387", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Frequency cutoff of 0.24% (>0.0024 at 99.99% CI w/subpopulation w/min of 5 alleles)." }, { "baseStrength": "Benign", "id": "135639386", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639386", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Do not use this rule as an individual can be a carrier of an unrelated pathogenic variant for a recessive disorder." }, { "baseStrength": "Pathogenic", "id": "135639385", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639385", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Use decision tree as per SVI WG with specified “regions critical to protein function”." }, { "baseStrength": "Benign", "id": "135639382", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639382", "label": "BP4", "strengthDescriptor": "Supporting", "text": "REVEL score of < 0.25" }, { "baseStrength": "Pathogenic", "id": "135639379", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639379", "label": "PS2", "strengthDescriptor": "Strong", "text": "Use proposed SVI point recommendations.\n* Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant" }, { "baseStrength": "Pathogenic", "id": "135639379", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639379", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Use proposed SVI point recommendations.\n * Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant" }, { "baseStrength": "Pathogenic", "id": "638433055", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433055", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433055", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433055", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433055", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433055", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433055", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433055", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "135639390", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639390", "label": "BP7", "strengthDescriptor": "Supporting", "text": "Use with no specification." }, { "baseStrength": "Pathogenic", "id": "135639383", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639383", "label": "PP1", "strengthDescriptor": "Strong", "text": "Segregations in proband plus >2 affected relatives.\n * Affected relatives must have both variants identified in proband." }, { "baseStrength": "Pathogenic", "id": "135639383", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639383", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Segregation in proband plus 2 affected relatives.\n * Affected relatives must have both variants identified in proband." }, { "baseStrength": "Pathogenic", "id": "135639383", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639383", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Segregation in proband plus 1 affected relative.\n * Affected relatives must have both variants identified in proband." }, { "baseStrength": "Benign", "id": "135639378", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639378", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Use as written for recessive variants (i.e. - variant must be observed in cis with a pathogenic variant)" }, { "baseStrength": "Benign", "id": "135639375", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639375", "label": "BS4", "strengthDescriptor": "Strong", "text": "Variant not detected in an affected family member." }, { "baseStrength": "Pathogenic", "id": "135639392", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639392", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Rule does not apply due to genes being highly polymorphic." }, { "baseStrength": "Pathogenic", "id": "135639391", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639391", "label": "PP4", "strengthDescriptor": "Strong", "text": "Proband with clinical diagnosis of GT based on the presence of mucocutaneous bleeding and appropriate lab abnormalities. Full sequencing of both genes is required at this strength" }, { "baseStrength": "Pathogenic", "id": "135639391", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639391", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Proband with clinical diagnosis of GT based on the presence of mucocutaneous bleeding and appropriate lab abnormalities." }, { "baseStrength": "Pathogenic", "id": "135639391", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639391", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Patients phenotype or family history is highly specific for a disease with a single genetic etiology" }, { "baseStrength": "Pathogenic", "id": "135639389", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639389", "label": "PP3", "strengthDescriptor": "Supporting", "text": "REVEL score of ≥ 0.7\n OR\n>2 independent in silico missense predictors predict a damaging impact" }, { "baseStrength": "Pathogenic", "id": "135639384", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639384", "label": "PS4", "strengthDescriptor": "Strong", "text": "Rule does not apply due to rarity of disorder and lack of appropriate studies." }, { "baseStrength": "Pathogenic", "id": "135639377", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639377", "label": "PS1", "strengthDescriptor": "Strong", "text": "Use with no specification." }, { "baseStrength": "Pathogenic", "id": "135639371", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639371", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Use with no specification." }, { "baseStrength": "Benign", "id": "135639368", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639368", "label": "BS1", "strengthDescriptor": "Strong", "text": "Frequency cutoff of 0.158% (>0.00158 at 99.99% CI w/subpopulation w/min of 5 alleles)" }, { "baseStrength": "Benign", "id": "638433054", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433054", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433054", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433054", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433054", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433054", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433054", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433054", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135639388", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639388", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This rule does not apply because benign missense variants are not rare. This rule does not apply to GT due to the fact that these genes are thought to be highly polymorphic (PMID: 25827233)." }, { "baseStrength": "Pathogenic", "id": "135639388", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639388", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: This rule does not apply because benign missense variants are not rare. This rule does not apply to GT due to the fact that these genes are thought to be highly polymorphic (PMID: 25827233)." }, { "baseStrength": "Pathogenic", "id": "135639388", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639388", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: This rule does not apply because benign missense variants are not rare. This rule does not apply to GT due to the fact that these genes are thought to be highly polymorphic (PMID: 25827233)." }, { "baseStrength": "Pathogenic", "id": "135639388", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639388", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: This rule does not apply because benign missense variants are not rare. This rule does not apply to GT due to the fact that these genes are thought to be highly polymorphic (PMID: 25827233)." }, { "baseStrength": "Benign", "id": "135639374", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639374", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Rule does not apply as truncating variants do not predominate and missense variants are a known cause of disease." }, { "baseStrength": "Pathogenic", "id": "135639373", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639373", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Use with no specification." }, { "baseStrength": "Pathogenic", "id": "135639373", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639373", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Use at adjusted strength." }, { "baseStrength": "Benign", "id": "135639372", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639372", "label": "BS3", "strengthDescriptor": "Strong", "text": "* Must demonstrate normal aggregometry in a transgenic mouse model.\n OR\n* In a heterologous cell line, must demonstrate BOTH normal expression and normal protein function" }, { "baseStrength": "Pathogenic", "id": "135639381", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639381", "label": "PS3", "strengthDescriptor": "Strong", "text": "* In a transgenic animal model, must demonstrate minimal to no function.\n OR\n* In a model organism or heterologous cell line, EITHER (A) when expression is normal or reduced, disruption of protein function must be demonstrated OR (B) Absent surface protein expression (<5%)." }, { "baseStrength": "Pathogenic", "id": "135639381", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639381", "label": "PS3", "strengthDescriptor": "Moderate", "text": "In a model organism or heterologous cell line, significantly reduced surface protein expression (5\n * 25%)." }, { "baseStrength": "Benign", "id": "135639380", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639380", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Use with no specification" }, { "baseStrength": "Pathogenic", "id": "135639376", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639376", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Use proposed SVI point recommendations.\n* Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant" }, { "baseStrength": "Pathogenic", "id": "135639376", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639376", "label": "PM6", "strengthDescriptor": "Strong", "text": "Use proposed SVI point recommendations.\n * Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant" }, { "baseStrength": "Pathogenic", "id": "135639376", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639376", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Use proposed SVI point recommendations.\n * Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant" }, { "baseStrength": "Pathogenic", "id": "135639376", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639376", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Use proposed SVI point recommendations.\n * Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant" }, { "baseStrength": "Benign", "id": "135639370", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639370", "label": "BS2", "strengthDescriptor": "Strong", "text": ">1 homozygote who is unaffected proven with at least aggregometry." }, { "baseStrength": "Pathogenic", "id": "135639369", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639369", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications." }, { "baseStrength": "Pathogenic", "id": "135639369", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639369", "label": "PM3", "strengthDescriptor": "Strong", "text": "Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications." }, { "baseStrength": "Pathogenic", "id": "135639369", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639369", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications." }, { "baseStrength": "Pathogenic", "id": "135639369", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639369", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications." } ], "diseases": [ { "id": "MONDO:0100326", "iri": "https://genboree.org/cspec/Disease/id/467880243", "label": "Glanzmann thrombasthenia" }, { "id": "MONDO:0100326", "iri": "https://genboree.org/cspec/Disease/id/467880243", "label": "Glanzmann thrombasthenia" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641918", "label": "ITGA2B" }, { "iri": "https://genboree.org/cspec/Gene/id/135641919", "label": "ITGB3" } ], "ruleSet": { "id": "135640993", "iri": "https://genboree.org/cspec/RuleSet/id/135640993" }, "svi": { "id": "GN011", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637583", "label": "ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2.1" } }, { "codes": [ { "baseStrength": "Benign", "id": "638433084", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433084", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433084", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433084", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433084", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433084", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433084", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433084", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135639474", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639474", "label": "PM2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: PM2 is not used alone." }, { "baseStrength": "Pathogenic", "id": "135639474", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639474", "label": "PM2", "strengthDescriptor": "Strong", "text": "Not Applicable: PM2 is not used alone." }, { "baseStrength": "Pathogenic", "id": "135639474", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639474", "label": "PM2", "strengthDescriptor": "Moderate", "text": "Not Applicable: PM2 is not used alone." }, { "baseStrength": "Pathogenic", "id": "135639474", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639474", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Not Applicable: PM2 is not used alone." }, { "baseStrength": "Pathogenic", "id": "135639466", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639466", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: PVS1 is not applicable. MHS is due to gain of function variants in RYR1." }, { "baseStrength": "Pathogenic", "id": "135639466", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639466", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Not Applicable: PVS1 is not applicable. MHS is due to gain of function variants in RYR1." }, { "baseStrength": "Pathogenic", "id": "135639466", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639466", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Not Applicable: PVS1 is not applicable. MHS is due to gain of function variants in RYR1." }, { "baseStrength": "Pathogenic", "id": "135639466", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639466", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "Not Applicable: PVS1 is not applicable. MHS is due to gain of function variants in RYR1." }, { "baseStrength": "Benign", "id": "135639456", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639456", "label": "BS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: BS4 is not applicable. Phenotype for MHS is routinely determined based on the vitro contraction test (IVCT) that has a false positive rate of approximately 6% (PP1) or the caffeine-halothane contracture test (CHCT). As the phenotype in individuals who have not experienced an MH crisis cannot be reliably determined BS4 is not utilized." }, { "baseStrength": "Benign", "id": "135639456", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639456", "label": "BS4", "strengthDescriptor": "Strong", "text": "Not Applicable: BS4 is not applicable. Phenotype for MHS is routinely determined based on the vitro contraction test (IVCT) that has a false positive rate of approximately 6% (PP1) or the caffeine-halothane contracture test (CHCT). As the phenotype in individuals who have not experienced an MH crisis cannot be reliably determined BS4 is not utilized." }, { "baseStrength": "Benign", "id": "135639456", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639456", "label": "BS4", "strengthDescriptor": "Moderate", "text": "Not Applicable: BS4 is not applicable. Phenotype for MHS is routinely determined based on the vitro contraction test (IVCT) that has a false positive rate of approximately 6% (PP1) or the caffeine-halothane contracture test (CHCT). As the phenotype in individuals who have not experienced an MH crisis cannot be reliably determined BS4 is not utilized." }, { "baseStrength": "Benign", "id": "135639456", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639456", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Not Applicable: BS4 is not applicable. Phenotype for MHS is routinely determined based on the vitro contraction test (IVCT) that has a false positive rate of approximately 6% (PP1) or the caffeine-halothane contracture test (CHCT). As the phenotype in individuals who have not experienced an MH crisis cannot be reliably determined BS4 is not utilized." }, { "baseStrength": "Pathogenic", "id": "135639452", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639452", "label": "PM4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: PM4 is not applicable. The majority of RYR1 variants that are causative for MHS are missense variants." }, { "baseStrength": "Pathogenic", "id": "135639452", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639452", "label": "PM4", "strengthDescriptor": "Strong", "text": "Not Applicable: PM4 is not applicable. The majority of RYR1 variants that are causative for MHS are missense variants." }, { "baseStrength": "Pathogenic", "id": "135639452", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639452", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Not Applicable: PM4 is not applicable. The majority of RYR1 variants that are causative for MHS are missense variants." }, { "baseStrength": "Pathogenic", "id": "135639452", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639452", "label": "PM4", "strengthDescriptor": "Supporting", "text": "Not Applicable: PM4 is not applicable. The majority of RYR1 variants that are causative for MHS are missense variants." }, { "baseStrength": "Pathogenic", "id": "135639473", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639473", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Located in a mutational hot spot and/or critical and well established functional domain.\n* Residues 1-552 (N-terminal region) and 2,101-2,458 (central region) \n* PM1 should not be applied at a moderate weight with PS1/PM5, see PM1_Supporting." }, { "baseStrength": "Pathogenic", "id": "135639473", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639473", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Located in a mutational hot spot and/or critical and well established functional domain.\n* Residues 1-552 (N-terminal region) and 2,101-2,458 (central region), if PS1/PM5 applicable then PM1 should be used at supporting \n* Residues 4,631-4,991 (C-terminal region)." }, { "baseStrength": "Pathogenic", "id": "135639472", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639472", "label": "PP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: PP4 is not applicable, variants in CACNA1S also result in MHS." }, { "baseStrength": "Pathogenic", "id": "135639472", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639472", "label": "PP4", "strengthDescriptor": "Strong", "text": "Not Applicable: PP4 is not applicable, variants in CACNA1S also result in MHS." }, { "baseStrength": "Pathogenic", "id": "135639472", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639472", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Not Applicable: PP4 is not applicable, variants in CACNA1S also result in MHS." }, { "baseStrength": "Pathogenic", "id": "135639472", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639472", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Not Applicable: PP4 is not applicable, variants in CACNA1S also result in MHS." }, { "baseStrength": "Benign", "id": "135639461", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639461", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: BP3 is not applicable. RYR1 does not have repetitive regions without known function." }, { "baseStrength": "Benign", "id": "135639461", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639461", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: BP3 is not applicable. RYR1 does not have repetitive regions without known function." }, { "baseStrength": "Benign", "id": "135639461", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639461", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: BP3 is not applicable. RYR1 does not have repetitive regions without known function." }, { "baseStrength": "Benign", "id": "135639461", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639461", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: BP3 is not applicable. RYR1 does not have repetitive regions without known function." }, { "baseStrength": "Benign", "id": "135639459", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639459", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Observed in cis with a pathogenic variant in any inheritance pattern" }, { "baseStrength": "Pathogenic", "id": "135639457", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639457", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, ≥8 points" }, { "baseStrength": "Pathogenic", "id": "135639457", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639457", "label": "PM6", "strengthDescriptor": "Strong", "text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 4-7 points" }, { "baseStrength": "Pathogenic", "id": "135639457", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639457", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 2-3 points" }, { "baseStrength": "Pathogenic", "id": "135639457", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639457", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 1 point" }, { "baseStrength": "Benign", "id": "135639451", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639451", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.\n * Two or more variant positive individuals with a negative IVCT/CHCT test" }, { "baseStrength": "Benign", "id": "135639451", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639451", "label": "BS2", "strengthDescriptor": "Moderate", "text": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.\n * One variant positive individual with a negative IVCT/CHCT test" }, { "baseStrength": "Pathogenic", "id": "135639450", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639450", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: PM3 is not applicable. MHS is inherited as an autosomal dominant trait with reduced penetrance." }, { "baseStrength": "Pathogenic", "id": "135639450", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639450", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: PM3 is not applicable. MHS is inherited as an autosomal dominant trait with reduced penetrance." }, { "baseStrength": "Pathogenic", "id": "135639450", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639450", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: PM3 is not applicable. MHS is inherited as an autosomal dominant trait with reduced penetrance." }, { "baseStrength": "Pathogenic", "id": "135639450", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639450", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: PM3 is not applicable. MHS is inherited as an autosomal dominant trait with reduced penetrance." }, { "baseStrength": "Benign", "id": "135639449", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639449", "label": "BS1", "strengthDescriptor": "Strong", "text": "Popmax allele frequency >0.0008 (0.08%)" }, { "baseStrength": "Pathogenic", "id": "638433085", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433085", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433085", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433085", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433085", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433085", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433085", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433085", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "135639471", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639471", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved" }, { "baseStrength": "Pathogenic", "id": "135639469", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639469", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: PP2 is not applicable. RYR1 does not appear to be constrained for missense variation with a z-score of 1.92 in gnomAD." }, { "baseStrength": "Pathogenic", "id": "135639469", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639469", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: PP2 is not applicable. RYR1 does not appear to be constrained for missense variation with a z-score of 1.92 in gnomAD." }, { "baseStrength": "Pathogenic", "id": "135639469", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639469", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: PP2 is not applicable. RYR1 does not appear to be constrained for missense variation with a z-score of 1.92 in gnomAD." }, { "baseStrength": "Pathogenic", "id": "135639469", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639469", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: PP2 is not applicable. RYR1 does not appear to be constrained for missense variation with a z-score of 1.92 in gnomAD." }, { "baseStrength": "Benign", "id": "135639467", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639467", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: BP5 is not applicable as individuals have been described with MHS and two pathogenic variants in RYR1." }, { "baseStrength": "Benign", "id": "135639467", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639467", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable: BP5 is not applicable as individuals have been described with MHS and two pathogenic variants in RYR1." }, { "baseStrength": "Benign", "id": "135639467", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639467", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: BP5 is not applicable as individuals have been described with MHS and two pathogenic variants in RYR1." }, { "baseStrength": "Benign", "id": "135639467", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639467", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: BP5 is not applicable as individuals have been described with MHS and two pathogenic variants in RYR1." }, { "baseStrength": "Pathogenic", "id": "135639465", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639465", "label": "PS4", "strengthDescriptor": "Strong", "text": "The prevalence of the variant in affected individuals significantly increased compared with the prevalence in controls.\n* ≥7 MH case points. Probands with a personal or family history of an MH event are awarded 0.5 points, probands with a personal or family history of a positive (MHS) IVCT/CHCT are awarded an additional 0.5 points. Probands with multiple variants in RYR1 classified as VUS, likely pathogenic or pathogenic are not considered. Popmax in gnomAD ≤0.00006.\n * For variants with popmax MAF gnomAD >0.00006, an odds ratio of ≥18.7 when comparing MH case points to allele count in gnomAD can qualify. Popmax in gnomAD must be <0.0038." }, { "baseStrength": "Pathogenic", "id": "135639465", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639465", "label": "PS4", "strengthDescriptor": "Moderate", "text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 2-6 MH case points. Probands with a personal or family history of an MH event are awarded 0.5 points, probands with a personal or family history of a positive (MHS) IVCT/CHCT are awarded an additional 0.5 points. Probands with multiple variants in RYR1 classified as VUS, likely pathogenic or pathogenic are not considered. Popmax in gnomAD ≤0.00006.\n* For variants with popmax MAF in gnomAD >0.00006, an odds ratio of ≥4.33 when comparing MH case points to allele count in gnomAD can qualify. Popmax in gnomAD must be <0.0038." }, { "baseStrength": "Pathogenic", "id": "135639465", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639465", "label": "PS4", "strengthDescriptor": "Supporting", "text": "The prevalence of the variant in affected individuals is significantly increased compared withthe prevalence in controls.\n* 1 MH case point. Probands with a personal or family history of an MH event are awarded 0.5 points, probands with a personal or family history of a positive (MHS) IVCT/CHCT are awarded an additional 0.5 points. Probands with multiple variants in RYR1 classified as VUS, likely pathogenic or pathogenic are not considered. Popmax in gnomAD ≤0.00006.\nFor variants with popmax MAF in gnomAD >0.00006, an odds ratio of ≥2.08 when comparing MH case points to allele count in gnomAD can qualify. Popmax in gnomAD must be <0.0038." }, { "baseStrength": "Benign", "id": "135639463", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639463", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Computational evidence suggest no impact on gene or gene product, REVEL score of <0.5" }, { "baseStrength": "Pathogenic", "id": "135639454", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639454", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Missense change at an amino acid residue where a different missense varaint previously determined to be pathogenic\n * Previously established pathogenic variant must reach a classification of pathogenicity without PM5\n * Grantham score for alternate pathogenic variant must be less than for variant being assessed" }, { "baseStrength": "Pathogenic", "id": "135639454", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639454", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Missense change at an amino acid residue where a different missense variant previously determined to be pathogenic.\n * Previously established likely pathogenic variant can be considered supporting evidence, must reach a classification of likely pathogenic without PM5.\n* Grantham score for alternate likely pathogenic variant must be less than for variant being assessed." }, { "baseStrength": "Benign", "id": "135639453", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639453", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Well-established functional studies show no damaging effect on protein function\n * Three or more independent ex vivo studies, NO significant release of Ca2+ in response to agonist" }, { "baseStrength": "Benign", "id": "135639453", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639453", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Well-established functional studies show no damaging effect on protein function\n * No significant increased sensitivity to RYR1 agonist in an approved in vitro assay, Ca2+ release measured, n≥3\n * One or two independent ex vivo studies, NO significant release of Ca2+ in response to agonist\n * Knock-in mouse showing no MH reaction in response to RYR1 agonist AND no increased sensitivity to RYR1 agonists in ex vivo tissue/cells" }, { "baseStrength": "Benign", "id": "135639468", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639468", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Popmax allele frequency >0.0038 (0.38%)" }, { "baseStrength": "Pathogenic", "id": "135639464", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639464", "label": "PP1", "strengthDescriptor": "Strong", "text": "Co-segregation with disease in ≥7 reported meioses" }, { "baseStrength": "Pathogenic", "id": "135639464", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639464", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Co-segregation with disease in 5-6 reported meioses" }, { "baseStrength": "Pathogenic", "id": "135639464", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639464", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Co-segregation with disease in 3-4 reported meioses" }, { "baseStrength": "Pathogenic", "id": "135639462", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639462", "label": "PS3", "strengthDescriptor": "Strong", "text": "Well-established functional studies supportive of a damaging effect on protein function\n * Knock-in mouse showing MH reaction in response to RYR1 agonist AND increased sensitivity to RYR1 agonists in ex vivo tisue/cells" }, { "baseStrength": "Pathogenic", "id": "135639462", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639462", "label": "PS3", "strengthDescriptor": "Moderate", "text": "Well-established functional studies supportive of a damaging effect on protein function\n * Increased sensitivity to RYR1 agonist in HEK293 in vitro assay, Ca2+ release significantly increased compared to WT, controls to include known pathogenic and benign variants, n≥3.\n * Three or more independent ex vivo studies all showing release of Ca2+ in response to RYR1 agonist\n * Knock-in mouse showing MH reaction in response to RYR1 agonist OR increased sensitivity to RYR1 agonists in ex vivo tissue/cells (but not both, which would be PS3_strong)" }, { "baseStrength": "Pathogenic", "id": "135639462", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639462", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Well-established functional studies supportive of a damaging effect on protein function\n * Two independent ex vivo studies all showing release of Ca2+ in response to RYR1 agonist" }, { "baseStrength": "Pathogenic", "id": "135639460", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639460", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, ≥8 points" }, { "baseStrength": "Pathogenic", "id": "135639460", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639460", "label": "PS2", "strengthDescriptor": "Strong", "text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 4-7 points" }, { "baseStrength": "Pathogenic", "id": "135639460", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639460", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 2-3 points" }, { "baseStrength": "Pathogenic", "id": "135639460", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639460", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 1 point" }, { "baseStrength": "Benign", "id": "135639455", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639455", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: BP1 is not applicable. MH is caused primarily by missense variants in RYR1." }, { "baseStrength": "Benign", "id": "135639455", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639455", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: BP1 is not applicable. MH is caused primarily by missense variants in RYR1." }, { "baseStrength": "Benign", "id": "135639455", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639455", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: BP1 is not applicable. MH is caused primarily by missense variants in RYR1." }, { "baseStrength": "Benign", "id": "135639455", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639455", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: BP1 is not applicable. MH is caused primarily by missense variants in RYR1." }, { "baseStrength": "Pathogenic", "id": "135639470", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639470", "label": "PP3", "strengthDescriptor": "Moderate", "text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product\n * Use REVEL score of >0.85" }, { "baseStrength": "Pathogenic", "id": "135639458", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639458", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change\n * Previously established pathogenic variant must reach a classification of pathogenic without PS1" }, { "baseStrength": "Pathogenic", "id": "135639458", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639458", "label": "PS1", "strengthDescriptor": "Moderate", "text": "Same amino acid change as a previously established likely pathogenic variant regardless of nucleotide change.\n* Previously established likely pathogenic variant must reach a classification of likely pathogenic without PS1." } ], "diseases": [ { "id": "MONDO:0018493", "iri": "https://genboree.org/cspec/Disease/id/135642187", "label": "malignant hyperthermia of anesthesia" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641927", "label": "RYR1" } ], "ruleSet": { "id": "135641053", "iri": "https://genboree.org/cspec/RuleSet/id/135641053" }, "svi": { "id": "GN012", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637584", "label": "ClinGen Malignant Hyperthermia Susceptibility Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RYR1 Version 2" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "135639547", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639547", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts." }, { "baseStrength": "Pathogenic", "id": "135639547", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639547", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts." }, { "baseStrength": "Pathogenic", "id": "135639547", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639547", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts." }, { "baseStrength": "Pathogenic", "id": "135639547", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639547", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts." }, { "baseStrength": "Pathogenic", "id": "135639541", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639541", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "135639541", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639541", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "135639541", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639541", "label": "PS2", "strengthDescriptor": "Moderate", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "135639541", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639541", "label": "PS2", "strengthDescriptor": "Supporting", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "135639531", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639531", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase." }, { "baseStrength": "Pathogenic", "id": "135639531", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639531", "label": "PM3", "strengthDescriptor": "Strong", "text": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase." }, { "baseStrength": "Pathogenic", "id": "135639531", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639531", "label": "PM3", "strengthDescriptor": "Moderate", "text": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase." }, { "baseStrength": "Pathogenic", "id": "135639531", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639531", "label": "PM3", "strengthDescriptor": "Supporting", "text": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase." }, { "baseStrength": "Benign", "id": "135639530", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639530", "label": "BS1", "strengthDescriptor": "Strong", "text": "Allele frequency is greater than expected for disorder." }, { "baseStrength": "Benign", "id": "135639530", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639530", "label": "BS1", "strengthDescriptor": "Moderate", "text": "Allele frequency is greater than expected for disorder." }, { "baseStrength": "Benign", "id": "135639530", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639530", "label": "BS1", "strengthDescriptor": "Supporting", "text": "Allele frequency is greater than expected for disorder." }, { "baseStrength": "Pathogenic", "id": "135639555", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639555", "label": "PM2", "strengthDescriptor": "Moderate", "text": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing." }, { "baseStrength": "Pathogenic", "id": "135639555", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639555", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing." }, { "baseStrength": "Pathogenic", "id": "135639553", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639553", "label": "PP4", "strengthDescriptor": "Strong", "text": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." }, { "baseStrength": "Pathogenic", "id": "135639553", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639553", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." }, { "baseStrength": "Pathogenic", "id": "135639553", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639553", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." }, { "baseStrength": "Pathogenic", "id": "135639550", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639550", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease." }, { "baseStrength": "Pathogenic", "id": "135639545", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639545", "label": "PP1", "strengthDescriptor": "Strong", "text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data." }, { "baseStrength": "Pathogenic", "id": "135639545", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639545", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data." }, { "baseStrength": "Pathogenic", "id": "135639545", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639545", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data." }, { "baseStrength": "Benign", "id": "135639544", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639544", "label": "BP4", "strengthDescriptor": "Strong", "text": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant." }, { "baseStrength": "Benign", "id": "135639544", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639544", "label": "BP4", "strengthDescriptor": "Moderate", "text": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant." }, { "baseStrength": "Benign", "id": "135639544", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639544", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant." }, { "baseStrength": "Benign", "id": "135639542", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639542", "label": "BP3", "strengthDescriptor": "Strong", "text": "In frame-deletions/insertions in a repetitive region without a known function." }, { "baseStrength": "Benign", "id": "135639542", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639542", "label": "BP3", "strengthDescriptor": "Moderate", "text": "In frame-deletions/insertions in a repetitive region without a known function." }, { "baseStrength": "Benign", "id": "135639542", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639542", "label": "BP3", "strengthDescriptor": "Supporting", "text": "In frame-deletions/insertions in a repetitive region without a known function." }, { "baseStrength": "Benign", "id": "135639536", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639536", "label": "BP1", "strengthDescriptor": "Strong", "text": "Missense variant in a gene for which primarily truncating variants are known to cause disease." }, { "baseStrength": "Benign", "id": "135639536", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639536", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Missense variant in a gene for which primarily truncating variants are known to cause disease." }, { "baseStrength": "Benign", "id": "135639536", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639536", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Missense variant in a gene for which primarily truncating variants are known to cause disease." }, { "baseStrength": "Pathogenic", "id": "135639535", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639535", "label": "PM5", "strengthDescriptor": "Strong", "text": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level." }, { "baseStrength": "Pathogenic", "id": "135639535", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639535", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level." }, { "baseStrength": "Pathogenic", "id": "135639535", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639535", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level." }, { "baseStrength": "Pathogenic", "id": "135639533", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639533", "label": "PM4", "strengthDescriptor": "Strong", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." }, { "baseStrength": "Pathogenic", "id": "135639533", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639533", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." }, { "baseStrength": "Pathogenic", "id": "135639533", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639533", "label": "PM4", "strengthDescriptor": "Supporting", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." }, { "baseStrength": "Benign", "id": "638432758", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432758", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432758", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432758", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432758", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432758", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638432758", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432758", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135639551", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639551", "label": "PP3", "strengthDescriptor": "Strong", "text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant." }, { "baseStrength": "Pathogenic", "id": "135639551", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639551", "label": "PP3", "strengthDescriptor": "Moderate", "text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant." }, { "baseStrength": "Pathogenic", "id": "135639551", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639551", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant." }, { "baseStrength": "Benign", "id": "135639548", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639548", "label": "BP5", "strengthDescriptor": "Strong", "text": "Variant found in a case with an alternate molecular basis for disease." }, { "baseStrength": "Benign", "id": "135639548", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639548", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Variant found in a case with an alternate molecular basis for disease." }, { "baseStrength": "Benign", "id": "135639548", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639548", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease." }, { "baseStrength": "Pathogenic", "id": "135639546", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639546", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence." }, { "baseStrength": "Pathogenic", "id": "135639546", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639546", "label": "PS4", "strengthDescriptor": "Strong", "text": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence." }, { "baseStrength": "Pathogenic", "id": "135639546", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639546", "label": "PS4", "strengthDescriptor": "Moderate", "text": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence." }, { "baseStrength": "Pathogenic", "id": "135639546", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639546", "label": "PS4", "strengthDescriptor": "Supporting", "text": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence." }, { "baseStrength": "Benign", "id": "135639540", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639540", "label": "BP2", "strengthDescriptor": "Strong", "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." }, { "baseStrength": "Benign", "id": "135639540", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639540", "label": "BP2", "strengthDescriptor": "Moderate", "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." }, { "baseStrength": "Benign", "id": "135639540", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639540", "label": "BP2", "strengthDescriptor": "Supporting", "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." }, { "baseStrength": "Pathogenic", "id": "135639539", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639539", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level." }, { "baseStrength": "Pathogenic", "id": "135639539", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639539", "label": "PS1", "strengthDescriptor": "Moderate", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level." }, { "baseStrength": "Pathogenic", "id": "135639539", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639539", "label": "PS1", "strengthDescriptor": "Supporting", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level." }, { "baseStrength": "Pathogenic", "id": "135639538", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639538", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Assumed de novo, but without confirmation of paternity and maternity." }, { "baseStrength": "Pathogenic", "id": "135639538", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639538", "label": "PM6", "strengthDescriptor": "Strong", "text": "Assumed de novo, but without confirmation of paternity and maternity." }, { "baseStrength": "Pathogenic", "id": "135639538", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639538", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Assumed de novo, but without confirmation of paternity and maternity." }, { "baseStrength": "Pathogenic", "id": "135639538", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639538", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Assumed de novo, but without confirmation of paternity and maternity." }, { "baseStrength": "Benign", "id": "135639537", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639537", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation." }, { "baseStrength": "Benign", "id": "135639537", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639537", "label": "BS4", "strengthDescriptor": "Moderate", "text": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation." }, { "baseStrength": "Benign", "id": "135639537", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639537", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation." }, { "baseStrength": "Pathogenic", "id": "135639554", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639554", "label": "PM1", "strengthDescriptor": "Strong", "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." }, { "baseStrength": "Pathogenic", "id": "135639554", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639554", "label": "PM1", "strengthDescriptor": "Moderate", "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." }, { "baseStrength": "Pathogenic", "id": "135639554", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639554", "label": "PM1", "strengthDescriptor": "Supporting", "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." }, { "baseStrength": "Benign", "id": "135639552", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639552", "label": "BP7", "strengthDescriptor": "Strong", "text": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved." }, { "baseStrength": "Benign", "id": "135639552", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639552", "label": "BP7", "strengthDescriptor": "Moderate", "text": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved." }, { "baseStrength": "Benign", "id": "135639552", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639552", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved." }, { "baseStrength": "Benign", "id": "135639549", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639549", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium." }, { "baseStrength": "Pathogenic", "id": "135639543", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639543", "label": "PS3", "strengthDescriptor": "Very Strong", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established." }, { "baseStrength": "Pathogenic", "id": "135639543", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639543", "label": "PS3", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established." }, { "baseStrength": "Pathogenic", "id": "135639543", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639543", "label": "PS3", "strengthDescriptor": "Moderate", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established." }, { "baseStrength": "Pathogenic", "id": "135639543", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639543", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established." }, { "baseStrength": "Benign", "id": "135639532", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639532", "label": "BS2", "strengthDescriptor": "Strong", "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." }, { "baseStrength": "Benign", "id": "135639532", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639532", "label": "BS2", "strengthDescriptor": "Moderate", "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." }, { "baseStrength": "Benign", "id": "135639532", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639532", "label": "BS2", "strengthDescriptor": "Supporting", "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." }, { "baseStrength": "Pathogenic", "id": "638432759", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432759", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432759", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432759", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432759", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432759", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638432759", "iri": "https://genboree.org/cspec/CriteriaCode/id/638432759", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "135639534", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639534", "label": "BS3", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing." }, { "baseStrength": "Benign", "id": "135639534", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639534", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing." }, { "baseStrength": "Benign", "id": "135639534", "iri": "https://genboree.org/cspec/CriteriaCode/id/135639534", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing." } ], "diseases": [], "geneType": "Nuclear", "genes": [], "ruleSet": { "id": "135641113", "iri": "https://genboree.org/cspec/RuleSet/id/135641113" }, "svi": { "id": "GN001", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585", "label": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "135637866", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637866", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Transporter assay showing loss of function" }, { "baseStrength": "Pathogenic", "id": "135637862", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637862", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change" }, { "baseStrength": "Pathogenic", "id": "135637858", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637858", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before" }, { "baseStrength": "Pathogenic", "id": "135637856", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637856", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants" }, { "baseStrength": "Pathogenic", "id": "135637874", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637874", "label": "PP3", "strengthDescriptor": "Supporting", "text": "No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively" }, { "baseStrength": "Benign", "id": "135637865", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637865", "label": "BP3", "strengthDescriptor": "Supporting", "text": "In-frame deletions/insertions in a repetitive region without a known function" }, { "baseStrength": "Benign", "id": "135637859", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637859", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637859", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637859", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637859", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637859", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637859", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637859", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637877", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637877", "label": "PM1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637877", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637877", "label": "PM1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637877", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637877", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637877", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637877", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637875", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637875", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved" }, { "baseStrength": "Benign", "id": "135637872", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637872", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": ">0.001 (>0.1%)" }, { "baseStrength": "Pathogenic", "id": "135637870", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637870", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Applied per PVS1 flowsheet of Abou Toyoun et al." }, { "baseStrength": "Pathogenic", "id": "135637869", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637869", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637869", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637869", "label": "PS4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637869", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637869", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637869", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637869", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637864", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637864", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo in a patient with the disease and no family history" }, { "baseStrength": "Benign", "id": "135637857", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637857", "label": "BS3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637857", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637857", "label": "BS3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637857", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637857", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637857", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637857", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "638433145", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433145", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433145", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433145", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433145", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433145", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433145", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433145", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135637878", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637878", "label": "PM2", "strengthDescriptor": "Moderate", "text": "<0.00005 (<0.0050%)" }, { "baseStrength": "Pathogenic", "id": "135637876", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637876", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Patient has/had MRI features of Leigh syndrome with clinical response to biotin/thiamine" }, { "baseStrength": "Pathogenic", "id": "135637873", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637873", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637873", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637873", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637873", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637873", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637873", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637873", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637871", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637871", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease" }, { "baseStrength": "Pathogenic", "id": "135637868", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637868", "label": "PP1", "strengthDescriptor": "Supporting", "text": "For segregation, an affected is defined as an individual who \n1) has brainstem or basal ganglia lesions compatible with SLC19A3-related Biotin-responsive basal ganglia disease OR \n2) a person with neurodevelopmental regression or MRI lesions compatible with SLC19A3-related Biotin-responsive basal ganglia disease who had significant clinical improvement in either symptoms or MRI lesions from treatment with biotin and thiamine." }, { "baseStrength": "Benign", "id": "135637867", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637867", "label": "BP4", "strengthDescriptor": "Supporting", "text": "No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively" }, { "baseStrength": "Benign", "id": "135637863", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637863", "label": "BP2", "strengthDescriptor": "Supporting", "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" }, { "baseStrength": "Pathogenic", "id": "135637861", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637861", "label": "PM6", "strengthDescriptor": "Strong", "text": "De novo in a patient with the disease and no family history" }, { "baseStrength": "Pathogenic", "id": "135637861", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637861", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Assumed de novo, but without confirmation of paternity and maternity" }, { "baseStrength": "Benign", "id": "135637855", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637855", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in a healthy, untreated, adult individual in the homozygous state" }, { "baseStrength": "Benign", "id": "638433144", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433144", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433144", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433144", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433144", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433144", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433144", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433144", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "135637860", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637860", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected and/or treated members of a family." }, { "baseStrength": "Pathogenic", "id": "135637854", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637854", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Use per SVI guidance" }, { "baseStrength": "Benign", "id": "135637853", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637853", "label": "BS1", "strengthDescriptor": "Strong", "text": ">0.0005 (>0.050%)" } ], "diseases": [ { "id": "MONDO:0011841", "iri": "https://genboree.org/cspec/Disease/id/135642197", "label": "biotin-responsive basal ganglia disease" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641937", "label": "SLC19A3" } ], "ruleSet": { "id": "135641173", "iri": "https://genboree.org/cspec/RuleSet/id/135641173" }, "svi": { "id": "GN014", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637587", "label": "ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_ntDNA" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "135637900", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637900", "label": "PP3", "strengthDescriptor": "Supporting", "text": "No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively" }, { "baseStrength": "Pathogenic", "id": "135637887", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637887", "label": "PM6", "strengthDescriptor": "Strong", "text": "De novo in a patient with the disease and no family history" }, { "baseStrength": "Pathogenic", "id": "135637887", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637887", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Assumed de novo, but without confirmation of paternity and maternity" }, { "baseStrength": "Pathogenic", "id": "135637882", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637882", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants" }, { "baseStrength": "Pathogenic", "id": "135637899", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637899", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637899", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637899", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637899", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637899", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637899", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637899", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637898", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637898", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": ">0.00092 (>0.092%)" }, { "baseStrength": "Pathogenic", "id": "135637894", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637894", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease" }, { "baseStrength": "Benign", "id": "135637893", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637893", "label": "BP4", "strengthDescriptor": "Supporting", "text": "No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively" }, { "baseStrength": "Pathogenic", "id": "638433172", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433172", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433172", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433172", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433172", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433172", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433172", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433172", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "135637901", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637901", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved" }, { "baseStrength": "Benign", "id": "135637886", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637886", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected and/or treated members of a family." }, { "baseStrength": "Pathogenic", "id": "135637903", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637903", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Located in one of the following functional domains:\n * thiamine pyrophosphate (TPP) binding site (aa positions 118Y, 119R, 165G, 167V, 195G, 196D, 197G, 198A, 225N, 227Y, 292H).\n * α β heterodimer interface (aa positions 160F, 162G, 164N, 169A, 172P, 173L, 176G, 177I, 179L, 180A,183Y, 202G,203Q, 209N, 210M, 213L).\n * α2 β2 heterotetramer interface (aa positions 88R, 140G, 165G, 166I, 197G, 199A, 200N, 201Q, 202G, 205F, 209N, 213L, 228G, 229M, 230G, 231T, 245R, 296D, 300S).\n * Phosphorylation loop region (aa positions 287Y, 288R, 289Y, 290H, 291G, 292H, 293S, 295S, 296D, 297P, 298G, 299V, 300S, 301Y, 302R, 303T, 304R, 305E, 314S, 315D, 316P)." }, { "baseStrength": "Benign", "id": "135637897", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637897", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease" }, { "baseStrength": "Pathogenic", "id": "135637896", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637896", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Applied per PVS1 flowsheet of Abou Toyoun et al." }, { "baseStrength": "Pathogenic", "id": "135637892", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637892", "label": "PS3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637892", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637892", "label": "PS3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637892", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637892", "label": "PS3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637892", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637892", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637889", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637889", "label": "BP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637889", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637889", "label": "BP2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637889", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637889", "label": "BP2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637889", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637889", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637883", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637883", "label": "BS3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637883", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637883", "label": "BS3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637883", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637883", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637883", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637883", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637881", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637881", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in at least two healthy male adults. Note: Individual’s phenotype is well-characterized (not just seen in database of presumed healthy individuals) AND/OR ≥16 hemizygotes in gnomAD" }, { "baseStrength": "Benign", "id": "135637881", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637881", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Observed in 4-15 hemizygotes in gnomAD AND/OR Pyruvate radioactive enzyme assay showing normal (defined as >3rd percentile of controls) for PDC, activated and normal ratios (PDC/E3 and/or PDC/CS) in fibroblasts with no evidence of skewed X-inactivation in fibroblasts." }, { "baseStrength": "Pathogenic", "id": "135637880", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637880", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637880", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637880", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637880", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637880", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637880", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637880", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637879", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637879", "label": "BS1", "strengthDescriptor": "Strong", "text": ">0.000092 (>0.0092%)" }, { "baseStrength": "Benign", "id": "638433171", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433171", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433171", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433171", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433171", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433171", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433171", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433171", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135637904", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637904", "label": "PM2", "strengthDescriptor": "Moderate", "text": "0.0000092 (<0.00092%)" }, { "baseStrength": "Pathogenic", "id": "135637902", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637902", "label": "PP4", "strengthDescriptor": "Supporting", "text": "One of the following criteria are met: \n(1) Pyruvate radioactive enzyme assay showing decreased (as defined as <3rd percentile of controls) for PDC, activated and decreased ratios (PDC/E3 and/or PDC/CS) in fibroblasts, muscle, and/or lymphocytes; \n(2) other assays showing decrease in PDC activity (ie: western blot, immunocapture, and activity; commercial kits for research); \n(3) abnormally high pyruvate and/or pyruvate/lactate ratio" }, { "baseStrength": "Pathogenic", "id": "135637895", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637895", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637895", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637895", "label": "PS4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637895", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637895", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637895", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637895", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637891", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637891", "label": "BP3", "strengthDescriptor": "Supporting", "text": "In-frame deletions/insertions in a repetitive region without a known function" }, { "baseStrength": "Pathogenic", "id": "135637890", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637890", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo in a patient with the disease and no family history" }, { "baseStrength": "Pathogenic", "id": "135637888", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637888", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change" }, { "baseStrength": "Benign", "id": "135637885", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637885", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637885", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637885", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637885", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637885", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637885", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637885", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637884", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637884", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before" } ], "diseases": [ { "id": "MONDO:0019169", "iri": "https://genboree.org/cspec/Disease/id/135642195", "label": "pyruvate dehydrogenase deficiency" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641935", "label": "PDHA1" } ], "ruleSet": { "id": "135641174", "iri": "https://genboree.org/cspec/RuleSet/id/135641174" }, "svi": { "id": "GN014", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637587", "label": "ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_ntDNA" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "135637922", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637922", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Applied per PVS1 flowsheet of Abou Toyoun et al." }, { "baseStrength": "Benign", "id": "135637911", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637911", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637911", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637911", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637911", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637911", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637911", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637911", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637907", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637907", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in a healthy adult individual in the homozygous state AND/OR Normal mtDNA content (1. Must be performed in muscle and/or liver; blood, fibroblast, and buccal not acceptable; 2. Must be performed in children only - defined as <18 years old; 3. A normal level is defined as >50%.)" }, { "baseStrength": "Benign", "id": "135637907", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637907", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Lack of COX negative fibers in muscle (children and adults)" }, { "baseStrength": "Benign", "id": "638433198", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433198", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433198", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433198", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433198", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433198", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433198", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433198", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "135637919", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637919", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively. Will also utilize POLG pathogenicity prediction server if/when live again (PMID: 28480171); both tools (REVEL and server) will have to be in agreement to score" }, { "baseStrength": "Pathogenic", "id": "135637916", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637916", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo in a patient with the disease and no family history" }, { "baseStrength": "Benign", "id": "135637909", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637909", "label": "BS3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637909", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637909", "label": "BS3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637909", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637909", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637909", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637909", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "638433199", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433199", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433199", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433199", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433199", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433199", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433199", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433199", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135637929", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637929", "label": "PM1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637929", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637929", "label": "PM1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637929", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637929", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637929", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637929", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637926", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637926", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively\n * Will also utilize POLG pathogenicity prediction server if/when live again (PMID: 28480171); both tools (REVEL and server) will have to be in agreement to score" }, { "baseStrength": "Pathogenic", "id": "135637920", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637920", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Further define “affected” as an individual in whom there is objective evidence of manifestations consistent with POLG-related disorders spectrum: Alpers-Huttenlocher syndrome (AHS), childhood myocerebrohepatopathy spectrum (MCHS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), and/or progressive external ophthalmoplegia (PEO)" }, { "baseStrength": "Pathogenic", "id": "135637914", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637914", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change" }, { "baseStrength": "Pathogenic", "id": "135637908", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637908", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants" }, { "baseStrength": "Pathogenic", "id": "135637906", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637906", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Use per SVI guidance.\nNote: T251I and P587L are almost always in cis" }, { "baseStrength": "Pathogenic", "id": "135637930", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637930", "label": "PM2", "strengthDescriptor": "Moderate", "text": "<0.0005 (<0.05% )" }, { "baseStrength": "Pathogenic", "id": "135637928", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637928", "label": "PP4", "strengthDescriptor": "Moderate", "text": "1. Mitochondrial DNA depletion showing ≤ 20% of controls, OR \n2. Multiple mitochondrial DNA deletions (NOTE:depletion and/or deletion analysis must be performed in muscle and/or liver; other tissues such as blood, fibroblast, and buccal are not acceptable; Must be performed in child, as defined as <18 years old) \nNote: For both scenarios 1 and 2, will only apply if other mtDNA maintenance disorders have been excluded (exome sequencing or comprehensive panel-based testing)" }, { "baseStrength": "Pathogenic", "id": "135637928", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637928", "label": "PP4", "strengthDescriptor": "Supporting", "text": "1. Mitochondrial DNA depletion showing 20-50% of controls in children (< 18 years of age), AND/OR \n2. COX negative fibers in muscle in children and/or adults\nNote: Will only apply if other mtDNA maintenance disorders have been excluded (exome sequencing or comprehensive panel-based testing)" }, { "baseStrength": "Benign", "id": "135637927", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637927", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved" }, { "baseStrength": "Benign", "id": "135637917", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637917", "label": "BP3", "strengthDescriptor": "Supporting", "text": "In-frame deletions/insertions in a repetitive region without a known function" }, { "baseStrength": "Benign", "id": "135637915", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637915", "label": "BP2", "strengthDescriptor": "Supporting", "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" }, { "baseStrength": "Pathogenic", "id": "135637913", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637913", "label": "PM6", "strengthDescriptor": "Strong", "text": "De novo in a patient with the disease and no family history" }, { "baseStrength": "Pathogenic", "id": "135637913", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637913", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Assumed de novo, but without confirmation of paternity and maternity" }, { "baseStrength": "Benign", "id": "135637905", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637905", "label": "BS1", "strengthDescriptor": "Strong", "text": ">0.005 (>0.5% - AR)" }, { "baseStrength": "Pathogenic", "id": "135637925", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637925", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637925", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637925", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637925", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637925", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637925", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637925", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637924", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637924", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": ">0.01 (>1%)" }, { "baseStrength": "Benign", "id": "135637923", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637923", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease" }, { "baseStrength": "Pathogenic", "id": "135637921", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637921", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637921", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637921", "label": "PS4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637921", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637921", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637921", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637921", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637918", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637918", "label": "PS3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637918", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637918", "label": "PS3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637918", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637918", "label": "PS3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637918", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637918", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637912", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637912", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected and/or treated members of a family." }, { "baseStrength": "Pathogenic", "id": "135637910", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637910", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before" } ], "diseases": [ { "id": "MONDO:0044970", "iri": "https://genboree.org/cspec/Disease/id/135642194", "label": "mitochondrial disease" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641934", "label": "POLG" } ], "ruleSet": { "id": "135641175", "iri": "https://genboree.org/cspec/RuleSet/id/135641175" }, "svi": { "id": "GN014", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637587", "label": "ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_ntDNA" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "135637954", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637954", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Individual has abnormally high urinary ethylmalonic acid AND one of the following: \n(1) All of the following symptoms present: -Acrocyanosis -Petechiae -Chronic diarrhea -Developmental delay \n(2) ≥3 or more of the following biochemical studies: -Abnormally high blood C4-Acylcarnitine esters -Abnormally high blood C5-acylcarnitine -Abnormally high plasma thiosulphate -Abnormally low cytochrome oxidase activity in skeletal muscle (without evidence of other complexes decreased)" }, { "baseStrength": "Pathogenic", "id": "135637954", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637954", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Individual has abnoramlly high urinary ethylmalonic acid AND one of the following: \n(1) 3 of the following features present: -Acrocyanosis -Petechiae -Chronic diarrhea -Developmental delay \n(2) abnormal laboratory studies in 2 of the following biochemical studies: -Abnormally high blood C4-Acylcarnitine esters -Abnormally high blood C5-acylcarnitine -Abnormally high plasma thiosulphate -Abnormally low cytochrome oxidase activity in skeletal muscle, without evidence of other complexes decreased" }, { "baseStrength": "Pathogenic", "id": "135637952", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637952", "label": "PP3", "strengthDescriptor": "Supporting", "text": "No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 f or PP3 and BP4, respectively" }, { "baseStrength": "Benign", "id": "135637950", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637950", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": ">0.001 (>0.1%)" }, { "baseStrength": "Pathogenic", "id": "135637948", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637948", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Applied per PVS1 flowsheet of Abou Toyoun et al." }, { "baseStrength": "Pathogenic", "id": "135637944", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637944", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Reduced ETHE1 persulfide dioxygenase" }, { "baseStrength": "Pathogenic", "id": "135637940", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637940", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change" }, { "baseStrength": "Pathogenic", "id": "135637939", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637939", "label": "PM6", "strengthDescriptor": "Strong", "text": "De novo in a patient with the disease and no family history" }, { "baseStrength": "Pathogenic", "id": "135637939", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637939", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Assumed de novo, but without confirmation of paternity and maternity" }, { "baseStrength": "Benign", "id": "135637937", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637937", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637937", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637937", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637937", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637937", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637937", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637937", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "638433226", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433226", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433226", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433226", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433226", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433226", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433226", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433226", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135637947", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637947", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637947", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637947", "label": "PS4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637947", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637947", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637947", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637947", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637946", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637946", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease" }, { "baseStrength": "Benign", "id": "135637943", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637943", "label": "BP3", "strengthDescriptor": "Supporting", "text": "In-frame deletions/insertions in a repetitive region without a known function" }, { "baseStrength": "Benign", "id": "135637941", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637941", "label": "BP2", "strengthDescriptor": "Supporting", "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" }, { "baseStrength": "Benign", "id": "135637938", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637938", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected and/or treated members of a family." }, { "baseStrength": "Pathogenic", "id": "135637934", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637934", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants" }, { "baseStrength": "Benign", "id": "638433225", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433225", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433225", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433225", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433225", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433225", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433225", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433225", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135637951", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637951", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637951", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637951", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637951", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637951", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637951", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637951", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637932", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637932", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Use per SVI guidance" }, { "baseStrength": "Pathogenic", "id": "135637955", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637955", "label": "PM1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637955", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637955", "label": "PM1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637955", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637955", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135637955", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637955", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637953", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637953", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved" }, { "baseStrength": "Benign", "id": "135637945", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637945", "label": "BP4", "strengthDescriptor": "Supporting", "text": "No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 f or PP3 and BP4, respectively" }, { "baseStrength": "Benign", "id": "135637935", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637935", "label": "BS3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637935", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637935", "label": "BS3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637935", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637935", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637935", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637935", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135637931", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637931", "label": "BS1", "strengthDescriptor": "Strong", "text": ">0.0002 (>0.020%)" }, { "baseStrength": "Pathogenic", "id": "135637956", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637956", "label": "PM2", "strengthDescriptor": "Moderate", "text": "<0.00002 (<0.0020%)" }, { "baseStrength": "Benign", "id": "135637949", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637949", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease" }, { "baseStrength": "Pathogenic", "id": "135637942", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637942", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo in a patient with the disease and no family history" }, { "baseStrength": "Pathogenic", "id": "135637936", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637936", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before" }, { "baseStrength": "Benign", "id": "135637933", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637933", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in a healthy adult individual in the homozygous state" }, { "baseStrength": "Benign", "id": "135637933", "iri": "https://genboree.org/cspec/CriteriaCode/id/135637933", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Normal laboratory values (specific labs outlined in PP4)" } ], "diseases": [ { "id": "MONDO:0011229", "iri": "https://genboree.org/cspec/Disease/id/135642196", "label": "ethylmalonic encephalopathy" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641936", "label": "ETHE1" } ], "ruleSet": { "id": "135641176", "iri": "https://genboree.org/cspec/RuleSet/id/135641176" }, "svi": { "id": "GN014", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637587", "label": "ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_ntDNA" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "135638272", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638272", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Decreased ETC enzyme activity (<20%) performed in a CLIA-approved (or equivalently-certified) laboratory in muscle, liver, and/or fibroblasts (for fibroblasts, must be seen in multiple unrelated probands and/or assayed in different individuals)." }, { "baseStrength": "Pathogenic", "id": "135638269", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638269", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: mtDNA exhibits lack of recombination and a relatively high mutation rate (due to lack of histones or other protective structures) that allows for mtDNA variants to accumulate over time." }, { "baseStrength": "Pathogenic", "id": "135638269", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638269", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: mtDNA exhibits lack of recombination and a relatively high mutation rate (due to lack of histones or other protective structures) that allows for mtDNA variants to accumulate over time." }, { "baseStrength": "Pathogenic", "id": "135638269", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638269", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: mtDNA exhibits lack of recombination and a relatively high mutation rate (due to lack of histones or other protective structures) that allows for mtDNA variants to accumulate over time." }, { "baseStrength": "Pathogenic", "id": "135638269", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638269", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: mtDNA exhibits lack of recombination and a relatively high mutation rate (due to lack of histones or other protective structures) that allows for mtDNA variants to accumulate over time." }, { "baseStrength": "Pathogenic", "id": "135638266", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638266", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Large heteroplasmic mtDNA deletions, where at least one gene is completely deleted" }, { "baseStrength": "Pathogenic", "id": "135638266", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638266", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Assessment of small deletions, nonsense, and frameshift variants in protein-coding genes should follow established guidelines (Abou Tayoun et al., 2018)" }, { "baseStrength": "Pathogenic", "id": "135638266", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638266", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Assessment of small deletions, nonsense, and frameshift variants in protein-coding genes should follow established guidelines (Abou Tayoun et al., 2018)" }, { "baseStrength": "Pathogenic", "id": "135638266", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638266", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "Assessment of small deletions, nonsense, and frameshift variants in protein-coding genes should follow established guidelines (Abou Tayoun et al., 2018)" }, { "baseStrength": "Benign", "id": "135638261", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638261", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: There are a few locations in the mtDNA genome where indels within a repetitive region are observed outside of two common locations: one is in the hypervariable region 1 (around position 16,189) and the other in hypervariable region 2 (around position 310). These indels are well-known benign findings." }, { "baseStrength": "Benign", "id": "135638261", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638261", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: There are a few locations in the mtDNA genome where indels within a repetitive region are observed outside of two common locations: one is in the hypervariable region 1 (around position 16,189) and the other in hypervariable region 2 (around position 310). These indels are well-known benign findings." }, { "baseStrength": "Benign", "id": "135638261", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638261", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: There are a few locations in the mtDNA genome where indels within a repetitive region are observed outside of two common locations: one is in the hypervariable region 1 (around position 16,189) and the other in hypervariable region 2 (around position 310). These indels are well-known benign findings." }, { "baseStrength": "Benign", "id": "135638261", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638261", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: There are a few locations in the mtDNA genome where indels within a repetitive region are observed outside of two common locations: one is in the hypervariable region 1 (around position 16,189) and the other in hypervariable region 2 (around position 310). These indels are well-known benign findings." }, { "baseStrength": "Pathogenic", "id": "135638260", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638260", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance" }, { "baseStrength": "Pathogenic", "id": "135638260", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638260", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance" }, { "baseStrength": "Pathogenic", "id": "135638260", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638260", "label": "PS2", "strengthDescriptor": "Moderate", "text": "De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance" }, { "baseStrength": "Pathogenic", "id": "135638260", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638260", "label": "PS2", "strengthDescriptor": "Supporting", "text": "De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance" }, { "baseStrength": "Benign", "id": "135638256", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638256", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected members of a family and/or segregation of disease in paternal family members" }, { "baseStrength": "Pathogenic", "id": "638433256", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433256", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433256", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433256", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433256", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433256", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433256", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433256", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135638264", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638264", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Co-segregation with disease in 5+ maternal family members and level of heteroplasmy segregating with disease manifestations" }, { "baseStrength": "Pathogenic", "id": "135638264", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638264", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Co-segregation with disease in 2-4 maternal family members and level of heteroplasmy segregating with disease manifestations" }, { "baseStrength": "Benign", "id": "135638263", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638263", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, etc)" }, { "baseStrength": "Pathogenic", "id": "135638257", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638257", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Assumed de novo, but without confirmation of maternity (maternal testing done by targeted variant analysis and/or targeted gene sequencing)" }, { "baseStrength": "Pathogenic", "id": "135638257", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638257", "label": "PM6", "strengthDescriptor": "Strong", "text": "Assumed de novo, but without confirmation of maternity (maternal testing done by targeted variant analysis and/or targeted gene sequencing)" }, { "baseStrength": "Pathogenic", "id": "135638257", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638257", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Assumed de novo, but without confirmation of maternity (maternal testing done by targeted variant analysis and/or targeted gene sequencing)" }, { "baseStrength": "Pathogenic", "id": "135638257", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638257", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Assumed de novo, but without confirmation of maternity (maternal testing done by targeted variant analysis and/or targeted gene sequencing)" }, { "baseStrength": "Pathogenic", "id": "135638250", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638250", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: mtDNA variants are maternally inherited and not inherited in an autosomal recessive manner." }, { "baseStrength": "Pathogenic", "id": "135638250", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638250", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: mtDNA variants are maternally inherited and not inherited in an autosomal recessive manner." }, { "baseStrength": "Pathogenic", "id": "135638250", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638250", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: mtDNA variants are maternally inherited and not inherited in an autosomal recessive manner." }, { "baseStrength": "Pathogenic", "id": "135638250", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638250", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: mtDNA variants are maternally inherited and not inherited in an autosomal recessive manner." }, { "baseStrength": "Benign", "id": "638433255", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433255", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433255", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433255", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433255", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433255", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433255", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433255", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "135638273", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638273", "label": "PM1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135638273", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638273", "label": "PM1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135638273", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638273", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "135638273", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638273", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "135638268", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638268", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Top-level haplogroup defining variants in individuals that are members of that same top-level haplogroup OR Allele frequency > 0.01 (1%)" }, { "baseStrength": "Pathogenic", "id": "135638265", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638265", "label": "PS4", "strengthDescriptor": "Strong", "text": "Variant present in ≥16 unrelated probands" }, { "baseStrength": "Pathogenic", "id": "135638265", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638265", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Variant present in ≥4 unrelated probands" }, { "baseStrength": "Pathogenic", "id": "135638265", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638265", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Variant present in 2 unrelated probands in different top-level haplogroups" }, { "baseStrength": "Pathogenic", "id": "135638262", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638262", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Functional validation is present in cybrid studies or single fiber analysis" }, { "baseStrength": "Benign", "id": "135638259", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638259", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Other mtDNA variant is observed in individual’s mtDNA that has previously been confirmed to be pathogenic" }, { "baseStrength": "Benign", "id": "135638255", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638255", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Most variants in protein-coding mtDNA genes are not truncating, but rather missense variants. Even if truncating variants were more common, this would not preclude missense variants from also causing a loss of protein function." }, { "baseStrength": "Benign", "id": "135638255", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638255", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Most variants in protein-coding mtDNA genes are not truncating, but rather missense variants. Even if truncating variants were more common, this would not preclude missense variants from also causing a loss of protein function." }, { "baseStrength": "Benign", "id": "135638255", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638255", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Most variants in protein-coding mtDNA genes are not truncating, but rather missense variants. Even if truncating variants were more common, this would not preclude missense variants from also causing a loss of protein function." }, { "baseStrength": "Benign", "id": "135638255", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638255", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Most variants in protein-coding mtDNA genes are not truncating, but rather missense variants. Even if truncating variants were more common, this would not preclude missense variants from also causing a loss of protein function." }, { "baseStrength": "Pathogenic", "id": "135638252", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638252", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Applied per original ACMG/AMP guidelines" }, { "baseStrength": "Pathogenic", "id": "135638258", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638258", "label": "PS1", "strengthDescriptor": "Strong", "text": "Applied per original ACMG/AMP guidelines" }, { "baseStrength": "Pathogenic", "id": "135638254", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638254", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Applied per original ACMG/AMP guidelines (protein-coding genes)" }, { "baseStrength": "Pathogenic", "id": "135638254", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638254", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Same nucleotide position as previously established pathogenic variant in a rRNA/tRNA" }, { "baseStrength": "Benign", "id": "135638251", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638251", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed at a higher heteroplasmy in a healthy adult individual, especially in healthy maternal family members, than in same tissue tested in an affected individual" }, { "baseStrength": "Benign", "id": "135638251", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638251", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Observed at a higher heteroplasmy in a healthy adult individual, especially in healthy maternal family members, than in different tissue(s) tested in an affected individual" }, { "baseStrength": "Pathogenic", "id": "135638274", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638274", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Frequency <0.00002 (0.002%, 1/50,000) from controls" }, { "baseStrength": "Benign", "id": "135638271", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638271", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) variant." }, { "baseStrength": "Pathogenic", "id": "135638270", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638270", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, etc)" }, { "baseStrength": "Benign", "id": "135638267", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638267", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Mitochondrial DNA variant found in a case with a nuclear DNA-related disease" }, { "baseStrength": "Benign", "id": "135638253", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638253", "label": "BS3", "strengthDescriptor": "Supporting", "text": "No evidence of functional effect in cybrid studies or single fiber analysis is present (no statistically significant difference from control; mean values of <2 SD from control mean, or 50% enzyme activity compared to controls)." }, { "baseStrength": "Benign", "id": "135638249", "iri": "https://genboree.org/cspec/CriteriaCode/id/135638249", "label": "BS1", "strengthDescriptor": "Strong", "text": "Allele frequency 0.005 - 0.0099 (0.5% - 0.99%)" } ], "diseases": [], "geneType": "mitochondrial", "genes": [], "ruleSet": { "id": "135641398", "iri": "https://genboree.org/cspec/RuleSet/id/135641398" }, "svi": { "id": "GN015", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637588", "label": "ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_mtDNA" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "1566584496", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584496", "label": "PS4", "strengthDescriptor": "Strong", "text": "Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk  ≥3 OR lower 95% CI ≥1.5)." }, { "baseStrength": "Benign", "id": "1566584519", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584519", "label": "BP7", "strengthDescriptor": "Strong", "text": "BP7\\_Strong(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. May reduce weight applied depending on assay quality." }, { "baseStrength": "Benign", "id": "1566584519", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584519", "label": "BP7", "strengthDescriptor": "Moderate", "text": "* BP7\\_Variable(RNA):Observed Lack of aberrant RNA defect with variable weight applied depending on assay quality" }, { "baseStrength": "Benign", "id": "1566584519", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584519", "label": "BP7", "strengthDescriptor": "Supporting", "text": "* BP7: Synonymous and deep intronic\n* BP7\\_Variable(RNA): Observed Lack of aberrant RNA defect with variable weight applied depending on assay quality" }, { "baseStrength": "Benign", "id": "1566584518", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584518", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1566584518", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584518", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1566584518", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584518", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1566584518", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584518", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1566584515", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584515", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Do not use: small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity for PALB2. In addition, PALB2 is not considered to have repetitive regions without known function" }, { "baseStrength": "Benign", "id": "1566584515", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584515", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Do not use: small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity for PALB2. In addition, PALB2 is not considered to have repetitive regions without known function" }, { "baseStrength": "Benign", "id": "1566584515", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584515", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Do not use: small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity for PALB2. In addition, PALB2 is not considered to have repetitive regions without known function" }, { "baseStrength": "Benign", "id": "1566584515", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584515", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Do not use: small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity for PALB2. In addition, PALB2 is not considered to have repetitive regions without known function" }, { "baseStrength": "Benign", "id": "1566584514", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584514", "label": "BP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Do not use: See Fanconi Anemia BS2 table " }, { "baseStrength": "Benign", "id": "1566584514", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584514", "label": "BP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Do not use: See Fanconi Anemia BS2 table " }, { "baseStrength": "Benign", "id": "1566584514", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584514", "label": "BP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Do not use: See Fanconi Anemia BS2 table " }, { "baseStrength": "Benign", "id": "1566584514", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584514", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Do not use: See Fanconi Anemia BS2 table " }, { "baseStrength": "Benign", "id": "1566584513", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584513", "label": "BP1", "strengthDescriptor": "Supporting", "text": " Apply to all missense variants." }, { "baseStrength": "Benign", "id": "1566584511", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584511", "label": "BS3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: ●\tDo not use: Protein functional studies (BS3) See PS3 for details \n●\tRNA functional studies (Use BP7_Variable(RNA))" }, { "baseStrength": "Benign", "id": "1566584511", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584511", "label": "BS3", "strengthDescriptor": "Strong", "text": "Not Applicable: ●\tDo not use: Protein functional studies (BS3) See PS3 for details \n●\tRNA functional studies (Use BP7_Variable(RNA))" }, { "baseStrength": "Benign", "id": "1566584511", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584511", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Not Applicable: ●\tDo not use: Protein functional studies (BS3) See PS3 for details \n●\tRNA functional studies (Use BP7_Variable(RNA))" }, { "baseStrength": "Benign", "id": "1566584511", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584511", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Not Applicable: ●\tDo not use: Protein functional studies (BS3) See PS3 for details \n●\tRNA functional studies (Use BP7_Variable(RNA))" }, { "baseStrength": "Benign", "id": "1566584509", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584509", "label": "BS1", "strengthDescriptor": "Strong", "text": "GnomAD **Filtering Allele Frequency** greater than expected for disease\n\n**\\>.01%**" }, { "baseStrength": "Pathogenic", "id": "1566584507", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584507", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1566584507", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584507", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1566584507", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584507", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1566584507", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584507", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1566584504", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584504", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2" }, { "baseStrength": "Pathogenic", "id": "1566584504", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584504", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2" }, { "baseStrength": "Pathogenic", "id": "1566584504", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584504", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2" }, { "baseStrength": "Pathogenic", "id": "1566584504", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584504", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2" }, { "baseStrength": "Pathogenic", "id": "1566584499", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584499", "label": "PM3", "strengthDescriptor": "Strong", "text": "Use Fanconi Anemia PM3 tables" }, { "baseStrength": "Pathogenic", "id": "1566584499", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584499", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Use Fanconi Anemia PM3 tables" }, { "baseStrength": "Pathogenic", "id": "1566584499", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584499", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Use Fanconi Anemia PM3 tables" }, { "baseStrength": "Pathogenic", "id": "1566584497", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584497", "label": "PM1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease." }, { "baseStrength": "Pathogenic", "id": "1566584497", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584497", "label": "PM1", "strengthDescriptor": "Strong", "text": "Not Applicable: Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease." }, { "baseStrength": "Pathogenic", "id": "1566584497", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584497", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease." }, { "baseStrength": "Pathogenic", "id": "1566584497", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584497", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease." }, { "baseStrength": "Pathogenic", "id": "1566584506", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584506", "label": "PP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes.\nFor AR disorder, use PM3 for specific phenotype considerations\n" }, { "baseStrength": "Pathogenic", "id": "1566584506", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584506", "label": "PP4", "strengthDescriptor": "Strong", "text": "Not Applicable: Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes.\nFor AR disorder, use PM3 for specific phenotype considerations\n" }, { "baseStrength": "Pathogenic", "id": "1566584506", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584506", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes.\nFor AR disorder, use PM3 for specific phenotype considerations\n" }, { "baseStrength": "Pathogenic", "id": "1566584506", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584506", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes.\nFor AR disorder, use PM3 for specific phenotype considerations\n" }, { "baseStrength": "Pathogenic", "id": "1566584503", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584503", "label": "PP1", "strengthDescriptor": "Strong", "text": "LOD ≥1.26 or Bayes Factor (LR) ≥18:1" }, { "baseStrength": "Pathogenic", "id": "1566584503", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584503", "label": "PP1", "strengthDescriptor": "Moderate", "text": "LOD ≥.60 or Bayes Factor (LR) ≥4:1" }, { "baseStrength": "Pathogenic", "id": "1566584503", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584503", "label": "PP1", "strengthDescriptor": "Supporting", "text": "LOD ≥0.3 or Bayes Factor (LR) ≥2:1" }, { "baseStrength": "Pathogenic", "id": "1566584498", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584498", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Variant absent in gnomAD or present in ≤ 1/300,000 alleles" }, { "baseStrength": "Benign", "id": "1566584512", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584512", "label": "BS4", "strengthDescriptor": "Strong", "text": "LOD ≤ -1.28 or Bayes Factor (LR) LR≤.053:1" }, { "baseStrength": "Benign", "id": "1566584512", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584512", "label": "BS4", "strengthDescriptor": "Moderate", "text": "LOD ≤ -.64 or Bayes Factor (LR) ≤.23" }, { "baseStrength": "Benign", "id": "1566584512", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584512", "label": "BS4", "strengthDescriptor": "Supporting", "text": "LOD ≤-.32 or Bayes Factor (LR) ≤.48" }, { "baseStrength": "Benign", "id": "1566584510", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584510", "label": "BS2", "strengthDescriptor": "Strong", "text": "Per Fanconi Anemia BS2 tables" }, { "baseStrength": "Benign", "id": "1566584510", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584510", "label": "BS2", "strengthDescriptor": "Moderate", "text": "Per Fanconi Anemia BS2 tables" }, { "baseStrength": "Benign", "id": "1566584510", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584510", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Per Fanconi Anemia BS2 tables" }, { "baseStrength": "Pathogenic", "id": "1566584505", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584505", "label": "PP3", "strengthDescriptor": "Supporting", "text": "* Protein: Do not use.\n* RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing" }, { "baseStrength": "Pathogenic", "id": "1566584502", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584502", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase" }, { "baseStrength": "Pathogenic", "id": "1566584502", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584502", "label": "PM6", "strengthDescriptor": "Strong", "text": "Not Applicable: Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase" }, { "baseStrength": "Pathogenic", "id": "1566584502", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584502", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Not Applicable: Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase" }, { "baseStrength": "Pathogenic", "id": "1566584502", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584502", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Not Applicable: Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase" }, { "baseStrength": "Pathogenic", "id": "1566584501", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584501", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, based on location of the most C-terminal known pathogenic variant, p.Tyr1183\\*" }, { "baseStrength": "Pathogenic", "id": "1566584500", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584500", "label": "PM4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: ●\tDo not use for in-frame deletions/insertions that are not already PVS1-eligible as no information is available to justify the application of this rule. \n●\tIn addition, missense and small in-frame indels are not yet confirmed as a mechanism of disease for PALB2.\n●\tDo not use for stop-loss due to lack of data on stop-loss variants. \n\n" }, { "baseStrength": "Pathogenic", "id": "1566584500", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584500", "label": "PM4", "strengthDescriptor": "Strong", "text": "Not Applicable: ●\tDo not use for in-frame deletions/insertions that are not already PVS1-eligible as no information is available to justify the application of this rule. \n●\tIn addition, missense and small in-frame indels are not yet confirmed as a mechanism of disease for PALB2.\n●\tDo not use for stop-loss due to lack of data on stop-loss variants. \n\n" }, { "baseStrength": "Pathogenic", "id": "1566584500", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584500", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Not Applicable: ●\tDo not use for in-frame deletions/insertions that are not already PVS1-eligible as no information is available to justify the application of this rule. \n●\tIn addition, missense and small in-frame indels are not yet confirmed as a mechanism of disease for PALB2.\n●\tDo not use for stop-loss due to lack of data on stop-loss variants. \n\n" }, { "baseStrength": "Pathogenic", "id": "1566584500", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584500", "label": "PM4", "strengthDescriptor": "Supporting", "text": "Not Applicable: ●\tDo not use for in-frame deletions/insertions that are not already PVS1-eligible as no information is available to justify the application of this rule. \n●\tIn addition, missense and small in-frame indels are not yet confirmed as a mechanism of disease for PALB2.\n●\tDo not use for stop-loss due to lack of data on stop-loss variants. \n\n" }, { "baseStrength": "Pathogenic", "id": "1566584495", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584495", "label": "PS3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: ●\tProtein: Do not use: Lack of known positive controls \n●\tRNA: Do not use: See code PVS1_Variable(RNA)\n" }, { "baseStrength": "Pathogenic", "id": "1566584495", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584495", "label": "PS3", "strengthDescriptor": "Strong", "text": "Not Applicable: ●\tProtein: Do not use: Lack of known positive controls \n●\tRNA: Do not use: See code PVS1_Variable(RNA)\n" }, { "baseStrength": "Pathogenic", "id": "1566584495", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584495", "label": "PS3", "strengthDescriptor": "Moderate", "text": "Not Applicable: ●\tProtein: Do not use: Lack of known positive controls \n●\tRNA: Do not use: See code PVS1_Variable(RNA)\n" }, { "baseStrength": "Pathogenic", "id": "1566584495", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584495", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Not Applicable: ●\tProtein: Do not use: Lack of known positive controls \n●\tRNA: Do not use: See code PVS1_Variable(RNA)\n" }, { "baseStrength": "Pathogenic", "id": "1566584494", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584494", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: ●\tDo not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase\n●\tAutosomal Dominant Disease: Do not use-Informative de novo occurrences have not yet been observed for autosomal dominant disease. As breast cancer is relatively common and occurs frequently as an apparently sporadic event, de novo is unlikely to ever be informative unless specific features of PALB2-related cancer predisposition are identified.\n●\tAutosomal Recessive Disease: Do not use - de novo occurrences are too rare to be informative at this time. In addition, in a biallelic state, de novo occurrences have an exceedingly low probability of being able to be confirmed as in trans because parental testing (and identification of one variant in each parent) is typically required without the use of long-range technologies.\n" }, { "baseStrength": "Pathogenic", "id": "1566584494", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584494", "label": "PS2", "strengthDescriptor": "Strong", "text": "Not Applicable: ●\tDo not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase\n●\tAutosomal Dominant Disease: Do not use-Informative de novo occurrences have not yet been observed for autosomal dominant disease. As breast cancer is relatively common and occurs frequently as an apparently sporadic event, de novo is unlikely to ever be informative unless specific features of PALB2-related cancer predisposition are identified.\n●\tAutosomal Recessive Disease: Do not use - de novo occurrences are too rare to be informative at this time. In addition, in a biallelic state, de novo occurrences have an exceedingly low probability of being able to be confirmed as in trans because parental testing (and identification of one variant in each parent) is typically required without the use of long-range technologies.\n" }, { "baseStrength": "Pathogenic", "id": "1566584494", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584494", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Not Applicable: ●\tDo not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase\n●\tAutosomal Dominant Disease: Do not use-Informative de novo occurrences have not yet been observed for autosomal dominant disease. As breast cancer is relatively common and occurs frequently as an apparently sporadic event, de novo is unlikely to ever be informative unless specific features of PALB2-related cancer predisposition are identified.\n●\tAutosomal Recessive Disease: Do not use - de novo occurrences are too rare to be informative at this time. In addition, in a biallelic state, de novo occurrences have an exceedingly low probability of being able to be confirmed as in trans because parental testing (and identification of one variant in each parent) is typically required without the use of long-range technologies.\n" }, { "baseStrength": "Pathogenic", "id": "1566584494", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584494", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Not Applicable: ●\tDo not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase\n●\tAutosomal Dominant Disease: Do not use-Informative de novo occurrences have not yet been observed for autosomal dominant disease. As breast cancer is relatively common and occurs frequently as an apparently sporadic event, de novo is unlikely to ever be informative unless specific features of PALB2-related cancer predisposition are identified.\n●\tAutosomal Recessive Disease: Do not use - de novo occurrences are too rare to be informative at this time. In addition, in a biallelic state, de novo occurrences have an exceedingly low probability of being able to be confirmed as in trans because parental testing (and identification of one variant in each parent) is typically required without the use of long-range technologies.\n" }, { "baseStrength": "Benign", "id": "1566584517", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584517", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2). In addition, PALB2 has moderate penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population." }, { "baseStrength": "Benign", "id": "1566584517", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584517", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable: Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2). In addition, PALB2 has moderate penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population." }, { "baseStrength": "Benign", "id": "1566584517", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584517", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2). In addition, PALB2 has moderate penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population." }, { "baseStrength": "Benign", "id": "1566584517", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584517", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2). In addition, PALB2 has moderate penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population." }, { "baseStrength": "Benign", "id": "1566584516", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584516", "label": "BP4", "strengthDescriptor": "Supporting", "text": "● Protein: Do not use. So far, published predictors have yet to achieve functional outcome for PALB2 missense variants \n\n● RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows no impact on splicing \n\no NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) \n\no NOTE: BP4 for splice predictions may not be applied in conjunction with BP7\\_Variable(RNA) (a lack of observed RNA defect) \n\no Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism." }, { "baseStrength": "Benign", "id": "1566584508", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584508", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "GnomAD **Filtering Allele Frequency** Allele frequency\n\n**\\>0.1%**" }, { "baseStrength": "Pathogenic", "id": "1566584493", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584493", "label": "PS1", "strengthDescriptor": "Strong", "text": "Use PALB2 PS1 Splicing table" }, { "baseStrength": "Pathogenic", "id": "1566584493", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584493", "label": "PS1", "strengthDescriptor": "Moderate", "text": "Use PALB2 PS1 Splicing table" }, { "baseStrength": "Pathogenic", "id": "1566584493", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584493", "label": "PS1", "strengthDescriptor": "Supporting", "text": "Use PALB2 PS1 Splicing table" }, { "baseStrength": "Pathogenic", "id": "1566584492", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584492", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Use PALB2 PVS1 Decision Tree" }, { "baseStrength": "Pathogenic", "id": "1566584492", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584492", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Use PALB2 PVS1 Decision Tree." }, { "baseStrength": "Pathogenic", "id": "1566584492", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584492", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Use PALB2 PVS1 Decision Tree." }, { "baseStrength": "Pathogenic", "id": "1566584492", "iri": "https://genboree.org/cspec/CriteriaCode/id/1566584492", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "Use PALB2 PVS1 Decision Tree" } ], "diseases": [ { "id": "MONDO:0016419", "iri": "https://genboree.org/cspec/Disease/id/467880845", "label": "hereditary breast carcinoma" }, { "id": "MONDO:0015278", "iri": "https://genboree.org/cspec/Disease/id/467895128", "label": "familial pancreatic carcinoma" }, { "id": "MONDO:0012565", "iri": "https://genboree.org/cspec/Disease/id/467875876", "label": "Fanconi anemia complementation group N" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467844262", "label": "PALB2" } ], "ruleSet": { "id": "1526222369", "iri": "https://genboree.org/cspec/RuleSet/id/1526222369" }, "svi": { "id": "GN077", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1526222356", "label": "ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PALB2 Version 1.1.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1743943310", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943310", "label": "BP7", "strengthDescriptor": "Supporting", "text": "To evaluate splice prediction, use the BP4 code. If BP4 is met for lack of splice effect, BP7 can be applied to silent or intronic variants where the PhyloP score is ≤0.2." }, { "baseStrength": "Benign", "id": "1743943306", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943306", "label": "BP3", "strengthDescriptor": "Supporting", "text": "BP3 can be applied to the 8x GXEEX AA repeat motif in the 5’ end of VHL p30 (AA14-AA48). Otherwise, the rest of the coding regions in VHL do not contain repeats (and none contain LINE/SINE, low complexity or other repeat types as identified by RepeatMasker) and BP3 is not applicable." }, { "baseStrength": "Pathogenic", "id": "1743943293", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943293", "label": "PM6", "strengthDescriptor": "Moderate", "text": "See PS2 evidence code for scoring and phenotypes. Assumed _de novo_ receives half the points as compared to maternity and paternity confirmed _de novo_. If paternity and maternity are not confirmed, score as the PM6 code. PM6 can receive “VeryStrong” strength. For example, if there are >4 de novo probands with Danish Criteria and none have paternity confirmed, this can receive PM6\\_VeryStrong. Note: the VCI as of Nov 2022 does not allow PM6\\_VeryStrong. Instead apply the PS2 evidence code and increase the strength to “VeryStrong” with a note that paternity and/or maternity is not confirmed." }, { "baseStrength": "Benign", "id": "1743943305", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943305", "label": "BP2", "strengthDescriptor": "Strong", "text": "i) -variant observed in trans with a known pathogenic variant (phase confirmed), in the absence of congenital polycythemia (clinical manifestations or molecular)\n\nii) -OR observed in the homozygous state in an individual without personal &/or family history of Von Hippel-Lindau disease or congenital polycythemia\n\niii) -OR observed _in cis_ or with unknown phase with three or more different pathogenic _VHL_ variants" }, { "baseStrength": "Benign", "id": "1743943305", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943305", "label": "BP2", "strengthDescriptor": "Supporting", "text": "\\-variant is observed _in cis_ (or phase is unknown) w/ a pathogenic _VHL_ variant" }, { "baseStrength": "Benign", "id": "1743943304", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943304", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This rule code does not apply to this gene, as truncating variants account for only a portion of disease-causing variants." }, { "baseStrength": "Benign", "id": "1743943304", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943304", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: This rule code does not apply to this gene, as truncating variants account for only a portion of disease-causing variants." }, { "baseStrength": "Benign", "id": "1743943304", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943304", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: This rule code does not apply to this gene, as truncating variants account for only a portion of disease-causing variants." }, { "baseStrength": "Benign", "id": "1743943304", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943304", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: This rule code does not apply to this gene, as truncating variants account for only a portion of disease-causing variants." }, { "baseStrength": "Benign", "id": "1743943303", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943303", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation is seen in affected members of ≥2 families" }, { "baseStrength": "Benign", "id": "1743943303", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943303", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Lack of segregation is seen in 1 family." }, { "baseStrength": "Pathogenic", "id": "1743943298", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943298", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1743943298", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943298", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1743943298", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943298", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1743943298", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943298", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1743943296", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943296", "label": "PP3", "strengthDescriptor": "Supporting", "text": "For missense variants, use REVEL score >=0.664. \n\nFor splice variants, concordance of Splice AI (>0.5) and VarSeak (class 4 or class 5)." }, { "baseStrength": "Pathogenic", "id": "1743943291", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943291", "label": "PM4", "strengthDescriptor": "Moderate", "text": "In-frame insertion / deletions in the B and alpha domains and stop-loss variants adding significant additional amino acids to VHL [15](#pmid_20560986) cites multiple pathogenic cases and experimental evidence of stop loss extensions in VHL that are associated with Type 2A VHL disease).  The functional domains are: Beta (β) domain (AA 63 - 155, Nuclear Export), Alpha (ɑ) domain (AA 156-192, Elongin C binding), and Second Beta (β) domain (AA 193-204). \n\nPM4 does not apply to in-frame indels prior to codon 54 that do not alter the Met54 VHL p19 codon and beyond." }, { "baseStrength": "Pathogenic", "id": "1743943289", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943289", "label": "PM2", "strengthDescriptor": "Supporting", "text": "PM2\\_Supporting can be applied for variants either absent from gnomAD or with \\<= 0.00000156 (0.000156%) GroupMax Filtering Allele Frequency in gnomAD (based on gnomAD v4 release). If no GroupMax Filtering Allele Frequency is calculated (ex. due to a single variant present), PM2\\_Supporting may also be applied." }, { "baseStrength": "Pathogenic", "id": "1743943287", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943287", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "**16+ points the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.**" }, { "baseStrength": "Pathogenic", "id": "1743943287", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943287", "label": "PS4", "strengthDescriptor": "Strong", "text": "**5-15 points the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.**" }, { "baseStrength": "Pathogenic", "id": "1743943287", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943287", "label": "PS4", "strengthDescriptor": "Moderate", "text": "**2 – 4 points the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.**" }, { "baseStrength": "Pathogenic", "id": "1743943287", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943287", "label": "PS4", "strengthDescriptor": "Supporting", "text": "**1 point the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.**" }, { "baseStrength": "Pathogenic", "id": "1743943284", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943284", "label": "PS1", "strengthDescriptor": "Strong", "text": "Applied only to variants with interpretation by the VHL VCEP or by a variant with pathogenicity established using VHL VCEP specifications." }, { "baseStrength": "Pathogenic", "id": "1743943297", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943297", "label": "PP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Combine with PS4 to avoid double counting probands. " }, { "baseStrength": "Pathogenic", "id": "1743943297", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943297", "label": "PP4", "strengthDescriptor": "Strong", "text": "Not Applicable: Combine with PS4 to avoid double counting probands. " }, { "baseStrength": "Pathogenic", "id": "1743943297", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943297", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Combine with PS4 to avoid double counting probands. " }, { "baseStrength": "Pathogenic", "id": "1743943297", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943297", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Combine with PS4 to avoid double counting probands. " }, { "baseStrength": "Pathogenic", "id": "1743943288", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943288", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Putative missense variants that are known germline hotspots AND/OR in key functional domains AND/OR somatic variants that have ≥10 instances for the same AA in cancerhotspots.org. See the table of Germline and Somatic Hotspots." }, { "baseStrength": "Pathogenic", "id": "1743943288", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943288", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Putative missense variants seen in somatic databases, having \\<10 instances for the same AA in cancerhotspots.org. See the table of Germline and Somatic Hotspots." }, { "baseStrength": "Pathogenic", "id": "1743943285", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943285", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "A single proband cannot be very strong evidence, but multiple probands can be combined to reach very strong (4+ points)." }, { "baseStrength": "Pathogenic", "id": "1743943285", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943285", "label": "PS2", "strengthDescriptor": "Strong", "text": "Phenotype highly specific for the gene (Danish Criteria) (≥2 but less than 4 _de novo_ points)." }, { "baseStrength": "Pathogenic", "id": "1743943285", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943285", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Phenotype consistent but not highly specific. Ex. VHL spectrum cancer without family history or strong indication of VHL phenotype. (≥1 but less than 2 _de novo_ points)" }, { "baseStrength": "Pathogenic", "id": "1743943285", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943285", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Phenotype consistent but not highly specific (≥0.5 but less than 1 _de novo_ points) Ex. subject included in a VHL cohort, but specific information on tumor types is not provided." }, { "baseStrength": "Pathogenic", "id": "1743943283", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943283", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "**LINK TO PVS1 DECISION TREE DOCUMENT:** [**https://drive.google.com/file/d/1mGfChgxbGVbzYn6Ggmb9rYvoGGah25ll/view?usp=sharing**](https://drive.google.com/file/d/1mGfChgxbGVbzYn6Ggmb9rYvoGGah25ll/view?usp=sharing)\n\n**Do not apply PVS1 for truncations that occur prior to Codon 54 (including frameshift events that start and end prior to Codon 54 but the truncation extends beyond Codon 54.)**\n\n**Note1: Exon presence in biologically relevant transcripts:** In some transcripts exon 2 of _VHL_ is skipped and expressed at low levels. The function of this transcript is not fully known. Exon 2 comprises almost the entirety of the nuclear export function region of the Beta domain and is critical for known VHL function. Exon 1 contains the only initiator codons in _VHL_. Exon 3 contains the elongin binding function. _**All exons should be considered as \"present in biologically relevant transcripts\" in the PVS1 decision tree.**_\n\n**Note 2: The 10% PVS1 downgrade to Moderate cannot apply to VHL** because of the small size.\n\n**Nonsense Mediated Decay** [5](#pmid_22825683) [4](#pmid_20145706)  **NMD experimental evidence in 1st exon after codon 54 and to 5' region of 2nd exon (codon 138)**.\\*\\*\n\n**Critical Domains:**\n\n1st Beta (β) domain (63-154), especially Nuclear Export (114-155)\n\nAlpha (ɑ) domain (155-192), especially Elongin C binding (157 - 172)\n\nSecond Beta domain (193-204)   \n\n_Truncating variants after Met54 and predicted to undergo NMD (from AA55-AA136/c.408) or in the beta or alpha domains can receive PVS1, and those outside the second Beta domain (205-213) can receive PVS1\\_Moderate downgrade to account for minimal loss of VHL protein. Notably a frame shift deletion at 205 is pathogenic in ClinVar (ID 18971) as are stop loss extension variants in the last codons (see PM4)._\n\n**SPLICE: If any canonical exon is skipped, the variant receives PVS1.** If a cryptic splice disrupts the reading frame, and is in a critical domain (AA63-AA204) or is predicted to undergo NMD (AA55-AA136) it receives PVS1. If it is outside a critical domain and predicted to undergo NMD (AA55-62), it receives PVS1\\_Strong (the second site outside of critical domains AA205-213 is not predicted to undergo NMD). If a cryptic splice does not alter the reading frame, and is in a critical domain (AA 63-204), it can receive PVS1\\_Strong, and if it is outside the critical domain (AA 205-213) or  in an NMD prediction (AA 55-62), it receives PVS1\\_Moderate. Note:  There is a cryptic exon (E1) in intron 1 [7](#pmid_31996412) [6](#pmid_29891534), and silent variants in exon 2 that are reported to cause skipping of exon 1. If there is functional evidence of exon skipping (RNA splice assay) then PVS1 can apply. Do not double count evidence. Ex. PVS1 should be used in place of PS3 functional evidence confirming splice alteration, but PS3 evidence code could still apply to other relevant assays confirming effect on HIF1/2a presence etc. \n\n**EXON DELETION:** SVI PVS1 decision tree modified for whole exon deletions. There are only 3 exons in _VHL_ and each has an important functional domain. Any exon deletion of _VHL_ receives PVS1. \n\n**EXON DUPLICATION:** Follow PVS1 decision tree. Note: few pathogenic exon duplications are reported in ClinVar.   (ID:417571, ID:584137). These have no literature cited. \n\n**INITIATION CODON:** VHL Met 1 (in VHL p30) truncation or missense would not affect VHL p19, as VHL has a second start at codon 54 (VHL p19), it cannot be scored in the PVS1 decision tree. After that, no other viable alternative starts are known. Start loss at codon 54 would presumably result in an impact, as VHL p30 and p19 would be truncated prior to any known functional domains (PVS1). Ong 2007 has 1 family (2 subjects) with Met54X and reports cerebellar hemangioblastomas. There is no functional study in the paper for this variant. Olschwang et al 1998 VHL Type 2A, one subject with 161insT (FS result). There is no functional study in the paper. Missense at Met 54 (VHL p19 initiation codon) would presumably not result in as strong an impact as the full length VHL p30 would still be produced (PVS1 decision tree = N/A). ClinVar has M54T (ID:819688) and M54L (ID:843990). M54T is uncertain, with no other evidence provided. M54L references M54I which segregates in homozygous state with erythrocytosis in individuals of Moroccan descent [9](#pmid_26224408) [8](#pmid_27578599), and those heterozygous for M54I did not present VHL phenotype [9](#pmid_26224408)." }, { "baseStrength": "Benign", "id": "1743943309", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943309", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1743943309", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943309", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1743943309", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943309", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1743943309", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943309", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1743943307", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943307", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Due to the lack of benign variants, and the drop in classification accuracy for benign VHL variants, missense predictors should not be used to assign the BP4 evidence code. \n\nBP4 can be applied to assess lack of splicing impact, with concordance of Splice AI (≤0.1) and VarSeak (Class 1 or Class 2)." }, { "baseStrength": "Benign", "id": "1743943302", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943302", "label": "BS3", "strengthDescriptor": "Supporting", "text": "• HIF 1/2a assay replicates WT function and/or\n\n• VBC complex stability is not affected and/or \n\n• ECM formation/fibronectin binding is unaffected \n\nThis rule can be used and weighted as appropriate for functional tests of variants prior to codon 54 (which show the VHL19 product is not impacted). Evidence of benign effect for VHL Type 1 and 2A/B can be seen when HIF1/2a displays degradation (i.e. replicates WT function), and/or the VHL Elongin C, Elongin B, Cullin2 RBX1 (VCB-CR) E3 ubiquitin ligase complex stability is not affected and/or ECM formation/fibronectin binding is unaffected. Note: VHL Type 2C variants typically do not affect HIF1/2a; absence of HIF1/2a alone when testing a suspected VHL Type 2C variant should not be used for BS3. Functional studies of fibronectin and ECM formation are needed for VHL Type 2C. Follow modified SVI guidance for functional assays, general controls and benign controls. For splicing variants (and intronic/synonymous), RNA assays must demonstrate no impact on splicing." }, { "baseStrength": "Benign", "id": "1743943301", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943301", "label": "BS2", "strengthDescriptor": "Strong", "text": "VHL is not highly penetrant _at an early age._ BS2 can be applied if: There are at least 3 individuals, all >=65yo, unaffected, harboring the same variant, _**with full phenotyping and screening**_ for the absence of VHL-related cancers." }, { "baseStrength": "Benign", "id": "1743943301", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943301", "label": "BS2", "strengthDescriptor": "Supporting", "text": "VHL is not highly penetrant _at an early age._ BS2\\_Supporting can be applied if: At least 3 individuals, all >=65yo, unaffected, harboring the same variant, _**lacking full phenotyping and screening**_, with no noted VHL-related cancers" }, { "baseStrength": "Benign", "id": "1743943300", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943300", "label": "BS1", "strengthDescriptor": "Strong", "text": "Use BS1 cut off of  >=0.0000156 (0.00156%) GroupMax Filtering Allele Frequency in gnomAD (based on gnomAD v4)." }, { "baseStrength": "Pathogenic", "id": "1743943290", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943290", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Autosomal dominant." }, { "baseStrength": "Pathogenic", "id": "1743943290", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943290", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: Autosomal dominant." }, { "baseStrength": "Pathogenic", "id": "1743943290", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943290", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Autosomal dominant." }, { "baseStrength": "Pathogenic", "id": "1743943290", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943290", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Autosomal dominant." }, { "baseStrength": "Pathogenic", "id": "1743943286", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943286", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Acceptable assays that display functional effect in VHL are the following:  \n\n• HIF 1/2a degradation assays -- HIF1/2a is not degraded and/or \n\n• VBC complex stability is affected and/or\n\n• Pathogenicity supported by abnormal ECM formation and impaired fibronectin binding [1](#pmid_9651579) , [2](#pmid_11331613) , [3](#pmid_11358843) , [17](#pmid_14706840)\n\nMultiple studies and publications confirm the role of VHL in HIF1/2a regulation and VBC complex stability for VHL Type 1, and 2A/B, as well as fibronectin binding/deposition and assays evaluating extra-cellular matrix composition. In-vitro assays should display total loss of HIF1/2a degradation (i.e. HIF1/2a presence) for VHL Type 1, and 2A/B.  VHL Type 2C should display presence of HIF1/2a (with VBC complex stability variably affected and fibronectin deposition/extra cellular matrix composition affected). These assays are typically performed in Renal Cell Carcinoma (RCC) cells lacking VHL, introducing normal pVHL as a control in addition to a variant-VHL, then comparing HIF1/2a levels to WT pVHL. Brnich et al proposed 10 controls to achieve PS3\\_Supporting and 11 for PS3\\_Moderate [10](#pmid_31892348). We propose to _follow the workflow outlined in Brnich et al._  Type 2C VHL variants are typically missense variants in the alpha domain of VHL, and do not usually affect HIF1/2a. If HIF1/2a maintains presence and VHL Type 2C is suspected, assays evaluating fibronectin deposition or extracellular matrix assembly should be used. \n\n**SPLICING:** **PS3:** RNA transcripts carrying splicing mutation display splicing defects in patient cells. **PS3\\_Moderate**: RNA transcripts carrying splicing mutation display splicing defects in in-vivo or in-vitro assays.   **Functional Assay Documentation** : [https://drive.google.com/file/d/1w8P8zs1fHUolaAYmBL1jw-vcjsX3N_yh/view?usp=sharing](https://drive.google.com/file/d/1w8P8zs1fHUolaAYmBL1jw-vcjsX3N_yh/view?usp=sharing)" }, { "baseStrength": "Benign", "id": "1743943308", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943308", "label": "BP5", "strengthDescriptor": "Supporting", "text": "BP5 can be applied for two or more co-occurrences with pathogenic variants in a different gene that fully explained the patient's phenotype, but specific circumstances would need to be met in order for a case to be considered for inclusion. First, the variant in the other gene must be considered highly penetrant, with both the individual's age, tumour type and gender taken into consideration. Additionally, the patient's personal and family history (including up to 2nd degree relatives) should not overlap with features seen in VHL and VHL tumour histologies. As an example, an individual with a personal and family history of pheochromocytoma who harbored a _VHL_ variant in addition to a pathogenic SDHB variant BP5 would not apply, because pheochromocytoma is a known risk in VHL and the _VHL_ variant might have contributed to this individual's pheochromocytoma cancer risk. However, an individual with a personal and family history of chromophobic RCC who was positive for a _VHL_ variant as well as a pathogenic FLCN variant would be considered for BP5 application, as non-clear cell RCC is not associated with VHL disease." }, { "baseStrength": "Benign", "id": "1743943299", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943299", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Use a BA1 cut off of >=0.000156 (0.0156%) GroupMax Filtering Allele Frequency in gnomAD (based on gnomAD v4 release)." }, { "baseStrength": "Pathogenic", "id": "1743943295", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943295", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Do not use. While there are known pathogenic missense in VHL, there is also evidence of benign or common missense in VHL. gnomAD shows VHL is not intolerant to missense (Z score = -0.39). Missense variants in VHL will need to achieve pathogenic interpretation via other evidence codes." }, { "baseStrength": "Pathogenic", "id": "1743943295", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943295", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Do not use. While there are known pathogenic missense in VHL, there is also evidence of benign or common missense in VHL. gnomAD shows VHL is not intolerant to missense (Z score = -0.39). Missense variants in VHL will need to achieve pathogenic interpretation via other evidence codes." }, { "baseStrength": "Pathogenic", "id": "1743943295", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943295", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Do not use. While there are known pathogenic missense in VHL, there is also evidence of benign or common missense in VHL. gnomAD shows VHL is not intolerant to missense (Z score = -0.39). Missense variants in VHL will need to achieve pathogenic interpretation via other evidence codes." }, { "baseStrength": "Pathogenic", "id": "1743943295", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943295", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Do not use. While there are known pathogenic missense in VHL, there is also evidence of benign or common missense in VHL. gnomAD shows VHL is not intolerant to missense (Z score = -0.39). Missense variants in VHL will need to achieve pathogenic interpretation via other evidence codes." }, { "baseStrength": "Pathogenic", "id": "1743943294", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943294", "label": "PP1", "strengthDescriptor": "Strong", "text": "\\>7 meioses across >=2 families" }, { "baseStrength": "Pathogenic", "id": "1743943294", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943294", "label": "PP1", "strengthDescriptor": "Moderate", "text": "5 – 6 meioses across ≥1 family." }, { "baseStrength": "Pathogenic", "id": "1743943294", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943294", "label": "PP1", "strengthDescriptor": "Supporting", "text": "3 – 4 meioses across ≥1 family." }, { "baseStrength": "Pathogenic", "id": "1743943292", "iri": "https://genboree.org/cspec/CriteriaCode/id/1743943292", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Pathogenicity of prior variant is established by interpretation of the VHL VCEP or variants with pathogenicity established using VHL VCEP specifications. The Grantham distance should be used to compare variants. The variant under consideration must be equal or a larger distance than the classified pathogenic variant (Grantham, 1974, Table 2 [16](#pmid_4843792) ). Splice metapredictors should be used to ensure the variant is not predicted to have an effect on splicing." } ], "diseases": [], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467863504", "label": "VHL" } ], "ruleSet": { "id": "1527855768", "iri": "https://genboree.org/cspec/RuleSet/id/1527855768" }, "svi": { "id": "GN078", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1527855755", "label": "ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.0.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1620363716", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363716", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620363716", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363716", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620363716", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363716", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620363716", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363716", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620363713", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363713", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Proband must meet hemophilia B phenotype criteria AND have full gene sequencing and deletion/duplication analysis." }, { "baseStrength": "Pathogenic", "id": "1620363699", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363699", "label": "PS1", "strengthDescriptor": "Strong", "text": "This evidence code can be applied when there is 1 pathogenic variant or 2 likely pathogenic variants at the same residue based on _F9_ gene rule specifications from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect." }, { "baseStrength": "Pathogenic", "id": "1620363699", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363699", "label": "PS1", "strengthDescriptor": "Moderate", "text": "This evidence code can be applied when there is 1 likely pathogenic variants at the same residue based on _F9_ gene rule specifications from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect." }, { "baseStrength": "Benign", "id": "1620363694", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363694", "label": "BS3", "strengthDescriptor": "Strong", "text": "This code can be used for _F9_ gene variants studied in a cell line or mouse model setting that confer a normal factor IX activity AND normal factor IX antigen levels **OR** normal Western Blot." }, { "baseStrength": "Benign", "id": "1620363690", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363690", "label": "BS1", "strengthDescriptor": "Strong", "text": "MAF cutoff of greater than or equal to 0.00000556 (or 0.000556%)." }, { "baseStrength": "Pathogenic", "id": "1620363715", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363715", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Variant must be absent in males in population databases, such as gnomAD." }, { "baseStrength": "Benign", "id": "1620363712", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363712", "label": "BP7", "strengthDescriptor": "Supporting", "text": "Splicing prediction score of less than or equal to 0.01 is required. Conservation should be assess using PhyloP (cutoff less than 0.1) and PhastCons (cutoff less than 0.5)." }, { "baseStrength": "Pathogenic", "id": "1620363701", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363701", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Use the SVI recommendations for de novo cases; 4 points. Use de novo guidance below to determine point value." }, { "baseStrength": "Pathogenic", "id": "1620363701", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363701", "label": "PS2", "strengthDescriptor": "Strong", "text": "Use the SVI recommendations for de novo cases; 2 points. Use de novo guidance below to determine point value." }, { "baseStrength": "Pathogenic", "id": "1620363701", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363701", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Use the SVI recommendations for de novo cases; 1 point. Use de novo guidance below to determine point value." }, { "baseStrength": "Pathogenic", "id": "1620363701", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363701", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Use the SVI recommendations for de novo cases; 0.5 point. Use de novo guidance below to determine point value." }, { "baseStrength": "Benign", "id": "1620363692", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363692", "label": "BS2", "strengthDescriptor": "Strong", "text": "This evidence code can be used when a _F9_ variant is observed in a male with a normal factor IX activity level (\\<40% IU)." }, { "baseStrength": "Pathogenic", "id": "1620363691", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363691", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for the F9 gene." }, { "baseStrength": "Pathogenic", "id": "1620363691", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363691", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for the F9 gene." }, { "baseStrength": "Pathogenic", "id": "1620363691", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363691", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for the F9 gene." }, { "baseStrength": "Pathogenic", "id": "1620363691", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363691", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for the F9 gene." }, { "baseStrength": "Pathogenic", "id": "1620363710", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363710", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for F9." }, { "baseStrength": "Pathogenic", "id": "1620363710", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363710", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for F9." }, { "baseStrength": "Pathogenic", "id": "1620363710", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363710", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for F9." }, { "baseStrength": "Pathogenic", "id": "1620363710", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363710", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for F9." }, { "baseStrength": "Benign", "id": "1620363708", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363708", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This rule code is not recommended for use at this time. There is no known alternate cause of isolated factor IX deficiency." }, { "baseStrength": "Benign", "id": "1620363708", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363708", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This rule code is not recommended for use at this time. There is no known alternate cause of isolated factor IX deficiency." }, { "baseStrength": "Benign", "id": "1620363708", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363708", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This rule code is not recommended for use at this time. There is no known alternate cause of isolated factor IX deficiency." }, { "baseStrength": "Benign", "id": "1620363708", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363708", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This rule code is not recommended for use at this time. There is no known alternate cause of isolated factor IX deficiency." }, { "baseStrength": "Pathogenic", "id": "1620363703", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363703", "label": "PS3", "strengthDescriptor": "Strong", "text": "Abnormal factor IX activity level (\\<40 IU/dL or 40%) in a cell line and/or mouse model." }, { "baseStrength": "Pathogenic", "id": "1620363703", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363703", "label": "PS3", "strengthDescriptor": "Moderate", "text": "Abnormal factor IX activity level (\\<40 IU/dL or 40%) studied in an animal model setting other than mouse (i.e. – bovine factor IX activity levels compared to factor X levels)." }, { "baseStrength": "Pathogenic", "id": "1620363703", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363703", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Absent or significantly reduced factor IX antigen level compared to wildtype using conformation-specific reporter assay in cell lines." }, { "baseStrength": "Benign", "id": "1620363700", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363700", "label": "BP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not being used at this time. There are reports of males with hemophilia having two suspicious pathogenic variants." }, { "baseStrength": "Benign", "id": "1620363700", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363700", "label": "BP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Not being used at this time. There are reports of males with hemophilia having two suspicious pathogenic variants." }, { "baseStrength": "Benign", "id": "1620363700", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363700", "label": "BP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not being used at this time. There are reports of males with hemophilia having two suspicious pathogenic variants." }, { "baseStrength": "Benign", "id": "1620363700", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363700", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not being used at this time. There are reports of males with hemophilia having two suspicious pathogenic variants." }, { "baseStrength": "Benign", "id": "1620363696", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363696", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for F9 gene." }, { "baseStrength": "Benign", "id": "1620363696", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363696", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for F9 gene." }, { "baseStrength": "Benign", "id": "1620363696", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363696", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for F9 gene." }, { "baseStrength": "Benign", "id": "1620363696", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363696", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for F9 gene." }, { "baseStrength": "Benign", "id": "1620363709", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363709", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "MAF cutoff of greater than or equal to 0.0000556 (or 0.00556%)." }, { "baseStrength": "Pathogenic", "id": "1620363707", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363707", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree." }, { "baseStrength": "Pathogenic", "id": "1620363707", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363707", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree." }, { "baseStrength": "Pathogenic", "id": "1620363707", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363707", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree." }, { "baseStrength": "Pathogenic", "id": "1620363707", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363707", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree." }, { "baseStrength": "Pathogenic", "id": "1620363705", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363705", "label": "PP1", "strengthDescriptor": "Strong", "text": "This code is applicable when there ≥4 meioses across ≥2 families." }, { "baseStrength": "Pathogenic", "id": "1620363705", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363705", "label": "PP1", "strengthDescriptor": "Moderate", "text": "This code is applicable when there are at least 3 meioses across one or more families." }, { "baseStrength": "Pathogenic", "id": "1620363705", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363705", "label": "PP1", "strengthDescriptor": "Supporting", "text": "This code is applicable when there 2 meioses in one family **OR** 1 meiosis between 2 affected siblings." }, { "baseStrength": "Benign", "id": "1620363704", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363704", "label": "BP4", "strengthDescriptor": "Supporting", "text": "This code can be applied for variants reaching a REVEL score of 0.3 or below AND a Splice AI score of less than or equal to 0.01." }, { "baseStrength": "Benign", "id": "1620363702", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363702", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for F9 gene." }, { "baseStrength": "Benign", "id": "1620363702", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363702", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for F9 gene." }, { "baseStrength": "Benign", "id": "1620363702", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363702", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for F9 gene." }, { "baseStrength": "Benign", "id": "1620363702", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363702", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for F9 gene." }, { "baseStrength": "Pathogenic", "id": "1620363717", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363717", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620363717", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363717", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620363717", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363717", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620363717", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363717", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620363714", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363714", "label": "PM1", "strengthDescriptor": "Strong", "text": "This code can be used for variants affecting any of the 3 catalytic residues (H267, D315 or S411) and 2 activation residues (R191-A192 and R226-V227) in the _F9_ gene (PMID: 12554099)." }, { "baseStrength": "Pathogenic", "id": "1620363714", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363714", "label": "PM1", "strengthDescriptor": "Moderate", "text": "This code should be applied when the variant is within exons 3, 4 or 5." }, { "baseStrength": "Pathogenic", "id": "1620363711", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363711", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Code can be applied for variants where the REVEL score is greater than or equal to 0.6 or a SpliceAI score of greater than or equal to 0.5." }, { "baseStrength": "Pathogenic", "id": "1620363706", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363706", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "≥8 probands meet criteria described below" }, { "baseStrength": "Pathogenic", "id": "1620363706", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363706", "label": "PS4", "strengthDescriptor": "Strong", "text": "4-7 probands meet criteria described below" }, { "baseStrength": "Pathogenic", "id": "1620363706", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363706", "label": "PS4", "strengthDescriptor": "Moderate", "text": "2-3 probands meet criteria described below" }, { "baseStrength": "Pathogenic", "id": "1620363706", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363706", "label": "PS4", "strengthDescriptor": "Supporting", "text": "1 proband meets criteria described below" }, { "baseStrength": "Pathogenic", "id": "1620363698", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363698", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This rule code is combined with PS2. Please combined assumed de novo cases with confirmed de novo cases and apply PS2 at the appropriate weight." }, { "baseStrength": "Pathogenic", "id": "1620363698", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363698", "label": "PM6", "strengthDescriptor": "Strong", "text": "Not Applicable: This rule code is combined with PS2. Please combined assumed de novo cases with confirmed de novo cases and apply PS2 at the appropriate weight." }, { "baseStrength": "Pathogenic", "id": "1620363698", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363698", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This rule code is combined with PS2. Please combined assumed de novo cases with confirmed de novo cases and apply PS2 at the appropriate weight." }, { "baseStrength": "Pathogenic", "id": "1620363698", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363698", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This rule code is combined with PS2. Please combined assumed de novo cases with confirmed de novo cases and apply PS2 at the appropriate weight." }, { "baseStrength": "Benign", "id": "1620363697", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363697", "label": "BS4", "strengthDescriptor": "Strong", "text": "This evidence code can be used when a _F9_ variant is observed in a male with a family history of hemophilia B and has a normal factor IX activity level." }, { "baseStrength": "Pathogenic", "id": "1620363695", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363695", "label": "PM5", "strengthDescriptor": "Moderate", "text": "This evidence code can be applied when there is 1 pathogenic variant or 2 likely pathogenic variants at the same residue based on _F9_ rule specification from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect." }, { "baseStrength": "Pathogenic", "id": "1620363695", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363695", "label": "PM5", "strengthDescriptor": "Supporting", "text": "This evidence code can be applied when there is 1 likely pathogenic variant at the same residue based on _F9_ rule specifications Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect. A “highly suspicious” VUS is defined as a variant that is 1 supporting code away from reaching a likely pathogenic classification." }, { "baseStrength": "Pathogenic", "id": "1620363693", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620363693", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Use code with no specification." } ], "diseases": [ { "id": "MONDO:0010604", "iri": "https://genboree.org/cspec/Disease/id/467893780", "label": "hemophilia B" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467825577", "label": "F9" } ], "ruleSet": { "id": "1527859065", "iri": "https://genboree.org/cspec/RuleSet/id/1527859065" }, "svi": { "id": "GN080", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1527859052", "label": "ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "1611900920", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900920", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Use code for variants with a popmax MAF of \\<0.00002 in gnomAD." }, { "baseStrength": "Benign", "id": "1611900914", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900914", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Appropriate to use for variants with a popmax MAF of greater than or equal to 0.002 in gnomAD." }, { "baseStrength": "Benign", "id": "1611900899", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900899", "label": "BS3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: There are no available assays or model organisms that can recapitulate disease, and in vitro studies cannot dependably rule out pathogenicity." }, { "baseStrength": "Benign", "id": "1611900899", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900899", "label": "BS3", "strengthDescriptor": "Strong", "text": "Not Applicable: There are no available assays or model organisms that can recapitulate disease, and in vitro studies cannot dependably rule out pathogenicity." }, { "baseStrength": "Benign", "id": "1611900899", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900899", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Not Applicable: There are no available assays or model organisms that can recapitulate disease, and in vitro studies cannot dependably rule out pathogenicity." }, { "baseStrength": "Benign", "id": "1611900899", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900899", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Not Applicable: There are no available assays or model organisms that can recapitulate disease, and in vitro studies cannot dependably rule out pathogenicity." }, { "baseStrength": "Benign", "id": "1611900897", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900897", "label": "BS2", "strengthDescriptor": "Strong", "text": "This evidence code is available when the variant is identified in 2 or more heterozygotes or 1 or more homozygotes with normal antithrombin levels \\[> 0.8 IU/mL (or above the lower limit of a laboratory’s assays reference range)\\]." }, { "baseStrength": "Benign", "id": "1611900897", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900897", "label": "BS2", "strengthDescriptor": "Supporting", "text": "This evidence code is available when the variant is identified in 1 heterozygote with normal antithrombin levels \\[> 0.8 IU/mL (or above the lower limit of a laboratory’s assays reference range)\\]." }, { "baseStrength": "Benign", "id": "1611900921", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900921", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1611900921", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900921", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1611900921", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900921", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1611900921", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900921", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1611900916", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900916", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Appropriate to use for missense variants that have a REVEL score of greater or equal to 0.6. For potential splicing variants, use of 2 independent _in silico_ splicing tools must predict a damaging impact." }, { "baseStrength": "Pathogenic", "id": "1611900904", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900904", "label": "PS1", "strengthDescriptor": "Strong", "text": "Use with no specification except comparison variant must be classified as pathogenic using _SERPINC1_ rule specifications from the Thrombosis VCEP." }, { "baseStrength": "Pathogenic", "id": "1611900904", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900904", "label": "PS1", "strengthDescriptor": "Moderate", "text": "Use with no specification except comparison variant must be classified as likely pathogenic using _SERPINC1_ rule specifications from the Thrombosis VCEP." }, { "baseStrength": "Pathogenic", "id": "1611900900", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900900", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Use code when previously reported variant reaches a pathogenic classification using the _SERPINC1_ rule specifications from the Thrombosis VCEP." }, { "baseStrength": "Pathogenic", "id": "1611900900", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900900", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Use code when previously reported variant reaches a likely pathogenic classification using the _SERPINC1_ rule specifications from the Thrombosis VCEP." }, { "baseStrength": "Benign", "id": "1611900895", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900895", "label": "BS1", "strengthDescriptor": "Strong", "text": "Appropriate to use for variants with a Popmax MAF of >0.0002 in gnomAD." }, { "baseStrength": "Pathogenic", "id": "1611900922", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900922", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1611900922", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900922", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1611900922", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900922", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1611900922", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900922", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1611900917", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900917", "label": "BP7", "strengthDescriptor": "Supporting", "text": "Use tools VarSEAK and Splice AI to rule out a predicted splicing effect. Evolutionary conservation is defined as a PhyloP \\< 0.1 **OR** the reference nucleotide is present in 3 mammals or 1 primate." }, { "baseStrength": "Benign", "id": "1611900913", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900913", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This rule code is not recommended for use at this time. There are other genes that can be associated with decreased antithrombin activity levels, such as genes associated with the congenital disorders of glycosylation." }, { "baseStrength": "Benign", "id": "1611900913", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900913", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This rule code is not recommended for use at this time. There are other genes that can be associated with decreased antithrombin activity levels, such as genes associated with the congenital disorders of glycosylation." }, { "baseStrength": "Benign", "id": "1611900913", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900913", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This rule code is not recommended for use at this time. There are other genes that can be associated with decreased antithrombin activity levels, such as genes associated with the congenital disorders of glycosylation." }, { "baseStrength": "Benign", "id": "1611900913", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900913", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This rule code is not recommended for use at this time. There are other genes that can be associated with decreased antithrombin activity levels, such as genes associated with the congenital disorders of glycosylation." }, { "baseStrength": "Pathogenic", "id": "1611900906", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900906", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 4 points." }, { "baseStrength": "Pathogenic", "id": "1611900906", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900906", "label": "PS2", "strengthDescriptor": "Strong", "text": "Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 2 points." }, { "baseStrength": "Pathogenic", "id": "1611900906", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900906", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 1 point." }, { "baseStrength": "Pathogenic", "id": "1611900906", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900906", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 0.5 point." }, { "baseStrength": "Benign", "id": "1611900905", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900905", "label": "BP2", "strengthDescriptor": "Supporting", "text": "This rule can be applied when a _SERPINC1_ variant is _in cis_ with another pathogenic _SERPINC1_ variant. The pathogenic variant must be evaluated using ClinGen _SERPINC1_ specified rules. This rule cannot be applied to a variant _in trans_ with a pathogenic variant, as this scenario could reasonably occur and increase the risk of venous thrombosis." }, { "baseStrength": "Pathogenic", "id": "1611900915", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900915", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable due to presence of benign variation throughout the SERPINC1 gene. " }, { "baseStrength": "Pathogenic", "id": "1611900915", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900915", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable due to presence of benign variation throughout the SERPINC1 gene. " }, { "baseStrength": "Pathogenic", "id": "1611900915", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900915", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable due to presence of benign variation throughout the SERPINC1 gene. " }, { "baseStrength": "Pathogenic", "id": "1611900915", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900915", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable due to presence of benign variation throughout the SERPINC1 gene. " }, { "baseStrength": "Pathogenic", "id": "1611900912", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900912", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Use decision tree as per SVI WG with specified “regions critical to protein function”." }, { "baseStrength": "Pathogenic", "id": "1611900912", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900912", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Use decision tree as per SVI WG with specified “regions critical to protein function”." }, { "baseStrength": "Pathogenic", "id": "1611900912", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900912", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Use decision tree as per SVI WG with specified “regions critical to protein function”." }, { "baseStrength": "Pathogenic", "id": "1611900912", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900912", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "Use decision tree as per SVI WG with specified “regions critical to protein function”." }, { "baseStrength": "Pathogenic", "id": "1611900910", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900910", "label": "PP1", "strengthDescriptor": "Strong", "text": "Appropriate to use there are 7 or more meioses across more than one family." }, { "baseStrength": "Pathogenic", "id": "1611900910", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900910", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Appropriate to use there are 4-6 meioses across one or more families." }, { "baseStrength": "Pathogenic", "id": "1611900910", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900910", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Appropriate to use when there are 2-3 meioses across one or more families." }, { "baseStrength": "Benign", "id": "1611900909", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900909", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Use this code for missense variants with a REVEL score of \\< 0.30 and no evidence of a potential splicing effect using VarSEAK and Splice AI prediction tools, or for non-canonical intronic variants with no evidence of a potential splicing effect using VarSEAK and Splice AI prediction tools." }, { "baseStrength": "Benign", "id": "1611900907", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900907", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: ​​There are no known repetitive regions in the SERPINC1 gene without a known function. " }, { "baseStrength": "Benign", "id": "1611900907", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900907", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: ​​There are no known repetitive regions in the SERPINC1 gene without a known function. " }, { "baseStrength": "Benign", "id": "1611900907", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900907", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: ​​There are no known repetitive regions in the SERPINC1 gene without a known function. " }, { "baseStrength": "Benign", "id": "1611900907", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900907", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: ​​There are no known repetitive regions in the SERPINC1 gene without a known function. " }, { "baseStrength": "Pathogenic", "id": "1611900903", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900903", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Use the PS2 code in lieu of using this code for de novo variants." }, { "baseStrength": "Pathogenic", "id": "1611900903", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900903", "label": "PM6", "strengthDescriptor": "Strong", "text": "Not Applicable: Use the PS2 code in lieu of using this code for de novo variants." }, { "baseStrength": "Pathogenic", "id": "1611900903", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900903", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Not Applicable: Use the PS2 code in lieu of using this code for de novo variants." }, { "baseStrength": "Pathogenic", "id": "1611900903", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900903", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Not Applicable: Use the PS2 code in lieu of using this code for de novo variants." }, { "baseStrength": "Benign", "id": "1611900901", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900901", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This rule code does not apply to the SERPINC1 gene, as missense and truncating variants account for disease.\n" }, { "baseStrength": "Benign", "id": "1611900901", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900901", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: This rule code does not apply to the SERPINC1 gene, as missense and truncating variants account for disease.\n" }, { "baseStrength": "Benign", "id": "1611900901", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900901", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: This rule code does not apply to the SERPINC1 gene, as missense and truncating variants account for disease.\n" }, { "baseStrength": "Benign", "id": "1611900901", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900901", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: This rule code does not apply to the SERPINC1 gene, as missense and truncating variants account for disease.\n" }, { "baseStrength": "Pathogenic", "id": "1611900896", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900896", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Variants in this gene are being curated as a dominant condition, so this rule code does not apply." }, { "baseStrength": "Pathogenic", "id": "1611900896", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900896", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: Variants in this gene are being curated as a dominant condition, so this rule code does not apply." }, { "baseStrength": "Pathogenic", "id": "1611900896", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900896", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Variants in this gene are being curated as a dominant condition, so this rule code does not apply." }, { "baseStrength": "Pathogenic", "id": "1611900896", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900896", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Variants in this gene are being curated as a dominant condition, so this rule code does not apply." }, { "baseStrength": "Pathogenic", "id": "1611900919", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900919", "label": "PM1", "strengthDescriptor": "Moderate", "text": "This code is applicable for variants disrupting cystine residues involved in disulfide bridges (Cys40, Cys53, Cys127, Cys160, Cys279, Cys462)1, variants that would impact heparin binding site residues (Ile39, Arg56, Pro73, Arg79) and variants involving reactive site residues (Ala414 and Ala416)2." }, { "baseStrength": "Pathogenic", "id": "1611900918", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900918", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Proband must have an antithrombin activity level of \\< 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range). confirmed on repeated independent samples. An abnormal crossed immunoelectrophoresis assay demonstrating decreased antithrombin function may be used in lieu of low activity levels, which is typically caused by type II variants." }, { "baseStrength": "Pathogenic", "id": "1611900911", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900911", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Appropriate to use code when there 8 or more proband points that meet the defined antithrombin deficiency laboratory phenotype." }, { "baseStrength": "Pathogenic", "id": "1611900911", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900911", "label": "PS4", "strengthDescriptor": "Strong", "text": "Appropriate to use code when there 4-7 proband points that meet the defined antithrombin deficiency laboratory phenotype." }, { "baseStrength": "Pathogenic", "id": "1611900911", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900911", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Appropriate to use code when there 2-3 proband points that meet the defined antithrombin deficiency laboratory phenotype." }, { "baseStrength": "Pathogenic", "id": "1611900911", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900911", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Appropriate to use code when there is 1 proband point that meets the defined antithrombin deficiency laboratory phenotype." }, { "baseStrength": "Pathogenic", "id": "1611900908", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900908", "label": "PS3", "strengthDescriptor": "Supporting", "text": "See attached spreadsheet for list of approved assays to use for this rule code. Below is a general description of assays that can be used:\n\n - _In vitro_ functional studies in COS-1, HEK293T, HEK-EBNA cells demonstrating abnormal activity levels:\n\n* Antithrombin activity levels measured by FXa inhibition activity assay\n* Antithrombin activity levels measured by thrombin inhibition activity assay\n\nOR\n\n\\- _In vitro_ functional studies in COS-1, HEK293T, HEK-EBNA cells demonstrating abnormal antigen levels:\n\n* Antithrombin antigen levels measured by ELISA\n * Immunofluorescence assay – intracellular retention and secretion defects\n\nOR\n\n\\- _In vivo_ studies demonstrating rescue of antithrombin levels would be considered, but no studies are       known to be available at this time." }, { "baseStrength": "Benign", "id": "1611900902", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900902", "label": "BS4", "strengthDescriptor": "Strong", "text": "Appropriate to use when the variant is found not to segregate in a minimum of four relatives with abnormal antithrombin activity levels \\[\\< 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range)\\] within the same family, **OR** the variant does not segregate in 2 or more families. Non-segregation defined by having abnormal antithrombin activity levels without _SERPINC1_ variant of interest." }, { "baseStrength": "Benign", "id": "1611900902", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900902", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Appropriate to use when the variant is found not to segregate in a minimum of two relatives with abnormal antithrombin activity levels \\[\\< 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range)\\] within the same family." }, { "baseStrength": "Pathogenic", "id": "1611900898", "iri": "https://genboree.org/cspec/CriteriaCode/id/1611900898", "label": "PM4", "strengthDescriptor": "Moderate", "text": "No specification" } ], "diseases": [ { "id": "MONDO:0013144", "iri": "https://genboree.org/cspec/Disease/id/467885201", "label": "hereditary antithrombin deficiency" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467855776", "label": "SERPINC1" } ], "ruleSet": { "id": "1528074035", "iri": "https://genboree.org/cspec/RuleSet/id/1528074035" }, "svi": { "id": "GN084", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1528074022", "label": "ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1533887512", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887512", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1533887512", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887512", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1533887512", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887512", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1533887512", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887512", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1533887510", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887510", "label": "BS3", "strengthDescriptor": "Strong", "text": "Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing." }, { "baseStrength": "Benign", "id": "1533887510", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887510", "label": "BS3", "strengthDescriptor": "Supporting", "text": "List of approved functional studies and guidelines for interpretation of data.\n\n* EMSA for DNA binding \n * “No functional impact” is defined as ≥75% activity of wildtype \n * Note: the effect of the variant on DNA binding will be highly dependent on whether the variant is located within the DNA binding domain.\n* Luciferase assays for transactivation \n * “No functional impact” is defined as ≥75% activity of wildtype \n * Note: this threshold is not 100% specific for transactivation (TA) activity and is complicated by the fact that TA activity will vary depend on many factors, for instance cell line that is used (HeLa, INS, MIN6 etc). Assays should include controls for WT, T2DM and known MODY variants.\n* Western blotting and indirect immunofluorescence for protein expression (specifically levels and nuclear and cytoplasmic localization, respectively).   \n * Determining appropriate thresholds for protein expression is more difficult due to variability in results due to the complexity of the technique.  Sample preparations, gel loading, transfer efficiency, specificity of the antibody, choice of internal control and inaccurate detection and quantification are some of the factors that can contribute to varying and inconsistent results. If a difference in protein expression compared to WT is seen by immunoblotting, then further testing by quantitative PCR (qPCR) is recommended in order to measure the mRNA level and assess whether the difference in amount of protein is due to a reduced mRNA level." }, { "baseStrength": "Pathogenic", "id": "1533887506", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887506", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Phenotype: MODY Probability Calculator result ≥50% chance of testing positive[6](#url_187f5e4a-1941-5c2d-9c9f-1dc999cc5454) AND negative _HNF1A_ testing AND presence of at least one additional feature characteristic of \\__HNF4A_\\_-MODY:   \n\n* Antibody negative and/or persistent C-peptide after five years following T1DM diagnosis  \n* Personal or family history of persistent neonatal hypoglycemia  \n* Personal or family history of large for gestational age (LGA) infants or macrosomia in the absence of sufficient maternal hyperglycemia \n* Response to low-dose SU (extreme response- hypoglycemia) \n* Biochemical/Molecular phenotypic evidence from patient cell lines \n* Fanconi phenotype in conjunction with c.187C>T p.R63W" }, { "baseStrength": "Pathogenic", "id": "1533887506", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887506", "label": "PP4", "strengthDescriptor": "Supporting", "text": "MODY Probability Calculator (MPC)6 result ≥50% chance of testing positive AND negative _HNF1A_ testing" }, { "baseStrength": "Pathogenic", "id": "1533887502", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887502", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Subsumed by PS2." }, { "baseStrength": "Pathogenic", "id": "1533887502", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887502", "label": "PM6", "strengthDescriptor": "Strong", "text": "Not Applicable: Subsumed by PS2." }, { "baseStrength": "Pathogenic", "id": "1533887502", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887502", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Not Applicable: Subsumed by PS2." }, { "baseStrength": "Pathogenic", "id": "1533887502", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887502", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Not Applicable: Subsumed by PS2." }, { "baseStrength": "Pathogenic", "id": "1533887499", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887499", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1533887499", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887499", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1533887499", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887499", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1533887499", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887499", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1533887497", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887497", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Applicable to amino acids that directly bind DNA and are necessary for Zinc-finger or homodimer formation[2](#pmid_18829458) \n\n* Directly bind DNA: Asp43, His49, Tyr 50, Gly51, Asp56, Gly57, Lys59, Arg63, Arg64, Arg67, His70, Tyr72, Arg87, Asn88, Arg91, Arg94, Gln109, Arg112   \n* Homodimer: Arg75, Gln89, Glu111, Asp113 \n* Zinc finger: Cys38, Cys41, Cys55, Cys58, Cys74, Cys80, Cys90, Cys93" }, { "baseStrength": "Pathogenic", "id": "1533887497", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887497", "label": "PM1", "strengthDescriptor": "Supporting", "text": "This criterion can be used for missense variants in well-conserved regions within the DNA and ligand-binding domains. It can also be used for variants within certain transcription factor binding sites in the promoter (see below for details).\n\n* Promoter region: \n * c.-132 to c.-151 (HNF6/OC2 and IPF1 binding sites) \n * c.-169 to c.-181 (HNF1A/HNF1B binding sites)\n* DNA binding: \n * codons 37-113 (NM\\_175914.4:c.175C-339C p.Leu37-Asp113) (While the paper describing the crystal structure of _HNF4A_[2](#pmid_18829458) shows the sequence as amino acids 33-113, amino acids 33-36 do not bind DNA and the conserved sequence starts as Leu37.)\n* Ligand binding: \n * codons 180-220 and 300-350  \n * (NM\\_175914.4:c.538G-658G p.Ala180-Val220) \n * (NM\\_175914.4:c.898T-1048G p.Tyr300-Glu350)" }, { "baseStrength": "Pathogenic", "id": "1533887494", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887494", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions." }, { "baseStrength": "Pathogenic", "id": "1533887494", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887494", "label": "PS2", "strengthDescriptor": "Strong", "text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions." }, { "baseStrength": "Pathogenic", "id": "1533887494", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887494", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions." }, { "baseStrength": "Pathogenic", "id": "1533887494", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887494", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions." }, { "baseStrength": "Benign", "id": "1533887515", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887515", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2[3](#pmid_30661751),[4](#pmid_32123317)." }, { "baseStrength": "Benign", "id": "1533887511", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887511", "label": "BS4", "strengthDescriptor": "Strong", "text": "Applicable to family members without variant who have MPC6 score ≥50% (i.e., genotype negative, phenotype positive)." }, { "baseStrength": "Benign", "id": "1533887507", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887507", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "gnomAD 2.1.1\\* Popmax Filtering AF ≥ 1:10,000 (≥ 0.01% or 0.0001).\n\n\\*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used." }, { "baseStrength": "Pathogenic", "id": "1533887504", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887504", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: While missense variants in HNF4A are a common mechanism of monogenic diabetes, and the constraint score for HNF4A (gene) is 1.81, the MDEP does not support using this criterion at this time. " }, { "baseStrength": "Pathogenic", "id": "1533887504", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887504", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: While missense variants in HNF4A are a common mechanism of monogenic diabetes, and the constraint score for HNF4A (gene) is 1.81, the MDEP does not support using this criterion at this time. " }, { "baseStrength": "Pathogenic", "id": "1533887504", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887504", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: While missense variants in HNF4A are a common mechanism of monogenic diabetes, and the constraint score for HNF4A (gene) is 1.81, the MDEP does not support using this criterion at this time. " }, { "baseStrength": "Pathogenic", "id": "1533887504", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887504", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: While missense variants in HNF4A are a common mechanism of monogenic diabetes, and the constraint score for HNF4A (gene) is 1.81, the MDEP does not support using this criterion at this time. " }, { "baseStrength": "Pathogenic", "id": "1533887496", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887496", "label": "PS4", "strengthDescriptor": "Strong", "text": "7 (seven) or more unrelated occurrences = Strong. Variant should meet PM2\\_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region).  Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology.\n\n* One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD)[7](#pmid_21395678),[8](#pmid_28701371),[9](#pmid_30409810),[10](#pmid_31704690) \n* Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (\\<200pmol/L or 0.6ng/mL)[11](#pmid_30225972),[12](#pmid_23771925) or urinary C-peptide/creatinine ratio \\<0.2 nmol/mmol[8](#pmid_28701371),[9](#pmid_30409810)" }, { "baseStrength": "Pathogenic", "id": "1533887496", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887496", "label": "PS4", "strengthDescriptor": "Moderate", "text": "4-6 unrelated occurrences = Moderate. Variant should meet PM2\\_Supporting in order to use PS4 at any level. Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology.\n\n* One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD)[7](#pmid_21395678),[8](#pmid_28701371),[9](#pmid_30409810),[10](#pmid_31704690)\n* Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (\\<200pmol/L or 0.6ng/mL)[11](#pmid_30225972),[12](#pmid_23771925) or urinary C-peptide/creatinine ratio \\<0.2 nmol/mmol[8](#pmid_28701371),[9](#pmid_30409810)" }, { "baseStrength": "Pathogenic", "id": "1533887492", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887492", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Use _HNF4A_ PVS1 decision tree.\n\n* Variants generating PTCs in exon 10 and last 55 nucleotides of exon 9 (c.1162-1216) are not expected to cause NMD[1](#pmid_24274751)\n * The most 3’ nonsense or frameshift variant is c.1256C>G, p.S419X in the last exon. This variant has been classified as Pathogenic by the MDEP.  There are six other nonsense and frameshift variants in exon 10, none of which have case information and are all currently classified as VUS. The collective evidence supports applying PVS1 for variants at codon 419 (c.1257) and 5’ and PVS1\\_Supporting for variants at c.1258 (G)/p.Gly420 and 3’.\n* “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”\n * Exons 1, 2 (LRG 4), 3 (LRG 5), 4 (LRG 6), 6 (LRG 8): deletion or skipping causes frameshift: PVS1 \n * Exons 5 (LRG 7), 7 (LRG 9), 8 (LRG 10), 9 (LRG 11) - deletion or skipping causes in-frame deletion, 52/52/79/51-79 AA deleted, that is >10 % of the protein in each case - PVS1\\_Strong  \n * Exon 10 (LRG 12) - 46 AA, contains the transactivation domain, includes stop loss - PVS1\\_Strong" }, { "baseStrength": "Pathogenic", "id": "1533887492", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887492", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Use _HNF4A_ PVS1 decision tree.\n\n* “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” \n * Exons 5 (LRG 7), 7 (LRG 9), 8 (LRG 10), 9 (LRG 11) - deletion or skipping causes in-frame deletion, 52/52/79/51-79 AA deleted, that is >10 % of the protein in each case - PVS1\\_Strong  \n * Exon 10 (LRG 12) - 46 AA, contains the transactivation domain, includes stop loss - PVS1\\_Strong\n* Apply PVS1\\_Strong to initiation codon variants.  MDEP has classified two start codon variants as likely pathogenic (c.3G>A: PM2\\_Supporting + PP4\\_Moderate + PP1\\_Strong + PVS1\\_Moderate (c.1delA); c.1delA: PM2\\_Supporting + PP1 + PP4\\_Moderate + PVS1\\_Moderate) and there are multiple P/LP variants before the next methionine, p.Met71." }, { "baseStrength": "Pathogenic", "id": "1533887492", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887492", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "Use _HNF4A_ PVS1 decision tree.\n\nApply PVS1\\_Supporting to nonsense or frameshift variants at c.1258 (G)/p.Gly420 and 3’." }, { "baseStrength": "Benign", "id": "1533887514", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887514", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1533887514", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887514", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1533887514", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887514", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1533887514", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887514", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1533887513", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887513", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Also applicable when in cis or trans with a likely pathogenic variant." }, { "baseStrength": "Benign", "id": "1533887508", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887508", "label": "BS1", "strengthDescriptor": "Strong", "text": "gnomAD 2.1.1\\* Popmax Filtering AF  ≥ 1:30,000 (≥0.0033% or 0.000033).\n\n\\*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used." }, { "baseStrength": "Pathogenic", "id": "1533887503", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887503", "label": "PP1", "strengthDescriptor": "Strong", "text": "Use thresholds suggested by Jarvik and Browning[5](#pmid_27236918)\n\n* Single Family : ≤ 1/32 (5 meioses)\n* \\> 1 Family : ≤ 1/16 (4 meioses)" }, { "baseStrength": "Pathogenic", "id": "1533887503", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887503", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Use thresholds suggested by Jarvik and Browning[5](#pmid_27236918)\n\n* Single Family : ≤ 1/16 (4 meioses)\n* \\> 1 Family : ≤ 1/8 (3 meioses)" }, { "baseStrength": "Pathogenic", "id": "1533887503", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887503", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Use thresholds suggested by Jarvik and Browning[5](#pmid_27236918)\n\n* Single Family : ≤ 1/8 (3 meioses)\n* \\> 1 Family : ≤ ¼ (2 meioses)" }, { "baseStrength": "Pathogenic", "id": "1533887500", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887500", "label": "PM4", "strengthDescriptor": "Moderate", "text": "For single amino acid deletions, use as supporting level of evidence." }, { "baseStrength": "Pathogenic", "id": "1533887500", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887500", "label": "PM4", "strengthDescriptor": "Supporting", "text": "For single amino acid deletions/insertions, use as supporting level of evidence" }, { "baseStrength": "Pathogenic", "id": "1533887495", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887495", "label": "PS3", "strengthDescriptor": "Strong", "text": "Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing." }, { "baseStrength": "Pathogenic", "id": "1533887495", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887495", "label": "PS3", "strengthDescriptor": "Supporting", "text": "List of approved functional studies and guidelines for interpretation:\n\n* EMSA for DNA binding\n * “Decreased function” is defined as activity less than 60% of wildtype \n * Note: the effect of the variant on DNA binding will be highly dependent on whether the variant is located within the DNA binding domain.\n* Luciferase assays for transactivation \n * “Decreased function” is defined as activity less than 60% of wildtype  \n * Note: this threshold is not 100% specific for transactivation (TA) activity and is complicated by the fact that TA activity will vary depend on many factors, for instance cell line that is used (HeLa, INS, MIN6 etc).\n* Western blotting and indirect immunofluorescence for protein expression (specifically levels and nuclear and cytoplasmic localization, respectively).\n * Determining appropriate thresholds for protein expression is more difficult due to variability in results due to the complexity of the technique.  Sample preparations, gel loading, transfer efficiency, specificity of the antibody, choice of internal control and inaccurate detection and quantification are some of the factors that can contribute to varying and inconsistent results. If a reduction in protein expression is seen by immunoblotting, then further testing by quantitative PCR (qPCR) is recommended in order to measure the mRNA level and assess whether a reduction in amount of protein is due to a reduced mRNA level.\n* To use PS3\\_Supporting, functional study must have been performed on a transfected variant.  If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus wild-type allele) does not count as PS3\\_Supporting." }, { "baseStrength": "Pathogenic", "id": "1533887501", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887501", "label": "PM5", "strengthDescriptor": "Strong", "text": "Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue." }, { "baseStrength": "Pathogenic", "id": "1533887501", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887501", "label": "PM5", "strengthDescriptor": "Moderate", "text": "The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant." }, { "baseStrength": "Pathogenic", "id": "1533887501", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887501", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance than the novel variant." }, { "baseStrength": "Pathogenic", "id": "1533887498", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887498", "label": "PM2", "strengthDescriptor": "Supporting", "text": "gnomAD 2.1.1\\* Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in gnomAD European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population.\n\n\\*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used." }, { "baseStrength": "Pathogenic", "id": "1533887519", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887519", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1533887519", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887519", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1533887519", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887519", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1533887519", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887519", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1533887518", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887518", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1533887518", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887518", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1533887518", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887518", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1533887518", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887518", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1533887517", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887517", "label": "BP7", "strengthDescriptor": "Supporting", "text": "Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way \\< 2.0." }, { "baseStrength": "Benign", "id": "1533887516", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887516", "label": "BP5", "strengthDescriptor": "Supporting", "text": "A variant in another monogenic diabetes gene is Pathogenic/Likely Pathogenic." }, { "baseStrength": "Benign", "id": "1533887509", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887509", "label": "BS2", "strengthDescriptor": "Strong", "text": "Apply to normoglycemic individuals age 70 or older (i.e., genotype positive, phenotype negative)" }, { "baseStrength": "Pathogenic", "id": "1533887505", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887505", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is at least 0.2 [4](#pmid_32123317),[3](#pmid_30661751)." }, { "baseStrength": "Pathogenic", "id": "1533887493", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887493", "label": "PS1", "strengthDescriptor": "Strong", "text": "No change" }, { "baseStrength": "Pathogenic", "id": "1533887493", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533887493", "label": "PS1", "strengthDescriptor": "Supporting", "text": "PS1 may also be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact." } ], "diseases": [ { "id": "MONDO:0015967", "iri": "https://genboree.org/cspec/Disease/id/467884025", "label": "monogenic diabetes" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467829602", "label": "HNF4A" } ], "ruleSet": { "id": "1528338164", "iri": "https://genboree.org/cspec/RuleSet/id/1528338164" }, "svi": { "id": "GN085", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1528338151", "label": "ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF4A Version 2.0.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1533888302", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888302", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2[9](#pmid_32123317),[10](#pmid_30661751)." }, { "baseStrength": "Benign", "id": "1533888297", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888297", "label": "BS3", "strengthDescriptor": "Strong", "text": "Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing (see BP4)." }, { "baseStrength": "Benign", "id": "1533888297", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888297", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Use GCK PS3 decision tree, which incorporates the relative activity index (RAI), relative stability index (RSI) and assays that measure the impact of variants on binding with GKRP and GKA.\n\nEvidence of no impact on function:\n\n* Normal RAI (>0.5) + normal RSI (>0.5) + normal inhibition/activation with GKRP/GKA = BS3\\_Supporting \n* Normal RAI (>0.5) + normal RSI (>0.5) but no studies investigating GKRP/GKA = Cannot use PS3 or BS3\n\nGloyn, et al. 2005 [5](#pmid_15677479); Beer, et al. 2012 [6](#pmid_22611063); Raimondo, et al. 2014 [7](#pmid_25015100); Gloyn, et al. (2004)12." }, { "baseStrength": "Pathogenic", "id": "1533888287", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888287", "label": "PM4", "strengthDescriptor": "Moderate", "text": "For single amino acid deletions, use as supporting level of evidence." }, { "baseStrength": "Pathogenic", "id": "1533888287", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888287", "label": "PM4", "strengthDescriptor": "Supporting", "text": "For single amino acid deletions/insertions, use as supporting level of evidence" }, { "baseStrength": "Pathogenic", "id": "1533888282", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888282", "label": "PS3", "strengthDescriptor": "Strong", "text": "Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing." }, { "baseStrength": "Pathogenic", "id": "1533888282", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888282", "label": "PS3", "strengthDescriptor": "Moderate", "text": "See list of approved functional studies and guidelines for interpretation of data." }, { "baseStrength": "Pathogenic", "id": "1533888282", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888282", "label": "PS3", "strengthDescriptor": "Supporting", "text": "See list of approved functional studies and guidelines for interpretation of data (below)." }, { "baseStrength": "Pathogenic", "id": "1533888279", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888279", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": " Use _GCK_ PVS1 decision tree created based on PVS1 decision tree from ClinGen SVI group[1](#pmid_30096381)\n\n* Variants generating PTCs 3’ of c.1198 (p.Asp400) of NM\\_000162.3, which includes the last 55 nucleotides of exon 9 and exon 10, are not expected to cause NMD[2](#pmid_24274751). The α13 helix (p.444-456), located at the C-end of the protein, has a critical role in GCK conformational change upon glucose binding.  Individuals with PTCs in exon 10 have a MODY phenotype. Therefore, a “very strong” level of evidence will be applied for PTCs in exon 10.\n* “Exon skipping or  “use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” \n * single exon deletions \n * deletion of exon 1 is in-frame but over 20 families with GCK-MODY phenotype and exon 1 deletion (some also have promoter deletions) --> PVS1 \n * deletions of single **exons 2,3,6 and 7** cause frameshift --> **PVS1** \n * deletions or skipping of **exons 8 and 9** are in-frame and the proportion is >10 % (52 AA and 78 AA, respectively) --> **PVS1** \n * deletions or skipping of **exons 4 and 5** are in-frame and the proportion is \\<10 % (40 AA and 32 AA, respectively). Exon 4 (p.122-161) and exon 5 (p.162-193) contain each a part of the active site that binds glucose /p.151-180[3](#pmid_23957911) according to Beck et al., Biochemistry 2013/ --> **PVS1** \n * deletion of exon 10 (47 AA) – There are a number of patients with a GCK-MODY phenotype with reported with missense, frameshift, PTC, splice acceptor, and stop loss variants in exon 10  --> **PVS1**\n* Apply PVS1\\_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1\\_Supporting + PM2\\_Supporting; one case submitted, dx.53 and no other info provided to lab).  The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. \n* Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1." }, { "baseStrength": "Pathogenic", "id": "1533888279", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888279", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Use _GCK_ PVS1 decision tree.\n\nPer the SVI standard PVS1 decision tree, apply PVS1\\_Strong to duplications ≥ 1 exon in size, contained completely within gene, proven not in tandem, reading frame presumed disrupted, and NMD predicted to occur." }, { "baseStrength": "Pathogenic", "id": "1533888279", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888279", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "Use _GCK_ PVS1 decision tree.\n\n* Apply PVS1\\_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1\\_Supporting + PM2\\_Supporting; one case submitted, dx.53 and no other info provided to lab).  The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. \n* Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1." }, { "baseStrength": "Pathogenic", "id": "1533888306", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888306", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1533888306", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888306", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1533888306", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888306", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1533888306", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888306", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1533888303", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888303", "label": "BP5", "strengthDescriptor": "Supporting", "text": "A variant in another monogenic diabetes gene is P/LP." }, { "baseStrength": "Benign", "id": "1533888301", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888301", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1533888301", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888301", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1533888301", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888301", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1533888301", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888301", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1533888295", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888295", "label": "BS1", "strengthDescriptor": "Strong", "text": "gnomAD 2.1.1\\* Popmax Filtering AF ≥ 1:25,000 (0.004% or 0.00004).\n\n\\*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used." }, { "baseStrength": "Pathogenic", "id": "1533888293", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888293", "label": "PP4", "strengthDescriptor": "Moderate", "text": "HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL) AND presence of any of the following additional features:\n\n* PP4 phenotype found in pediatric patient (prepubertal or \\<10 years) (incidentally) AND \n * Not treated with insulin AND antibody negative \n * OR treated with insulin, antibody negative, and detectable C-peptide (> 0.6ng/mL) after 3 years\n* Multiple values (= persistent)—multiple levels (>=2 counts) or well-documented persistent impaired fasting glucose (IFG) \n* OGTT with minimal increment \\<3 mmol/l (54 mg/dl) \n* Antibody negative \n* Macrosomia in normoglycemic offspring of hyperglycemic gestational parent\n* Low birthweight in hyperglycemic offspring of hyperglycemic gestational parent. \n* Three-generation, dominant family history of diabetes or hyperglycemia (in a family not used for PP1)" }, { "baseStrength": "Pathogenic", "id": "1533888293", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888293", "label": "PP4", "strengthDescriptor": "Supporting", "text": "HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL)" }, { "baseStrength": "Pathogenic", "id": "1533888284", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888284", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Applicable for glucose- and ATP-binding sites (see attached chart)." }, { "baseStrength": "Benign", "id": "1533888300", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888300", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Also applicable when in cis or trans with a likely pathogenic variant." }, { "baseStrength": "Benign", "id": "1533888296", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888296", "label": "BS2", "strengthDescriptor": "Strong", "text": "We expect to see hyperglycemia at birth in an individual with \\_GCK\\_-MODY and therefore consider an individual unaffected if euglycemic in childhood or adulthood.  Since individuals typically do not present with symptoms of diabetes, evidence that someone is “nondiabetic” is insufficient; fasting glucose must be tested and found to be within normal limits (\\<100 mg/dl / 5.6 mmol/L)." }, { "baseStrength": "Benign", "id": "1533888294", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888294", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "gnomAD 2.1.1\\* Popmax Filtering AF ≥ 1:10,000 (≥ 0.01% or 0.0001).\n\n\\*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used." }, { "baseStrength": "Pathogenic", "id": "1533888292", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888292", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is at least 0.2[9](#pmid_32123317),[10](#pmid_30661751)" }, { "baseStrength": "Pathogenic", "id": "1533888289", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888289", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Subsumed in PS2." }, { "baseStrength": "Pathogenic", "id": "1533888289", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888289", "label": "PM6", "strengthDescriptor": "Strong", "text": "Not Applicable: Subsumed in PS2." }, { "baseStrength": "Pathogenic", "id": "1533888289", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888289", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Not Applicable: Subsumed in PS2." }, { "baseStrength": "Pathogenic", "id": "1533888289", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888289", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Not Applicable: Subsumed in PS2." }, { "baseStrength": "Pathogenic", "id": "1533888280", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888280", "label": "PS1", "strengthDescriptor": "Strong", "text": "No change" }, { "baseStrength": "Pathogenic", "id": "1533888280", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888280", "label": "PS1", "strengthDescriptor": "Supporting", "text": "PS1 may be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact." }, { "baseStrength": "Benign", "id": "1533888305", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888305", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1533888305", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888305", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1533888305", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888305", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1533888305", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888305", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1533888304", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888304", "label": "BP7", "strengthDescriptor": "Supporting", "text": "Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way \\< 2.0." }, { "baseStrength": "Benign", "id": "1533888298", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888298", "label": "BS4", "strengthDescriptor": "Strong", "text": "Applicable to family members without variant who meet PP4 criteria (HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL))" }, { "baseStrength": "Pathogenic", "id": "1533888291", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888291", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Apply to all missense variants in GCK. gnomAD missense constraint score for _GCK_ is 3.07 (observed/expected= 0.5), which is significant." }, { "baseStrength": "Pathogenic", "id": "1533888290", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888290", "label": "PP1", "strengthDescriptor": "Strong", "text": "Use thresholds suggested by Jarvik and Browning[8](#pmid_27236918)\n\n* Single Family : ≤ 1/32 (5 meioses)\n* \\>1 Family : ≤ 1/16 (4 meioses)" }, { "baseStrength": "Pathogenic", "id": "1533888290", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888290", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Use thresholds suggested by Jarvik and Browning[8](#pmid_27236918)\n\n* Single Family : ≤ 1/16 (4 meioses)\n* \\>1 Family : ≤ 1/8 (3 meioses)" }, { "baseStrength": "Pathogenic", "id": "1533888290", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888290", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Use thresholds suggested by Jarvik and Browning[8](#pmid_27236918)\n\n* Single Family : ≤ 1/8 (3 meioses)\n* \\>1 Family : ≤ ¼ (2 meioses)" }, { "baseStrength": "Pathogenic", "id": "1533888286", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888286", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Use SVI-recommended point-based system." }, { "baseStrength": "Pathogenic", "id": "1533888286", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888286", "label": "PM3", "strengthDescriptor": "Strong", "text": "Use SVI-recommended point-based system." }, { "baseStrength": "Pathogenic", "id": "1533888286", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888286", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Use SVI-recommended point-based system." }, { "baseStrength": "Pathogenic", "id": "1533888286", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888286", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Use SVI-recommended point-based system." }, { "baseStrength": "Pathogenic", "id": "1533888285", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888285", "label": "PM2", "strengthDescriptor": "Supporting", "text": "gnomAD 2.1.1\\* Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population.\n\n\\*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used." }, { "baseStrength": "Pathogenic", "id": "1533888283", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888283", "label": "PS4", "strengthDescriptor": "Strong", "text": "7 or more occurrences in unrelated individuals = Strong." }, { "baseStrength": "Pathogenic", "id": "1533888283", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888283", "label": "PS4", "strengthDescriptor": "Moderate", "text": "4-6 occurrences in unrelated individuals = Moderate." }, { "baseStrength": "Pathogenic", "id": "1533888281", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888281", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions. \n." }, { "baseStrength": "Pathogenic", "id": "1533888281", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888281", "label": "PS2", "strengthDescriptor": "Strong", "text": "Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions." }, { "baseStrength": "Pathogenic", "id": "1533888281", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888281", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions." }, { "baseStrength": "Pathogenic", "id": "1533888281", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888281", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions." }, { "baseStrength": "Benign", "id": "1533888299", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888299", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1533888299", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888299", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1533888299", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888299", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1533888299", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888299", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1533888288", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888288", "label": "PM5", "strengthDescriptor": "Strong", "text": "Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue." }, { "baseStrength": "Pathogenic", "id": "1533888288", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888288", "label": "PM5", "strengthDescriptor": "Moderate", "text": "The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant." }, { "baseStrength": "Pathogenic", "id": "1533888288", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533888288", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance." } ], "diseases": [ { "id": "MONDO:0015967", "iri": "https://genboree.org/cspec/Disease/id/467884025", "label": "monogenic diabetes" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467827496", "label": "GCK" } ], "ruleSet": { "id": "1528339124", "iri": "https://genboree.org/cspec/RuleSet/id/1528339124" }, "svi": { "id": "GN086", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1528339111", "label": "ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.3.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1553527160", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527160", "label": "BP4", "strengthDescriptor": "Supporting", "text": "**Missense variants:** BP4 is not applicable.\n\n**Synonymous (silent) or intronic variants**: Multiple in silico splicing predictors suggest no impact on gene or gene product." }, { "baseStrength": "Pathogenic", "id": "1553527150", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527150", "label": "PP3", "strengthDescriptor": "Supporting", "text": "**Missense variants:** Do not use computational prediction models for conservation, evolution, etc. _In silico_ splicing predictors should be used for presumed missense variants to reveal possible splicing effects.\n\n**Non-canonical splicing variants:** Multiple _in silico_ splicing predictors support a deleterious effect." }, { "baseStrength": "Benign", "id": "1553527138", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527138", "label": "BS3", "strengthDescriptor": "Strong", "text": "**RNA assay** of a synonymous or intronic variant in constitutional patient sample demonstrates no mRNA aberration\n\n**AND**\n\nbiallelic expression is shown and/or nonsense-mediated decay inhibition was used." }, { "baseStrength": "Benign", "id": "1553527138", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527138", "label": "BS3", "strengthDescriptor": "Supporting", "text": "**RNA assay** of a synonymous or intronic variant in constitutional patient sample demonstrates no mRNA aberration, without demonstration of biallelic expression or use of nonsense-mediated decay inhibition\n\n**OR**\n\n**Protein assay** show retention of β-catenin regulated transcription activity comparable to wild-type (only for variants within the β-catenin binding domain, which refers to codons 959-2129 of _APC_, see PMID: 33348689)" }, { "baseStrength": "Pathogenic", "id": "1553527137", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527137", "label": "PM5", "strengthDescriptor": "Moderate", "text": "The reported missense variant was determined to be Pathogenic according to the APC-specific modifications.\n\nThere are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other different missense variants at these positions meet PM5\\_supporting. No missense variant has been classified as Pathogenic based on current evidence. \n\nGrantham´s distance of the variant under assessment must have an equal or higher score than the reported variant \\[Reference 3\\]." }, { "baseStrength": "Pathogenic", "id": "1553527137", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527137", "label": "PM5", "strengthDescriptor": "Supporting", "text": "The reported missense variant was determined to be Likely Pathogenic according to the APC-specific modifications.\n\nThere are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other different missense variants at these positions meet PM5\\_supporting. No missense variant has been classified as Pathogenic based on current evidence. \n\nGrantham´s distance of the variant under assessment must have an equal or higher score than the reported variant \\[Reference 3\\]." }, { "baseStrength": "Pathogenic", "id": "1553527134", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527134", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Rare in controls, defined by an allele frequency ≤ 0.0003% (0.000003) if the allele count is > 1 OR by an allele frequency \\< 0.001% (0.00001) if the allele count is ≤ 1." }, { "baseStrength": "Benign", "id": "1553527152", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527152", "label": "BS1", "strengthDescriptor": "Strong", "text": "GnomAD Popmax Filtering Allele Frequency (AF) **≥ 0.001%** (0.00001)." }, { "baseStrength": "Pathogenic", "id": "1553527151", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527151", "label": "PS3", "strengthDescriptor": "Very Strong", "text": "**RNA assays** show\n\n1. a premature stop codon \n OR\n2. inframe skipping of exon 13 or 14\n\n**AND** the absence of full-length transcript." }, { "baseStrength": "Pathogenic", "id": "1553527151", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527151", "label": "PS3", "strengthDescriptor": "Strong", "text": "**RNA assays** show\n\n1. a premature stop codon \n **OR**\n2. inframe skipping of exon 13 or 14\n\n**AND** \\< 10% of full-length transcript." }, { "baseStrength": "Pathogenic", "id": "1553527151", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527151", "label": "PS3", "strengthDescriptor": "Moderate", "text": "**RNA assays** show \n\n1. a premature stop codon AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides \n **OR**\n2. inframe skipping of exon 13 or 14 AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides \n **OR**\n3. other inframe skipping AND absent or \\< 10% full-length transcript." }, { "baseStrength": "Pathogenic", "id": "1553527151", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527151", "label": "PS3", "strengthDescriptor": "Supporting", "text": "**RNA assays** show \n\n1. inframe skipping of exons other than exon 13 or 14 AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides \n **OR**\n2. over-expression of an alternative transcript (exons 10, 11 or 15)\n\n**Protein assays** show\n\nIncreased β-catenin regulated transcription activity and/or decreased binding to β-catenin by surface plasmon resonance (only for variants within the β-catenin binding domain, which refers to codons 959-2129 of _APC_) \\[Reference 2\\]." }, { "baseStrength": "Pathogenic", "id": "1553527148", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527148", "label": "PM6", "strengthDescriptor": "Strong", "text": "2-3.5 _de novo_ scores. For curation of _de novo_ score see **Tables 1** and **2**." }, { "baseStrength": "Pathogenic", "id": "1553527148", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527148", "label": "PM6", "strengthDescriptor": "Moderate", "text": "1-1.5 _de novo_ scores. For curation of _de novo_ score see **Tables 1** and **2**." }, { "baseStrength": "Pathogenic", "id": "1553527148", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527148", "label": "PM6", "strengthDescriptor": "Supporting", "text": "0.5 _de novo_ scores. For curation of _de novo_ score see **Tables 1** and **2**." }, { "baseStrength": "Pathogenic", "id": "1553527141", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527141", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1553527141", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527141", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1553527141", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527141", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1553527141", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527141", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1553527139", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527139", "label": "BS4", "strengthDescriptor": "Strong", "text": "Affected member without the variant must score at least 1 phenotype point or at least two affected members without the variant must each score at least 0.5 phenotype points (see **Table 1**)." }, { "baseStrength": "Benign", "id": "1553527139", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527139", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Affected member without the variant must score at least 0.5 phenotype points (see **Table 1**)." }, { "baseStrength": "Pathogenic", "id": "1553527145", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527145", "label": "PM1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1553527145", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527145", "label": "PM1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1553527145", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527145", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1553527145", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527145", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1553527144", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527144", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1553527144", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527144", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1553527144", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527144", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1553527144", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527144", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1553527143", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527143", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1553527143", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527143", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1553527143", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527143", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1553527143", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527143", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1553527157", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527157", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "≥ 4 _de novo_ scores. For curation of _de novo_ score see **Tables 1** and **2**." }, { "baseStrength": "Pathogenic", "id": "1553527157", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527157", "label": "PS2", "strengthDescriptor": "Strong", "text": "2-3.5 _de novo_ scores. For curation of _de novo_ score see **Tables 1** and **2**." }, { "baseStrength": "Pathogenic", "id": "1553527157", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527157", "label": "PS2", "strengthDescriptor": "Moderate", "text": "1-1.5 _de novo_ score. For curation of _de novo_ score see **Tables 1** and **2**." }, { "baseStrength": "Pathogenic", "id": "1553527154", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527154", "label": "PP1", "strengthDescriptor": "Strong", "text": "Variant segregates in ≥ 7 meioses in ≥ 2 families." }, { "baseStrength": "Pathogenic", "id": "1553527154", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527154", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Variant segregates in 5-6 meioses in ≥ 1 family." }, { "baseStrength": "Pathogenic", "id": "1553527154", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527154", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Variant segregates in 3-4 meioses in ≥ 1 family." }, { "baseStrength": "Benign", "id": "1553527153", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527153", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Only applicable for an alternate genetic basis of the colorectal polyposis phenotype." }, { "baseStrength": "Benign", "id": "1553527149", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527149", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) or intronic variant at or beyond +7/–21 for which multiple splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site." }, { "baseStrength": "Pathogenic", "id": "1553527146", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527146", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (**Figure 1**) \\[Reference 1\\]." }, { "baseStrength": "Pathogenic", "id": "1553527146", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527146", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (**Figure 1**) \\[Reference 1\\]." }, { "baseStrength": "Pathogenic", "id": "1553527146", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527146", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (**Figure 1**) \\[Reference 1\\]." }, { "baseStrength": "Pathogenic", "id": "1553527146", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527146", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (**Figure 1**) \\[Reference 1\\]." }, { "baseStrength": "Benign", "id": "1553527142", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527142", "label": "BS2", "strengthDescriptor": "Strong", "text": "≥ 10 points for healthy individuals **OR** ≥ 2 times in homozygous state.\n\nA **healthy individual** worth 1 point is defined by:\n\nAge ≥ 50 years  \n\\+ Less than 5 adenomatous polyps in a colonoscopy  \n\\+ Absence of features in Table 1\n\n**OR**\n\nAge ≥ 50 years  \n\\+ Colorectal cancer/polyposis was not the indication for testing\n\nA **healthy individual** worth 0.5 points is defined by keywords including control, non-cancer, normal, unaffected population." }, { "baseStrength": "Benign", "id": "1553527142", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527142", "label": "BS2", "strengthDescriptor": "Supporting", "text": "≥ 3 points for healthy individuals.\n\nA **healthy individual** worth 1 point is defined by:\n\nAge ≥ 50 years  \n\\+ Less than 5 adenomatous polyps in a colonoscopy  \n\\+ Absence of features in Table 1\n\n**OR**\n\nAge ≥ 50 years  \n\\+ Colorectal cancer/polyposis was not the indication for testing\n\nA **healthy individual** worth 0.5 points is defined by keywords including control, non-cancer, normal, unaffected population." }, { "baseStrength": "Benign", "id": "1553527140", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527140", "label": "BP1", "strengthDescriptor": "Supporting", "text": "BP1 is applicable to APC with the exception of missense variants located in the first 15-amino acid repeat of the β-catenin binding domain (codon 1021-1035)." }, { "baseStrength": "Pathogenic", "id": "1553527135", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527135", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "≥ 16 phenotype points. For phenotype points curation see **Table 1**." }, { "baseStrength": "Pathogenic", "id": "1553527135", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527135", "label": "PS4", "strengthDescriptor": "Strong", "text": "4-15.5 phenotype points. For phenotype points curation see **Table 1**." }, { "baseStrength": "Pathogenic", "id": "1553527135", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527135", "label": "PS4", "strengthDescriptor": "Moderate", "text": "2-3.5 phenotype points. For phenotype points curation see **Table 1**." }, { "baseStrength": "Pathogenic", "id": "1553527135", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527135", "label": "PS4", "strengthDescriptor": "Supporting", "text": "1-1.5 phenotype point. For phenotype points curation see **Table 1**." }, { "baseStrength": "Pathogenic", "id": "1553527133", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527133", "label": "PM4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1553527133", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527133", "label": "PM4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1553527133", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527133", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1553527133", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527133", "label": "PM4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1553527159", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527159", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1553527159", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527159", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1553527159", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527159", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1553527159", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527159", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1553527158", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527158", "label": "PS1", "strengthDescriptor": "Strong", "text": "The previously established variant was classified as Pathogenic according to the APC-specific modifications.\n\nThis criterion can be applied to both missense and splice variants in _APC_. \n\n**Missense variants:** when the variant under assessment results in the same amino acid change as previously established Pathogenic variant(s). \n\nThere are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other variants leading to the same missense change at these positions meet PS1\\_Moderate. No missense variant has been classified as Pathogenic based on current evidence. \n\n**Splice variants**: when the variant under assessment affects splicing at the same nucleotide as a previously established Pathogenic variant. The splice prediction must be above defined thresholds (see instructions) or similar to the previously established variant by multiple _in silico_ predictors." }, { "baseStrength": "Pathogenic", "id": "1553527158", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527158", "label": "PS1", "strengthDescriptor": "Moderate", "text": "The previously established variant was classified as Likely Pathogenic according to the APC-specific modifications.\n\nThis criterion can be applied to both missense and splice variants in _APC_. \n\n**Missense variants:** when the variant under assessment results in the same amino acid change as previously established Likely Pathogenic variant(s). \n\nThere are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other variants leading to the same missense change at these positions meet PS1\\_Moderate. No missense variant has been classified as Pathogenic based on current evidence. \n\n**Splice variants**: when the variant under assessment affects splicing at the same nucleotide as a previously established Likely Pathogenic variant. The splice prediction must be above defined thresholds (see instructions) or similar to the previously established variant by multiple _in silico_ predictors." }, { "baseStrength": "Pathogenic", "id": "1553527156", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527156", "label": "PP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1553527156", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527156", "label": "PP4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1553527156", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527156", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1553527156", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527156", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1553527155", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527155", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1553527155", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527155", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1553527155", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527155", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1553527155", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527155", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1553527147", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527147", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "GnomAD Popmax Filtering Allele Frequency (AF) **≥ 0.1%** (0.001)." }, { "baseStrength": "Benign", "id": "1553527136", "iri": "https://genboree.org/cspec/CriteriaCode/id/1553527136", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Observed _in trans_ with a (Likely) Pathogenic _APC_ variant **OR** ≥ 3 times in an unknown phase with different (Likely) Pathogenic _APC_ variants." } ], "diseases": [ { "id": "MONDO:0021056", "iri": "https://genboree.org/cspec/Disease/id/467886956", "label": "familial adenomatous polyposis 1" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467817382", "label": "APC" } ], "ruleSet": { "id": "1529292804", "iri": "https://genboree.org/cspec/RuleSet/id/1529292804" }, "svi": { "id": "GN089", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1529292791", "label": "ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.1.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1614165321", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165321", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF score ≤ 0.15 AND SpliceAI ≤0.1).\n\nSilent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1).\n\nIntronic variants outside of the native donor and acceptor splice sites (i.e. not +/- 1,2 positions) AND no predicted impact via splicing (SpliceAI ≤0.1).\n\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details." }, { "baseStrength": "Pathogenic", "id": "1614165318", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165318", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences." }, { "baseStrength": "Pathogenic", "id": "1614165318", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165318", "label": "PS2", "strengthDescriptor": "Strong", "text": "Not Applicable: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences." }, { "baseStrength": "Pathogenic", "id": "1614165318", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165318", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Not Applicable: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences." }, { "baseStrength": "Pathogenic", "id": "1614165318", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165318", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Not Applicable: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences." }, { "baseStrength": "Benign", "id": "1614165316", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165316", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Captured by bioinformatic tool prediction, and domain analysis. See Appendix J for details" }, { "baseStrength": "Benign", "id": "1614165316", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165316", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Captured by bioinformatic tool prediction, and domain analysis. See Appendix J for details" }, { "baseStrength": "Benign", "id": "1614165316", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165316", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Captured by bioinformatic tool prediction, and domain analysis. See Appendix J for details" }, { "baseStrength": "Benign", "id": "1614165316", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165316", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Captured by bioinformatic tool prediction, and domain analysis. See Appendix J for details" }, { "baseStrength": "Pathogenic", "id": "1614165312", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165312", "label": "PS3", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details." }, { "baseStrength": "Pathogenic", "id": "1614165311", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165311", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel no-AF score ≥0.28). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857.\n\nApply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of donor and acceptor 1,2 sites.\n\nSee Specifications Figure1A and Appendix J for details." }, { "baseStrength": "Pathogenic", "id": "1614165306", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165306", "label": "PM1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Considered as component of bioinformatic analysis (PP3/BP4). " }, { "baseStrength": "Pathogenic", "id": "1614165306", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165306", "label": "PM1", "strengthDescriptor": "Strong", "text": "Not Applicable: Considered as component of bioinformatic analysis (PP3/BP4). " }, { "baseStrength": "Pathogenic", "id": "1614165306", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165306", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Considered as component of bioinformatic analysis (PP3/BP4). " }, { "baseStrength": "Pathogenic", "id": "1614165306", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165306", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Considered as component of bioinformatic analysis (PP3/BP4). " }, { "baseStrength": "Pathogenic", "id": "1614165298", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165298", "label": "PM5", "strengthDescriptor": "Strong", "text": "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5\\_PTC code strengths applicable per exon. See Appendix D for additional details." }, { "baseStrength": "Pathogenic", "id": "1614165298", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165298", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5\\_PTC code strengths applicable per exon. See Appendix D for additional details." }, { "baseStrength": "Pathogenic", "id": "1614165298", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165298", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5\\_PTC code strengths applicable per exon. See Appendix D for additional details." }, { "baseStrength": "Pathogenic", "id": "1614165319", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165319", "label": "PS1", "strengthDescriptor": "Strong", "text": "Apply **PS1**, for predicted **missense** substitutions, where a previously classified **pathogenic** variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\n\nApply **PS1**, for exonic and intronic variants with same predicted impact on **splicing**, as a previously classified **pathogenic** variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. \n\nSee Specifications Table 5 and Appendix E, J and K for details." }, { "baseStrength": "Pathogenic", "id": "1614165319", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165319", "label": "PS1", "strengthDescriptor": "Moderate", "text": "Apply **PS1\\_Moderate**, for predicted **missense** substitutions, where previously classified **likely pathogenic** variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\n\nApply **PS1\\_Moderate**, for exonic and intronic variants with same predicted impact on **splicing**, as a previously classified **(likely) pathogenic** variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\n\nSee Specifications Table 5 and Appendix E, J and K for details." }, { "baseStrength": "Pathogenic", "id": "1614165319", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165319", "label": "PS1", "strengthDescriptor": "Supporting", "text": "Apply **PS1\\_Supporting**, for exonic and intronic variants with same predicted impact on **splicing,** as a previously classified **(likely) pathogenic** variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\n\nSee Specifications Table 5 and Appendix E, J and K for details." }, { "baseStrength": "Pathogenic", "id": "1614165305", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165305", "label": "PM3", "strengthDescriptor": "Strong", "text": "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis _≤5yr_.\n\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3\\_Strong = ≥4 points" }, { "baseStrength": "Pathogenic", "id": "1614165305", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165305", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis _≤5yr_.\n\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3 = 2 points" }, { "baseStrength": "Pathogenic", "id": "1614165305", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165305", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis _≤5yr_.\n\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3\\_Supporting = 1 point" }, { "baseStrength": "Benign", "id": "1614165299", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165299", "label": "BS3", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of no damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as BP7 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details." }, { "baseStrength": "Benign", "id": "1614165297", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165297", "label": "BP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Applied only in the context of BS2." }, { "baseStrength": "Benign", "id": "1614165297", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165297", "label": "BP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Applied only in the context of BS2." }, { "baseStrength": "Benign", "id": "1614165297", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165297", "label": "BP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Applied only in the context of BS2." }, { "baseStrength": "Benign", "id": "1614165297", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165297", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Applied only in the context of BS2." }, { "baseStrength": "Pathogenic", "id": "1614165309", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165309", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences." }, { "baseStrength": "Pathogenic", "id": "1614165309", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165309", "label": "PM6", "strengthDescriptor": "Strong", "text": "Not Applicable: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences." }, { "baseStrength": "Pathogenic", "id": "1614165309", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165309", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Not Applicable: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences." }, { "baseStrength": "Pathogenic", "id": "1614165309", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165309", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Not Applicable: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences." }, { "baseStrength": "Pathogenic", "id": "1614165307", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165307", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details." }, { "baseStrength": "Pathogenic", "id": "1614165307", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165307", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details." }, { "baseStrength": "Pathogenic", "id": "1614165307", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165307", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details." }, { "baseStrength": "Pathogenic", "id": "1614165307", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165307", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details." }, { "baseStrength": "Benign", "id": "1614165303", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165303", "label": "BS2", "strengthDescriptor": "Strong", "text": "Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2 = ≥ 4 points" }, { "baseStrength": "Benign", "id": "1614165303", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165303", "label": "BS2", "strengthDescriptor": "Moderate", "text": "Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2\\_Moderate = 2 points" }, { "baseStrength": "Benign", "id": "1614165303", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165303", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2\\_Supporting = 1 points" }, { "baseStrength": "Pathogenic", "id": "1614165302", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165302", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: High frequency of benign missense variants." }, { "baseStrength": "Pathogenic", "id": "1614165302", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165302", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: High frequency of benign missense variants." }, { "baseStrength": "Pathogenic", "id": "1614165302", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165302", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: High frequency of benign missense variants." }, { "baseStrength": "Pathogenic", "id": "1614165302", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165302", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: High frequency of benign missense variants." }, { "baseStrength": "Pathogenic", "id": "1614165295", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165295", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details." }, { "baseStrength": "Benign", "id": "1614165320", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165320", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1614165320", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165320", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1614165320", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165320", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1614165320", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165320", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1614165315", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165315", "label": "PP1", "strengthDescriptor": "Strong", "text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nPP1\\_Strong – LR>18.7:1\n\nPP1\\_Very Strong – LR>350:1" }, { "baseStrength": "Pathogenic", "id": "1614165315", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165315", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nPP1\\_Moderate – LR>4.3:1" }, { "baseStrength": "Pathogenic", "id": "1614165315", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165315", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nPP1 - LR >2.08:1" }, { "baseStrength": "Benign", "id": "1614165313", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165313", "label": "BS1", "strengthDescriptor": "Strong", "text": "Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details." }, { "baseStrength": "Benign", "id": "1614165313", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165313", "label": "BS1", "strengthDescriptor": "Supporting", "text": "Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details." }, { "baseStrength": "Benign", "id": "1614165310", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165310", "label": "BP7", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function _as measured by effect on mRNA transcript profile – mRNA assay only._ Apply as BP7 (RNA) for intronic and silent variants, as well as missense/in-frame variants located outside a (potentially) clinically important functional domain. See Specifications Figure1B and Appendix E for details.\n\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details." }, { "baseStrength": "Benign", "id": "1614165310", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165310", "label": "BP7", "strengthDescriptor": "Supporting", "text": "Silent variant inside a (potentially) clinically important functional domain, IF BP4 met.\n\nIntronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.\n\nSee Specifications Figure1A and Appendix J for additional details.\n\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details." }, { "baseStrength": "Benign", "id": "1614165308", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165308", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details." }, { "baseStrength": "Pathogenic", "id": "1614165304", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165304", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1614165304", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165304", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1614165304", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165304", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1614165304", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165304", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1614165301", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165301", "label": "BP1", "strengthDescriptor": "Strong", "text": "**Apply BP1\\_Strong** for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details." }, { "baseStrength": "Pathogenic", "id": "1614165296", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165296", "label": "PS4", "strengthDescriptor": "Strong", "text": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). See Appendix F for details." }, { "baseStrength": "Pathogenic", "id": "1614165294", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165294", "label": "PM4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Considered as component of bioinformatic analysis (PP3/BP4)." }, { "baseStrength": "Pathogenic", "id": "1614165294", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165294", "label": "PM4", "strengthDescriptor": "Strong", "text": "Not Applicable: Considered as component of bioinformatic analysis (PP3/BP4)." }, { "baseStrength": "Pathogenic", "id": "1614165294", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165294", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Considered as component of bioinformatic analysis (PP3/BP4)." }, { "baseStrength": "Pathogenic", "id": "1614165294", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165294", "label": "PM4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Considered as component of bioinformatic analysis (PP3/BP4)." }, { "baseStrength": "Pathogenic", "id": "1614165317", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165317", "label": "PP4", "strengthDescriptor": "Strong", "text": "Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4\\_Strong – LR>18.7:1\n\nPP4\\_Very Strong – LR>350:1\n\nCombined LR 1.00-2.08 is not informative (PP4 not applicable).\n\nSee Specifications Table7 and Appendix B for details." }, { "baseStrength": "Pathogenic", "id": "1614165317", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165317", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4\\_Moderate – LR>4.3:1\n\nCombined LR 1.00-2.08 is not informative (PP4 not applicable).\n\nSee Specifications Table7 and Appendix B for details." }, { "baseStrength": "Pathogenic", "id": "1614165317", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165317", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4 - LR >2.08:1 \n\nCombined LR 1.00-2.08 is not informative (PP4 not applicable).\n\nSee Specifications Table7 and Appendix B for details." }, { "baseStrength": "Benign", "id": "1614165314", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165314", "label": "BP5", "strengthDescriptor": "Strong", "text": "Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5\\_VeryStrong – LR \\<0.00285:1\n\nBP5\\_Strong  - LR \\<0.05:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype." }, { "baseStrength": "Benign", "id": "1614165314", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165314", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5\\_Moderate - LR \\<0.23:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype." }, { "baseStrength": "Benign", "id": "1614165314", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165314", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5 - LR 0.23-0.48:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype." }, { "baseStrength": "Benign", "id": "1614165300", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165300", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nBS4 - LR \\<0.05:1\n\nBS4\\_VeryStrong – LR \\<0.00285:1" }, { "baseStrength": "Benign", "id": "1614165300", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165300", "label": "BS4", "strengthDescriptor": "Moderate", "text": "Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nBS4\\_Moderate - LR \\<0.23:1" }, { "baseStrength": "Benign", "id": "1614165300", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614165300", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nBS4\\_Supporting  - LR 0.23-0.48:1" } ], "diseases": [ { "id": "MONDO:0011450", "iri": "https://genboree.org/cspec/Disease/id/467887429", "label": "breast-ovarian cancer, familial, susceptibility to, 1" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467818961", "label": "BRCA1" } ], "ruleSet": { "id": "1530970800", "iri": "https://genboree.org/cspec/RuleSet/id/1530970800" }, "svi": { "id": "GN092", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1530970787", "label": "ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1 Version 1.1.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1614166144", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166144", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF score ≤ 0.18 AND SpliceAI ≤0.1).\n\nSilent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1).\n\nIntronic variants outside of the native donor and acceptor splice sites (i.e. not +/- 1,2 positions) AND no predicted impact via splicing (SpliceAI ≤0.1).\n\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details." }, { "baseStrength": "Benign", "id": "1614166143", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166143", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1614166143", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166143", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1614166143", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166143", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1614166143", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166143", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1614166126", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166126", "label": "BS2", "strengthDescriptor": "Strong", "text": "Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2 = ≥ 4 points" }, { "baseStrength": "Benign", "id": "1614166126", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166126", "label": "BS2", "strengthDescriptor": "Moderate", "text": "Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2\\_Moderate = 2 points" }, { "baseStrength": "Benign", "id": "1614166126", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166126", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2\\_Supporting = 1 points" }, { "baseStrength": "Benign", "id": "1614166123", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166123", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nBS4 - LR \\<0.05:1\n\nBS4\\_VeryStrong – LR \\<0.00285:1" }, { "baseStrength": "Benign", "id": "1614166123", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166123", "label": "BS4", "strengthDescriptor": "Moderate", "text": "Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nBS4\\_Moderate - LR \\<0.23:1" }, { "baseStrength": "Benign", "id": "1614166123", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166123", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nBS4\\_Supporting  - LR 0.23-0.48:1" }, { "baseStrength": "Pathogenic", "id": "1614166121", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166121", "label": "PM5", "strengthDescriptor": "Strong", "text": "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5\\_PTC code strengths applicable per exon. See Appendix D for additional details." }, { "baseStrength": "Pathogenic", "id": "1614166121", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166121", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5\\_PTC code strengths applicable per exon. See Appendix D for additional details." }, { "baseStrength": "Pathogenic", "id": "1614166121", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166121", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5\\_PTC code strengths applicable per exon. See Appendix D for additional details." }, { "baseStrength": "Pathogenic", "id": "1614166118", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166118", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details." }, { "baseStrength": "Pathogenic", "id": "1614166138", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166138", "label": "PP1", "strengthDescriptor": "Strong", "text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nPP1\\_Strong – LR>18.7:1\n\nPP1\\_Very Strong – LR>350:1" }, { "baseStrength": "Pathogenic", "id": "1614166138", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166138", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nPP1\\_Moderate – LR>4.3:1" }, { "baseStrength": "Pathogenic", "id": "1614166138", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166138", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nPP1 - LR >2.08:1" }, { "baseStrength": "Benign", "id": "1614166133", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166133", "label": "BP7", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function _as measured by effect on mRNA transcript profile – mRNA assay only._ Apply as BP7\\_Strong (RNA) for intronic and silent variants, as well as missense/in-frame variants located outside a (potentially) clinically important functional domain. See Specifications Figure1B and Appendix E for details.\n\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details." }, { "baseStrength": "Benign", "id": "1614166133", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166133", "label": "BP7", "strengthDescriptor": "Supporting", "text": "Silent variant inside a (potentially) clinically important functional domain, IF BP4 met.\n\nIntronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.\n\nSee Specifications Figure1A and Appendix J for additional details.\n\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details." }, { "baseStrength": "Pathogenic", "id": "1614166128", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166128", "label": "PM3", "strengthDescriptor": "Strong", "text": "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis _≤5yr_.\n\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3\\_Strong = ≥4 points" }, { "baseStrength": "Pathogenic", "id": "1614166128", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166128", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis _≤5yr_.\n\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3 = 2 points" }, { "baseStrength": "Pathogenic", "id": "1614166128", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166128", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis _≤5yr_.\n\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3\\_Supporting = 1 point" }, { "baseStrength": "Pathogenic", "id": "1614166140", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166140", "label": "PP4", "strengthDescriptor": "Strong", "text": "Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4\\_Strong – LR>18.7:1\n\nPP4\\_Very Strong – LR>350:1\n\nCombined LR 1.00-2.08 is not informative (PP4 not applicable).\n\nSee Specifications Table7 and Appendix B for details." }, { "baseStrength": "Pathogenic", "id": "1614166140", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166140", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4\\_Moderate – LR>4.3:1\n\nCombined LR 1.00-2.08 is not informative (PP4 not applicable).\n\nSee Specifications Table7 and Appendix B for details." }, { "baseStrength": "Pathogenic", "id": "1614166140", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166140", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4 - LR >2.08:1 \n\nCombined LR 1.00-2.08 is not informative (PP4 not applicable).\n\nSee Specifications Table7 and Appendix B for details." }, { "baseStrength": "Benign", "id": "1614166139", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166139", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Captured by bioinformatic tool prediction, and domain analysis. See Appendix J for details" }, { "baseStrength": "Benign", "id": "1614166139", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166139", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Captured by bioinformatic tool prediction, and domain analysis. See Appendix J for details" }, { "baseStrength": "Benign", "id": "1614166139", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166139", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Captured by bioinformatic tool prediction, and domain analysis. See Appendix J for details" }, { "baseStrength": "Benign", "id": "1614166139", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166139", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Captured by bioinformatic tool prediction, and domain analysis. See Appendix J for details" }, { "baseStrength": "Benign", "id": "1614166136", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166136", "label": "BS1", "strengthDescriptor": "Strong", "text": "Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details." }, { "baseStrength": "Benign", "id": "1614166136", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166136", "label": "BS1", "strengthDescriptor": "Supporting", "text": "Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details." }, { "baseStrength": "Pathogenic", "id": "1614166132", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166132", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences." }, { "baseStrength": "Pathogenic", "id": "1614166132", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166132", "label": "PM6", "strengthDescriptor": "Strong", "text": "Not Applicable: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences." }, { "baseStrength": "Pathogenic", "id": "1614166132", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166132", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Not Applicable: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences." }, { "baseStrength": "Pathogenic", "id": "1614166132", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166132", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Not Applicable: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences." }, { "baseStrength": "Pathogenic", "id": "1614166130", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166130", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details." }, { "baseStrength": "Pathogenic", "id": "1614166130", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166130", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details." }, { "baseStrength": "Pathogenic", "id": "1614166130", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166130", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details." }, { "baseStrength": "Pathogenic", "id": "1614166130", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166130", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details." }, { "baseStrength": "Pathogenic", "id": "1614166141", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166141", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences." }, { "baseStrength": "Pathogenic", "id": "1614166141", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166141", "label": "PS2", "strengthDescriptor": "Strong", "text": "Not Applicable: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences." }, { "baseStrength": "Pathogenic", "id": "1614166141", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166141", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Not Applicable: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences." }, { "baseStrength": "Pathogenic", "id": "1614166141", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166141", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Not Applicable: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences." }, { "baseStrength": "Pathogenic", "id": "1614166135", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166135", "label": "PS3", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details." }, { "baseStrength": "Pathogenic", "id": "1614166127", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166127", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1614166127", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166127", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1614166127", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166127", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1614166127", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166127", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1614166125", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166125", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: High frequency of benign missense variants." }, { "baseStrength": "Pathogenic", "id": "1614166125", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166125", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: High frequency of benign missense variants." }, { "baseStrength": "Pathogenic", "id": "1614166125", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166125", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: High frequency of benign missense variants." }, { "baseStrength": "Pathogenic", "id": "1614166125", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166125", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: High frequency of benign missense variants." }, { "baseStrength": "Benign", "id": "1614166122", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166122", "label": "BS3", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of no damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as BP7 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details." }, { "baseStrength": "Benign", "id": "1614166120", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166120", "label": "BP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Applied only in the context of BS2." }, { "baseStrength": "Benign", "id": "1614166120", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166120", "label": "BP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Applied only in the context of BS2." }, { "baseStrength": "Benign", "id": "1614166120", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166120", "label": "BP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Applied only in the context of BS2." }, { "baseStrength": "Benign", "id": "1614166120", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166120", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Applied only in the context of BS2." }, { "baseStrength": "Pathogenic", "id": "1614166142", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166142", "label": "PS1", "strengthDescriptor": "Strong", "text": "Apply **PS1**, for predicted **missense** substitutions, where a previously classified **pathogenic** variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\n\nApply **PS1**, for exonic and intronic variants with same predicted impact on **splicing,** as a previously classified **pathogenic** variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. \n\nSee Specifications Table 5 and Appendix E, J and K for details." }, { "baseStrength": "Pathogenic", "id": "1614166142", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166142", "label": "PS1", "strengthDescriptor": "Moderate", "text": "Apply **PS1\\_Moderate**, for predicted **missense** substitutions, where a previously classified **likely pathogenic** variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\n\nApply **PS1\\_Moderate**, for exonic and intronic variants with same predicted impact on **splicing**, as a previously classified **(likely) pathogenic** variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\n\nSee Specifications Table 5 and Appendix E, J and K for details." }, { "baseStrength": "Pathogenic", "id": "1614166142", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166142", "label": "PS1", "strengthDescriptor": "Supporting", "text": "Apply **PS1**, for exonic and intronic variants with same predicted impact on **splicing**, as a previously classified **(likely) pathogenic** variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\n\nSee Specifications Table 5 and Appendix E, J and K for details." }, { "baseStrength": "Benign", "id": "1614166137", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166137", "label": "BP5", "strengthDescriptor": "Strong", "text": "Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5\\_VeryStrong – LR \\<0.00285:1\n\nBP5\\_Strong  - LR \\<0.05:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype." }, { "baseStrength": "Benign", "id": "1614166137", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166137", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5\\_Moderate - LR \\<0.23:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype." }, { "baseStrength": "Benign", "id": "1614166137", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166137", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5 - LR 0.23-0.48:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype." }, { "baseStrength": "Pathogenic", "id": "1614166134", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166134", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel no-AF score ≥0.30). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186.\n\nApply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of donor and acceptor 1,2 sites.\n\nSee Specifications Figure1A and Appendix J for details." }, { "baseStrength": "Benign", "id": "1614166131", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166131", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details." }, { "baseStrength": "Pathogenic", "id": "1614166129", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166129", "label": "PM1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Considered as component of bioinformatic analysis (PP3/BP4). " }, { "baseStrength": "Pathogenic", "id": "1614166129", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166129", "label": "PM1", "strengthDescriptor": "Strong", "text": "Not Applicable: Considered as component of bioinformatic analysis (PP3/BP4). " }, { "baseStrength": "Pathogenic", "id": "1614166129", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166129", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Considered as component of bioinformatic analysis (PP3/BP4). " }, { "baseStrength": "Pathogenic", "id": "1614166129", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166129", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Considered as component of bioinformatic analysis (PP3/BP4). " }, { "baseStrength": "Benign", "id": "1614166124", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166124", "label": "BP1", "strengthDescriptor": "Strong", "text": "**Apply BP1\\_Strong** for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details." }, { "baseStrength": "Pathogenic", "id": "1614166119", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166119", "label": "PS4", "strengthDescriptor": "Strong", "text": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). See Appendix F for details." }, { "baseStrength": "Pathogenic", "id": "1614166117", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166117", "label": "PM4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Considered as component of bioinformatic analysis (PP3/BP4)." }, { "baseStrength": "Pathogenic", "id": "1614166117", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166117", "label": "PM4", "strengthDescriptor": "Strong", "text": "Not Applicable: Considered as component of bioinformatic analysis (PP3/BP4)." }, { "baseStrength": "Pathogenic", "id": "1614166117", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166117", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Considered as component of bioinformatic analysis (PP3/BP4)." }, { "baseStrength": "Pathogenic", "id": "1614166117", "iri": "https://genboree.org/cspec/CriteriaCode/id/1614166117", "label": "PM4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Considered as component of bioinformatic analysis (PP3/BP4)." } ], "diseases": [ { "id": "MONDO:0012933", "iri": "https://genboree.org/cspec/Disease/id/467873801", "label": "breast-ovarian cancer, familial, susceptibility to, 2" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467818963", "label": "BRCA2" } ], "ruleSet": { "id": "1535438847", "iri": "https://genboree.org/cspec/RuleSet/id/1535438847" }, "svi": { "id": "GN097", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1535438831", "label": "ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 Version 1.1.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1620854955", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854955", "label": "BP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620854955", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854955", "label": "BP4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620854955", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854955", "label": "BP4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620854955", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854955", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620854954", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854954", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620854954", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854954", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620854954", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854954", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620854954", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854954", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620854947", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854947", "label": "BS1", "strengthDescriptor": "Strong", "text": "gnomAD popmax filtering allele frequency >0.001611\n\n1 Consider also bottleneck populations." }, { "baseStrength": "Benign", "id": "1620854942", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854942", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "gnomAD popmax filtering allele frequency >0.00721." }, { "baseStrength": "Benign", "id": "1620854933", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854933", "label": "BS3", "strengthDescriptor": "Supporting", "text": "The strength of evidence from cellular models/_in vitro_ studies is dependent upon the level of expressed ADA enzyme activity based on levels defined in Arredondo-Vega et al., 1998 (PMID: 9758612): \n\n* BS3\\_Supporting: Expressed ADA enzyme activity ≥4.8% of wild-type activity (based on group IV)." }, { "baseStrength": "Pathogenic", "id": "1620854952", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854952", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620854952", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854952", "label": "PS2", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620854952", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854952", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620854952", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854952", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Benign", "id": "1620854944", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854944", "label": "BP7", "strengthDescriptor": "Supporting", "text": "* Applicable to both synonymous variants and deep intronic variants affecting nucleotides at or beyond the +7 (donor) and -21 (acceptor) positions.\n* The variant should be predicted not to impact splicing by at least two out of three _in silico_ tools (freely available tools include GeneSplicer, MaxEntScan, NNSplice, SpliceAI, Splicing Sequences Finder (SSF), and varSEAK).\n* Given the potential for poor conservation of genes related to T cell and B cell development among vertebrates, nucleotide conservation is **not required** in order to apply BP7." }, { "baseStrength": "Pathogenic", "id": "1620854941", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854941", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042))." }, { "baseStrength": "Pathogenic", "id": "1620854941", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854941", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:\n\n* For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 12, or variants in the last 50 nucleotides of the penultimate exon after c.1028, codon 343, in exon 11), at least one pathogenic variant **must be** present downstream in order to apply PVS1\\_Strong." }, { "baseStrength": "Pathogenic", "id": "1620854941", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854941", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:\n\n* For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 12, or variants in the last 50 nucleotides of the penultimate exon after c.1028, codon 343, in exon 11), when at least one pathogenic variant is **not** present downstream downgrade to PVS1\\_Moderate." }, { "baseStrength": "Pathogenic", "id": "1620854938", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854938", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620854938", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854938", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620854938", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854938", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620854938", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854938", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620854937", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854937", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Only to be used when the variant is observed in the homozygous state in a healthy adult." }, { "baseStrength": "Benign", "id": "1620854931", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854931", "label": "BP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620854931", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854931", "label": "BP2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620854931", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854931", "label": "BP2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620854931", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854931", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620854930", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854930", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620854930", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854930", "label": "PS4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620854930", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854930", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620854930", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854930", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620854953", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854953", "label": "PS1", "strengthDescriptor": "Strong", "text": "It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T.\n\nApplicable if the previously established variant is classified as **pathogenic** by SCID VCEP specifications for _ADA._" }, { "baseStrength": "Pathogenic", "id": "1620854953", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854953", "label": "PS1", "strengthDescriptor": "Moderate", "text": "It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T\n\nApplicable if the previously established variant is classified as **likely pathogenic** by SCID VCEP specifications for _ADA._" }, { "baseStrength": "Pathogenic", "id": "1620854951", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854951", "label": "PP4", "strengthDescriptor": "Strong", "text": "A patient score of ≥ 9 points1. \n\n1CNV (Copy number variation) testing is required to consider PP4\\_Strong in order to certify that the variant in question is the causative for the phenotype and not one CNV event corrected by gene therapy and not identified previously (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620854951", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854951", "label": "PP4", "strengthDescriptor": "Moderate", "text": "A patient score of 2-\\<9 points (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620854951", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854951", "label": "PP4", "strengthDescriptor": "Supporting", "text": "A patient score of 1-\\<2 points (see instructions below)." }, { "baseStrength": "Benign", "id": "1620854950", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854950", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620854950", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854950", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620854950", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854950", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620854950", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854950", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Pathogenic", "id": "1620854946", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854946", "label": "PS3", "strengthDescriptor": "Strong", "text": "PS3 may potentially be applied at the default strength level of Strong for evidence from an animal model expressing the variant of interest and recapitulating the ADA-SCID phenotype." }, { "baseStrength": "Pathogenic", "id": "1620854946", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854946", "label": "PS3", "strengthDescriptor": "Moderate", "text": "The strength of evidence from cellular models/_in vitro_ studies is dependent upon the level of expressed ADA enzyme activity based on levels defined in Arredondo-Vega et al., 1998 (PMID: 9758612): \n\n* PS3\\_Moderate: ≤0.05% of wild-type activity (group I)\n\n_At least one previously observed proband with the expressed ADA variant meeting PP4 is required to apply PS3 at any strength on the basis of a cellular model/in vitro study._" }, { "baseStrength": "Pathogenic", "id": "1620854946", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854946", "label": "PS3", "strengthDescriptor": "Supporting", "text": "The strength of evidence from cellular models/_in vitro_ studies is dependent upon the level of expressed ADA enzyme activity based on levels defined in Arredondo-Vega et al., 1998 (PMID: 9758612):\n\n* PS3\\_Supporting: 0.06-0.6% of wild-type activity (groups II and III)\n\n_At least one previously observed proband with the expressed ADA variant meeting PP4 is required to apply PS3 at any strength on the basis of a cellular model/in vitro study._" }, { "baseStrength": "Pathogenic", "id": "1620854939", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854939", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _ADA._" }, { "baseStrength": "Pathogenic", "id": "1620854939", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854939", "label": "PM3", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _ADA._" }, { "baseStrength": "Pathogenic", "id": "1620854939", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854939", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _ADA._" }, { "baseStrength": "Pathogenic", "id": "1620854939", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854939", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _ADA._" }, { "baseStrength": "Benign", "id": "1620854934", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854934", "label": "BS4", "strengthDescriptor": "Strong", "text": "Can be applied without additional specifications." }, { "baseStrength": "Pathogenic", "id": "1620854929", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854929", "label": "PM2", "strengthDescriptor": "Supporting", "text": "gnomAD popmax filtering allele frequency  \\<0.0001742\n\n* An additional requirement is that **no homozygotes** have been observed in gnomAD." }, { "baseStrength": "Pathogenic", "id": "1620854928", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854928", "label": "PM4", "strengthDescriptor": "Moderate", "text": "When applied to deletion variants, the deleted region must contain a known **pathogenic** or **likely pathogenic** variant that is not predicted/observed to alter splicing." }, { "baseStrength": "Pathogenic", "id": "1620854928", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854928", "label": "PM4", "strengthDescriptor": "Supporting", "text": "When applied to deletion variants, the deleted region must contain a known **VUS** variant that is not predicted/observed to alter splicing." }, { "baseStrength": "Pathogenic", "id": "1620854945", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854945", "label": "PP3", "strengthDescriptor": "Supporting", "text": "* Only applicable to synonymous or intronic variants predicted to impact splicing by SpliceAI with a delta score greater than or equal to 0.2.\n* **Do not apply to missense variants.**" }, { "baseStrength": "Pathogenic", "id": "1620854943", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854943", "label": "PM6", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620854943", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854943", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620854943", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854943", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Benign", "id": "1620854935", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854935", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620854935", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854935", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620854935", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854935", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620854935", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854935", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Pathogenic", "id": "1620854932", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854932", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Applicable if a previously established variant is classified as **pathogenic** by SCID VCEP specifications for _ADA._ Previously established variant must be classified by SCID VCEP specifications for _ADA._" }, { "baseStrength": "Pathogenic", "id": "1620854932", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854932", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Applicable if a previously established variant is classified as **likely pathogenic** by SCID VCEP specifications for _ADA._ Previously established variant must be classified by SCID VCEP specifications for _ADA._" }, { "baseStrength": "Pathogenic", "id": "1620854949", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854949", "label": "PP1", "strengthDescriptor": "Strong", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Pathogenic", "id": "1620854949", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854949", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Pathogenic", "id": "1620854949", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854949", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Benign", "id": "1620854948", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854948", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620854948", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854948", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620854948", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854948", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620854948", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854948", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620854940", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854940", "label": "PM1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620854940", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854940", "label": "PM1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620854940", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854940", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620854940", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854940", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620854936", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854936", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for ADA (Z = 0.12) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in ADA.\n" }, { "baseStrength": "Pathogenic", "id": "1620854936", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854936", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for ADA (Z = 0.12) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in ADA.\n" }, { "baseStrength": "Pathogenic", "id": "1620854936", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854936", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for ADA (Z = 0.12) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in ADA.\n" }, { "baseStrength": "Pathogenic", "id": "1620854936", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620854936", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for ADA (Z = 0.12) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in ADA.\n" } ], "diseases": [ { "id": "MONDO:0007064", "iri": "https://genboree.org/cspec/Disease/id/467893418", "label": "severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467816330", "label": "ADA" } ], "ruleSet": { "id": "1564418413", "iri": "https://genboree.org/cspec/RuleSet/id/1564418413" }, "svi": { "id": "GN114", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1564418400", "label": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ADA Version 1.0.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1620856094", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856094", "label": "BP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620856094", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856094", "label": "BP4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620856094", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856094", "label": "BP4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620856094", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856094", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620856088", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856088", "label": "PP1", "strengthDescriptor": "Strong", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Pathogenic", "id": "1620856088", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856088", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Pathogenic", "id": "1620856088", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856088", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Pathogenic", "id": "1620856085", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856085", "label": "PS3", "strengthDescriptor": "Strong", "text": "PS3 may potentially be applied at the default strength level of Strong for evidence from an animal model expressing the variant of interest and recapitulating the DCLRE1C-SCID phenotype. Animal models will be reviewed on a case-by-case basis by the VCEP to determine the appropriate strength level." }, { "baseStrength": "Pathogenic", "id": "1620856085", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856085", "label": "PS3", "strengthDescriptor": "Moderate", "text": "The strength of evidence from cellular models/_in vitro_ studies is dependent upon abnormal results in _in vitro_ DNA repair activity and V(D)J recombination assays: \n\n* PS3\\_Moderate: Abnormal result in **both** an _in vitro_ DNA repair activity assay AND an _in vitro_ V(D)J recombination assay (defined as \\<25% of wild-type activity for both assays).\n\n_At least one previously observed proband with the DCLRE1C variant meeting PP4 is required to apply PS3 at any strength on the basis of a cellular model/in vitro study._\n\n* Approved assay instances:\n * DNA repair activity assay \n * Felgentreff et al., 2015 (PMID: 25917813)\n * V(D)J recombination assay \n * Pannicke et al., 2004 (PMID: 15071507)\n * Ege et al., 2005 (PMID: 15731174)\n * Felgentreff et al., 2015 (PMID: 25917813)\n * Volk et al., 2015 (PMID: 26476407)" }, { "baseStrength": "Pathogenic", "id": "1620856085", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856085", "label": "PS3", "strengthDescriptor": "Supporting", "text": "The strength of evidence from cellular models/_in vitro_ studies is dependent upon abnormal results in _in vitro_ DNA repair activity and V(D)J recombination assays: \n\n* PS3\\_Supporting: Abnormal result in an _in vitro_ V(D)J recombination assay (same threshold, \\<25% of wild-type activity).\n\n_At least one previously observed proband with the DCLRE1C variant meeting PP4 is required to apply PS3 at any strength on the basis of a cellular model/in vitro study._\n\n* Approved assay instances:\n * DNA repair activity assay \n * Felgentreff et al., 2015 (PMID: 25917813)\n * V(D)J recombination assay \n * Pannicke et al., 2004 (PMID: 15071507)\n * Ege et al., 2005 (PMID: 15731174)\n * Felgentreff et al., 2015 (PMID: 25917813)\n * Volk et al., 2015 (PMID: 26476407)" }, { "baseStrength": "Pathogenic", "id": "1620856084", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856084", "label": "PP3", "strengthDescriptor": "Supporting", "text": "* Only applicable to synonymous or intronic variants predicted to impact splicing by SpliceAI with a delta score greater than or equal to 0.2.\n* **Do not apply to missense variants.**" }, { "baseStrength": "Pathogenic", "id": "1620856078", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856078", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _DCLRE1C._" }, { "baseStrength": "Pathogenic", "id": "1620856078", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856078", "label": "PM3", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _DCLRE1C._" }, { "baseStrength": "Pathogenic", "id": "1620856078", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856078", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _DCLRE1C._" }, { "baseStrength": "Pathogenic", "id": "1620856078", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856078", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _DCLRE1C._" }, { "baseStrength": "Benign", "id": "1620856076", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856076", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Only to be used when the variant is observed in the homozygous state in a healthy adult." }, { "baseStrength": "Benign", "id": "1620856073", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856073", "label": "BS4", "strengthDescriptor": "Strong", "text": "Can be applied without additional specifications." }, { "baseStrength": "Benign", "id": "1620856089", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856089", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620856089", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856089", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620856089", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856089", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620856089", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856089", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620856081", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856081", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "gnomAD popmax filtering allele frequency >0.00346." }, { "baseStrength": "Pathogenic", "id": "1620856077", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856077", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620856077", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856077", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620856077", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856077", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620856077", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856077", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620856080", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856080", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042))." }, { "baseStrength": "Pathogenic", "id": "1620856080", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856080", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:\n\n* For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 14, or variants in the last 50 nucleotides of the penultimate exon after c.1106, codon 369, in exon 13), at least one pathogenic variant **must be** present downstream in order to apply PVS1\\_Strong.\n\n_Note: Exons 1-3 and exons 1-4 have been reported as a hot spot for deletion variants as a result of homologous recombination of the wild-type DCLRE1C gene with a DCLRE1C pseudogene (PMID: 19953608)._" }, { "baseStrength": "Pathogenic", "id": "1620856080", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856080", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:\n\n* For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 14, or variants in the last 50 nucleotides of the penultimate exon after c.1106, codon 369, in exon 13), when at least one pathogenic variant is **not** present downstream downgrade to PVS1\\_Moderate.\n\n_Note: Exons 1-3 and exons 1-4 have been reported as a hot spot for deletion variants as a result of homologous recombination of the wild-type DCLRE1C gene with a DCLRE1C pseudogene (PMID: 19953608)._" }, { "baseStrength": "Benign", "id": "1620856074", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856074", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply. DCLRE1C missense variants are a known mechanism of disease.\n" }, { "baseStrength": "Benign", "id": "1620856074", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856074", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply. DCLRE1C missense variants are a known mechanism of disease.\n" }, { "baseStrength": "Benign", "id": "1620856074", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856074", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply. DCLRE1C missense variants are a known mechanism of disease.\n" }, { "baseStrength": "Benign", "id": "1620856074", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856074", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply. DCLRE1C missense variants are a known mechanism of disease.\n" }, { "baseStrength": "Pathogenic", "id": "1620856067", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856067", "label": "PM4", "strengthDescriptor": "Moderate", "text": "When applied to deletion variants, the deleted region must contain a known **pathogenic** or **likely pathogenic** variant that is not predicted/observed to alter splicing." }, { "baseStrength": "Pathogenic", "id": "1620856067", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856067", "label": "PM4", "strengthDescriptor": "Supporting", "text": "When applied to deletion variants, the deleted region must contain a known **VUS** variant that is not predicted/observed to alter splicing." }, { "baseStrength": "Benign", "id": "1620856093", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856093", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620856093", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856093", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620856093", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856093", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620856093", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856093", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620856092", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856092", "label": "PS1", "strengthDescriptor": "Strong", "text": "It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T.\n\nApplicable if the previously established variant is classified as **pathogenic** by SCID VCEP specifications for _DCLRE1C._" }, { "baseStrength": "Pathogenic", "id": "1620856092", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856092", "label": "PS1", "strengthDescriptor": "Moderate", "text": "It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T\n\nApplicable if the previously established variant is classified as **likely pathogenic** by SCID VCEP specifications for _DCLRE1C._" }, { "baseStrength": "Pathogenic", "id": "1620856091", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856091", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620856091", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856091", "label": "PS2", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620856091", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856091", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620856091", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856091", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620856090", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856090", "label": "PP4", "strengthDescriptor": "Strong", "text": "A patient score of ≥ 7 points1. \n\n1CNV (Copy number variation) testing is required to consider PP4\\_Strong in order to certify that the variant in question is the causative for the phenotype and not one CNV event corrected by gene therapy and not identified previously (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620856090", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856090", "label": "PP4", "strengthDescriptor": "Moderate", "text": "A patient score of 2-\\<7 points (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620856090", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856090", "label": "PP4", "strengthDescriptor": "Supporting", "text": "A patient score of 1-\\<2 points (see instructions below)." }, { "baseStrength": "Benign", "id": "1620856086", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856086", "label": "BS1", "strengthDescriptor": "Strong", "text": "gnomAD popmax filtering allele frequency >0.000781\n\n1 Consider also bottleneck populations." }, { "baseStrength": "Pathogenic", "id": "1620856079", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856079", "label": "PM1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply. No known missense variation hot spots in the DCLRE1C gene have been described. See PVS1 for the note about a known hotspot for DCLRE1C deletion variants. Note: Exons 1-3 and exons 1-4 have been reported as a hot spot for deletion variants as a result of homologous recombination of the wild-type DCLRE1C gene with a DCLRE1C pseudogene (PMID: 19953608)." }, { "baseStrength": "Pathogenic", "id": "1620856079", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856079", "label": "PM1", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply. No known missense variation hot spots in the DCLRE1C gene have been described. See PVS1 for the note about a known hotspot for DCLRE1C deletion variants. Note: Exons 1-3 and exons 1-4 have been reported as a hot spot for deletion variants as a result of homologous recombination of the wild-type DCLRE1C gene with a DCLRE1C pseudogene (PMID: 19953608)." }, { "baseStrength": "Pathogenic", "id": "1620856079", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856079", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply. No known missense variation hot spots in the DCLRE1C gene have been described. See PVS1 for the note about a known hotspot for DCLRE1C deletion variants. Note: Exons 1-3 and exons 1-4 have been reported as a hot spot for deletion variants as a result of homologous recombination of the wild-type DCLRE1C gene with a DCLRE1C pseudogene (PMID: 19953608)." }, { "baseStrength": "Pathogenic", "id": "1620856079", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856079", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply. No known missense variation hot spots in the DCLRE1C gene have been described. See PVS1 for the note about a known hotspot for DCLRE1C deletion variants. Note: Exons 1-3 and exons 1-4 have been reported as a hot spot for deletion variants as a result of homologous recombination of the wild-type DCLRE1C gene with a DCLRE1C pseudogene (PMID: 19953608)." }, { "baseStrength": "Pathogenic", "id": "1620856075", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856075", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for DCLRE1C (Z = -0.68) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in DCLRE1C.\n" }, { "baseStrength": "Pathogenic", "id": "1620856075", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856075", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for DCLRE1C (Z = -0.68) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in DCLRE1C.\n" }, { "baseStrength": "Pathogenic", "id": "1620856075", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856075", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for DCLRE1C (Z = -0.68) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in DCLRE1C.\n" }, { "baseStrength": "Pathogenic", "id": "1620856075", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856075", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for DCLRE1C (Z = -0.68) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in DCLRE1C.\n" }, { "baseStrength": "Pathogenic", "id": "1620856071", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856071", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Applicable if a previously established variant is classified as **pathogenic** by SCID VCEP specifications for _DCLRE1C._ Previously established variant must be classified by SCID VCEP specifications for _DCLRE1C._" }, { "baseStrength": "Pathogenic", "id": "1620856071", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856071", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Applicable if a previously established variant is classified as **likely pathogenic** by SCID VCEP specifications for _DCLRE1C._ Previously established variant must be classified by SCID VCEP specifications for _DCLRE1C._" }, { "baseStrength": "Pathogenic", "id": "1620856068", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856068", "label": "PM2", "strengthDescriptor": "Supporting", "text": "gnomAD popmax filtering allele frequency  \\<0.00003266 \n\n* An additional requirement is that **no homozygotes** have been observed in gnomAD." }, { "baseStrength": "Benign", "id": "1620856087", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856087", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620856087", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856087", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620856087", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856087", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620856087", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856087", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620856083", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856083", "label": "BP7", "strengthDescriptor": "Supporting", "text": "* Applicable to both synonymous variants and deep intronic variants affecting nucleotides at or beyond the +7 (donor) and -21 (acceptor) positions.\n* The variant should be predicted not to impact splicing by at least two out of three _in silico_ tools (freely available tools include GeneSplicer, MaxEntScan, NNSplice, SpliceAI, Splicing Sequences Finder (SSF), and varSEAK).\n* Given the potential for poor conservation of genes related to T cell and B cell development among vertebrates, nucleotide conservation is **not required** in order to apply BP7." }, { "baseStrength": "Pathogenic", "id": "1620856082", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856082", "label": "PM6", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620856082", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856082", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620856082", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856082", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Benign", "id": "1620856072", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856072", "label": "BS3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: There is not a well-established functional study which can rule out all damaging effects on protein function." }, { "baseStrength": "Benign", "id": "1620856072", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856072", "label": "BS3", "strengthDescriptor": "Strong", "text": "Not Applicable: There is not a well-established functional study which can rule out all damaging effects on protein function." }, { "baseStrength": "Benign", "id": "1620856072", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856072", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Not Applicable: There is not a well-established functional study which can rule out all damaging effects on protein function." }, { "baseStrength": "Benign", "id": "1620856072", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856072", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Not Applicable: There is not a well-established functional study which can rule out all damaging effects on protein function." }, { "baseStrength": "Benign", "id": "1620856070", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856070", "label": "BP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620856070", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856070", "label": "BP2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620856070", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856070", "label": "BP2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620856070", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856070", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620856069", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856069", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620856069", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856069", "label": "PS4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620856069", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856069", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620856069", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620856069", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Not Applicable" } ], "diseases": [ { "id": "MONDO:0011225", "iri": "https://genboree.org/cspec/Disease/id/467888103", "label": "severe combined immunodeficiency due to DCLRE1C deficiency" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467823136", "label": "DCLRE1C" } ], "ruleSet": { "id": "1565017056", "iri": "https://genboree.org/cspec/RuleSet/id/1565017056" }, "svi": { "id": "GN116", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1565017043", "label": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DCLRE1C Version 1.0.0" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "1620857119", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857119", "label": "PP4", "strengthDescriptor": "Strong", "text": "A patient score of ≥ 6 points1. \n\n1CNV (Copy number variation) testing is required to consider PP4\\_Strong in order to certify that the variant in question is the causative for the phenotype and not one CNV event corrected by gene therapy and not identified previously (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620857119", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857119", "label": "PP4", "strengthDescriptor": "Moderate", "text": "A patient score of 2-\\<6 points (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620857119", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857119", "label": "PP4", "strengthDescriptor": "Supporting", "text": "A patient score of 1-\\<2 points (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620857117", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857117", "label": "PP1", "strengthDescriptor": "Strong", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Pathogenic", "id": "1620857117", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857117", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Pathogenic", "id": "1620857117", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857117", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Benign", "id": "1620857116", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857116", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620857116", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857116", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620857116", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857116", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620857116", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857116", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620857105", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857105", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Only to be used when the variant is observed in the homozygous state in a healthy adult." }, { "baseStrength": "Pathogenic", "id": "1620857096", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857096", "label": "PM4", "strengthDescriptor": "Moderate", "text": "When applied to deletion variants, the deleted region must contain a known **pathogenic** or **likely pathogenic** variant that is not predicted/observed to alter splicing." }, { "baseStrength": "Pathogenic", "id": "1620857096", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857096", "label": "PM4", "strengthDescriptor": "Supporting", "text": "When applied to deletion variants, the deleted region must contain a known **VUS** variant that is not predicted/observed to alter splicing." }, { "baseStrength": "Benign", "id": "1620857123", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857123", "label": "BP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620857123", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857123", "label": "BP4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620857123", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857123", "label": "BP4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620857123", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857123", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620857120", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857120", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620857120", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857120", "label": "PS2", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620857120", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857120", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620857120", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857120", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620857114", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857114", "label": "PS3", "strengthDescriptor": "Strong", "text": "PS3 may potentially be applied at the default strength level of strong for evidence from an animal model expressing the variant of interest and recapitulating the IL7R-SCID phenotype. Animal models will be reviewed on a case-by-case basis by the VCEP to determine the appropriate strength level." }, { "baseStrength": "Pathogenic", "id": "1620857114", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857114", "label": "PS3", "strengthDescriptor": "Supporting", "text": "PS3\\_Supporting can be applied based on an abnormal result in **at least** **one** approved _in vitro_ assay (IL-7-induced Jak3 phosphorylation assay, IL-7 binding assay, IL-7-induced STAT5 DNA binding/transcriptional induction).\n\n* Approved assay instances:\n * IL-7-induced Jak3 phosphorylation assay\n * Roifman et al., 2000 (PMID: 11023514)\n * IL-7 binding assay\n * Puel et al., 1998 (PMID: 9843216)\n * IL-7-induced STAT5 DNA binding/transcriptional induction\n * Puel et al., 1998 (PMID: 9843216)\n\n_At least one previously observed proband with the expressed IL7R variant meeting PP4 is required to apply PS3 at any strength on the basis of a cellular model/in vitro study._" }, { "baseStrength": "Benign", "id": "1620857112", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857112", "label": "BP7", "strengthDescriptor": "Supporting", "text": "* Applicable to both synonymous variants and deep intronic variants affecting nucleotides at or beyond the +7 (donor) and -21 (acceptor) positions.\n* The variant should be predicted not to impact splicing by at least two out of three _in silico_ tools (freely available tools include GeneSplicer, MaxEntScan, NNSplice, SpliceAI, Splicing Sequences Finder (SSF), and varSEAK).\n* Given the potential for poor conservation of genes related to T cell and B cell development among vertebrates, nucleotide conservation is not required in order to apply BP7." }, { "baseStrength": "Pathogenic", "id": "1620857109", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857109", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042))." }, { "baseStrength": "Pathogenic", "id": "1620857109", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857109", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with two specifications:\n\n* For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 8, or variants in the last 50 nucleotides of the penultimate exon after c.826, codon 276, in exon 7), at least one pathogenic variant **must be** present downstream in order to apply PVS1\\_Strong.\n* PVS1\\_Strong can be applied to variants not predicted to undergo nonsense-mediated decay but causing truncation of the transmembrane domain (which begins at amino acid 240) or any distal region (i.e. cytoplasmatic domain)." }, { "baseStrength": "Pathogenic", "id": "1620857109", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857109", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:\n\n* For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 8, or variants in the last 50 nucleotides of the penultimate exon after c.826, codon 276, in exon 7), when at least one pathogenic variant is **not** present downstream downgrade to PVS1\\_Moderate." }, { "baseStrength": "Pathogenic", "id": "1620857106", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857106", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620857106", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857106", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620857106", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857106", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620857106", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857106", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620857103", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857103", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply. IL7R missense variants are a known mechanism of disease.\n" }, { "baseStrength": "Benign", "id": "1620857103", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857103", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply. IL7R missense variants are a known mechanism of disease.\n" }, { "baseStrength": "Benign", "id": "1620857103", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857103", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply. IL7R missense variants are a known mechanism of disease.\n" }, { "baseStrength": "Benign", "id": "1620857103", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857103", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply. IL7R missense variants are a known mechanism of disease.\n" }, { "baseStrength": "Benign", "id": "1620857101", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857101", "label": "BS3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: There is not a well-established functional study which can rule out all damaging effects on protein function." }, { "baseStrength": "Benign", "id": "1620857101", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857101", "label": "BS3", "strengthDescriptor": "Strong", "text": "Not Applicable: There is not a well-established functional study which can rule out all damaging effects on protein function." }, { "baseStrength": "Benign", "id": "1620857101", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857101", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Not Applicable: There is not a well-established functional study which can rule out all damaging effects on protein function." }, { "baseStrength": "Benign", "id": "1620857101", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857101", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Not Applicable: There is not a well-established functional study which can rule out all damaging effects on protein function." }, { "baseStrength": "Benign", "id": "1620857099", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857099", "label": "BP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620857099", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857099", "label": "BP2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620857099", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857099", "label": "BP2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620857099", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857099", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620857113", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857113", "label": "PP3", "strengthDescriptor": "Supporting", "text": "* Only applicable to synonymous or intronic variants predicted to impact splicing by SpliceAI with a delta score greater than or equal to 0.2.\n* **Do not apply to missense variants.**" }, { "baseStrength": "Pathogenic", "id": "1620857107", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857107", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _IL7R._" }, { "baseStrength": "Pathogenic", "id": "1620857107", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857107", "label": "PM3", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _IL7R._" }, { "baseStrength": "Pathogenic", "id": "1620857107", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857107", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _IL7R._" }, { "baseStrength": "Pathogenic", "id": "1620857107", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857107", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _IL7R._" }, { "baseStrength": "Benign", "id": "1620857102", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857102", "label": "BS4", "strengthDescriptor": "Strong", "text": "Can be applied without additional specifications." }, { "baseStrength": "Pathogenic", "id": "1620857100", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857100", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Applicable if a previously established variant is classified as **pathogenic** by SCID VCEP specifications for _IL7R._ Previously established variant must be classified by SCID VCEP specifications for _IL7R._" }, { "baseStrength": "Pathogenic", "id": "1620857100", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857100", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Applicable if a previously established variant is classified as **likely pathogenic** by SCID VCEP specifications for _IL7R._ Previously established variant must be classified by SCID VCEP specifications for _IL7R._" }, { "baseStrength": "Pathogenic", "id": "1620857097", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857097", "label": "PM2", "strengthDescriptor": "Supporting", "text": "gnomAD popmax filtering allele frequency \\<0.00004129.\n\n* An additional requirement is that **no homozygotes** have been observed in gnomAD." }, { "baseStrength": "Benign", "id": "1620857118", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857118", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620857118", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857118", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620857118", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857118", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620857118", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857118", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620857115", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857115", "label": "BS1", "strengthDescriptor": "Strong", "text": "gnomAD popmax filtering allele frequency >0.001261\n\n1Consider also bottleneck populations." }, { "baseStrength": "Pathogenic", "id": "1620857108", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857108", "label": "PM1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620857108", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857108", "label": "PM1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620857108", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857108", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620857108", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857108", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620857104", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857104", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for IL7R (Z = -1.29) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in IL7R.\n" }, { "baseStrength": "Pathogenic", "id": "1620857104", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857104", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for IL7R (Z = -1.29) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in IL7R.\n" }, { "baseStrength": "Pathogenic", "id": "1620857104", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857104", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for IL7R (Z = -1.29) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in IL7R.\n" }, { "baseStrength": "Pathogenic", "id": "1620857104", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857104", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for IL7R (Z = -1.29) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in IL7R.\n" }, { "baseStrength": "Benign", "id": "1620857122", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857122", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620857122", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857122", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620857122", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857122", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620857122", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857122", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620857121", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857121", "label": "PS1", "strengthDescriptor": "Strong", "text": "It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T.\n\nApplicable if the previously established variant is classified as **pathogenic** by SCID VCEP specifications for _IL7R._" }, { "baseStrength": "Pathogenic", "id": "1620857121", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857121", "label": "PS1", "strengthDescriptor": "Moderate", "text": "It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T\n\nApplicable if the previously established variant is classified as **likely pathogenic** by SCID VCEP specifications for _IL7R._" }, { "baseStrength": "Pathogenic", "id": "1620857111", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857111", "label": "PM6", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620857111", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857111", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620857111", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857111", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Benign", "id": "1620857110", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857110", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "gnomAD popmax filtering allele frequency >0.00566." }, { "baseStrength": "Pathogenic", "id": "1620857098", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857098", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620857098", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857098", "label": "PS4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620857098", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857098", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620857098", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620857098", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Not Applicable" } ], "diseases": [ { "id": "MONDO:0012163", "iri": "https://genboree.org/cspec/Disease/id/467871171", "label": "immunodeficiency 104" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467831052", "label": "IL7R" } ], "ruleSet": { "id": "1566364251", "iri": "https://genboree.org/cspec/RuleSet/id/1566364251" }, "svi": { "id": "GN119", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1566364238", "label": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for IL7R Version 1.0.0" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "1622503925", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503925", "label": "PS3", "strengthDescriptor": "Supporting", "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 isomerhydrolase activity, cutoff is ≤10% of wild-type control." }, { "baseStrength": "Benign", "id": "1622503924", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503924", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for RPE65." }, { "baseStrength": "Benign", "id": "1622503924", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503924", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for RPE65." }, { "baseStrength": "Benign", "id": "1622503924", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503924", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for RPE65." }, { "baseStrength": "Benign", "id": "1622503924", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503924", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for RPE65." }, { "baseStrength": "Pathogenic", "id": "1622503913", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503913", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1622503913", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503913", "label": "PS4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1622503913", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503913", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1622503913", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503913", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1622503908", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503908", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Not applicable for splicing effects (replaced by BP7\\_Strong (RNA)).\n\nSee attached table for list of acceptable functional studies.\n\nFor studies reporting isomerohydrolase activity, activity must be ≥50% of wild-type control." }, { "baseStrength": "Benign", "id": "1622503932", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503932", "label": "BP7", "strengthDescriptor": "Strong", "text": "BP7\\_Strong (RNA) Used to designate capture of splicing data (not BS3). See RPE65-specific PVS1 Decision Tree, file attached, for weighting and combining with other codes." }, { "baseStrength": "Benign", "id": "1622503932", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503932", "label": "BP7", "strengthDescriptor": "Supporting", "text": "Use for 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 RPE65-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" }, { "baseStrength": "Pathogenic", "id": "1622503927", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503927", "label": "PP1", "strengthDescriptor": "Strong", "text": "Co-segregation with disease in multiple affected family members and evidence that this variant and another RPE65 variant are _in trans_.\n\n* Requires segregation in proband plus ≥3 similarly affected relatives" }, { "baseStrength": "Pathogenic", "id": "1622503927", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503927", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Co-segregation with disease in multiple affected family members and evidence that this variant and another RPE65 variant are _in trans_.\n\n* Requires segregation in proband plus 2 similarly affected relatives" }, { "baseStrength": "Pathogenic", "id": "1622503927", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503927", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Co-segregation with disease in multiple affected family members and evidence that this variant and another RPE65 variant are _in trans_.\n\n* Requires segregation in proband plus 1 similarly affected relative" }, { "baseStrength": "Benign", "id": "1622503923", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503923", "label": "BP2", "strengthDescriptor": "Supporting", "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." }, { "baseStrength": "Benign", "id": "1622503919", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503919", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for RPE65." }, { "baseStrength": "Benign", "id": "1622503919", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503919", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for RPE65." }, { "baseStrength": "Benign", "id": "1622503919", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503919", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for RPE65." }, { "baseStrength": "Benign", "id": "1622503919", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503919", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for RPE65." }, { "baseStrength": "Pathogenic", "id": "1622503918", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503918", "label": "PM4", "strengthDescriptor": "Moderate", "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)." }, { "baseStrength": "Pathogenic", "id": "1622503918", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503918", "label": "PM4", "strengthDescriptor": "Supporting", "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)." }, { "baseStrength": "Benign", "id": "1622503917", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503917", "label": "BS1", "strengthDescriptor": "Strong", "text": "Allele frequency greater than expected for disorder. Use gnomAD PopMax FAF if available.\n\n* Allele frequency of between 8x10-3 and 8x10-4" }, { "baseStrength": "Pathogenic", "id": "1622503916", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503916", "label": "PM3", "strengthDescriptor": "Very Strong", "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" }, { "baseStrength": "Pathogenic", "id": "1622503916", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503916", "label": "PM3", "strengthDescriptor": "Strong", "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" }, { "baseStrength": "Pathogenic", "id": "1622503916", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503916", "label": "PM3", "strengthDescriptor": "Moderate", "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" }, { "baseStrength": "Pathogenic", "id": "1622503916", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503916", "label": "PM3", "strengthDescriptor": "Supporting", "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" }, { "baseStrength": "Pathogenic", "id": "1622503911", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503911", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for RPE65." }, { "baseStrength": "Pathogenic", "id": "1622503911", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503911", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for RPE65." }, { "baseStrength": "Pathogenic", "id": "1622503911", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503911", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for RPE65." }, { "baseStrength": "Pathogenic", "id": "1622503911", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503911", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for RPE65." }, { "baseStrength": "Pathogenic", "id": "1622503910", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503910", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n\n* Met by variants encoding missense substitutions at His180, His182, His241, His313, Glu417, or His527, which are required residues located within the active site[16](#PMID_34492281).\n* Met by variants encoding missense substitutions between Ala107 and Gly125, which are known to mediate localization to the ER membrane[15](#PMID_36265895)." }, { "baseStrength": "Pathogenic", "id": "1622503909", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503909", "label": "PM5", "strengthDescriptor": "Moderate", "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* For assessing same amino acid changes, SpliceAI scores for both variants should be within 10% of each other." }, { "baseStrength": "Pathogenic", "id": "1622503909", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503909", "label": "PM5", "strengthDescriptor": "Supporting", "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* For assessing same amino acid changes, SpliceAI scores for both variants should be within 10% of each other." }, { "baseStrength": "Pathogenic", "id": "1622503906", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503906", "label": "PP4", "strengthDescriptor": "Moderate", "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." }, { "baseStrength": "Pathogenic", "id": "1622503906", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503906", "label": "PP4", "strengthDescriptor": "Supporting", "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." }, { "baseStrength": "Pathogenic", "id": "1622503931", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503931", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1622503931", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503931", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1622503931", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503931", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1622503931", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503931", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1622503926", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503926", "label": "BP4", "strengthDescriptor": "Moderate", "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." }, { "baseStrength": "Benign", "id": "1622503926", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503926", "label": "BP4", "strengthDescriptor": "Supporting", "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 RPE65-specific PVS1 Decision Tree **part (a)** for SpliceAI flowchart.\n\n* Please note that BP7 can be met as well." }, { "baseStrength": "Benign", "id": "1622503920", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503920", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected members of a family.\n\n* One or both variants are absent in a similarly affected family member." }, { "baseStrength": "Benign", "id": "1622503915", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503915", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Use gnomAD PopMax FAF if available, cutoff of  ≥8 x 10-3\n\n* Use large population databases (i.e. gnomAD)." }, { "baseStrength": "Benign", "id": "1622503907", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503907", "label": "BS2", "strengthDescriptor": "Strong", "text": "Variant is present in ≥ 3 homozygotes without any features of the phenotype. This rule only applies to individuals found in the literature who have been well-phenotyped  and are unaffected by age 40.\n\nPresence in databases such as gnomAD are not considered." }, { "baseStrength": "Benign", "id": "1622503930", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503930", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1622503930", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503930", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1622503930", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503930", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1622503930", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503930", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1622503928", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503928", "label": "PVS1", "strengthDescriptor": "Very Strong", "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 [16](#pmid_30192042) and as updated by the ClinGen SVI Splicing Subgroup [17](#pmid_37352859)\n* Refer to RPE65-specific PVS1 Decision Tree, file attached.\n * PVS1: Predicted splice defects at +/- 1,2 in exons 1-14\n * PVS1: Single to multi-exon deletions, with or without predicted NMD. All exons are considered critical to protein function.\n * PVS1: Nonsense or frameshift mutations from p.Ser2 through p.Gly528\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." }, { "baseStrength": "Pathogenic", "id": "1622503928", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503928", "label": "PVS1", "strengthDescriptor": "Strong", "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 [16](#pmid_30192042) and as updated by the ClinGen SVI Splicing Subgroup [17](#pmid_37352859)\n* Refer to RPE65-specific PVS1 Decision Tree, file attached.\n * PVS1\\_Strong:Applied to variants in the initiation codon. The second in-frame methionine is located at residue 93, and there is no known study indicating that this methionine in _RPE65_ can be used as start codon. Variants affecting Met1 can lead to a complete absence of the protein product. Even though we cannot exclude the possibility of a 2nd Met being used as start codon, the translation efficiency maybe significantly reduced due to lack of other important elements (Kozak sequence, etc.). Also, there are multiple variants located upstream of Met93 having been reported as a pathogenic variant in HGMD and ClinVar, evidence that this region of the protein is functionally important.\n * PVS1\\_Strong: Nonsense or frameshift mutations from p.Leu529 through p.Ser533\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." }, { "baseStrength": "Pathogenic", "id": "1622503922", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503922", "label": "PS1", "strengthDescriptor": "Strong", "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* For assessing same amino acid changes, SpliceAI scores for both variants should be within 10% of each other.\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 RPE65-specific PVS1 Decision Tree **part (b)** (Table 2 from Walker 2023)." }, { "baseStrength": "Pathogenic", "id": "1622503922", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503922", "label": "PS1", "strengthDescriptor": "Moderate", "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* For assessing same amino acid changes, SpliceAI scores for both variants should be within 10% of each other.\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 RPE65-specific PVS1 Decision Tree **part (b)** (Table 2 from Walker 2023)." }, { "baseStrength": "Pathogenic", "id": "1622503922", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503922", "label": "PS1", "strengthDescriptor": "Supporting", "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 RPE65-specific PVS1 Decision Tree **part (b)** (Table 2 from Walker 2023)." }, { "baseStrength": "Pathogenic", "id": "1622503914", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503914", "label": "PS2", "strengthDescriptor": "Very Strong", "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). Use option 3 “Phenotype consistent with gene but not highly specific and high genetic heterogeneity” (maximum 0.5 points/proband)\n* Total of 4 or more points required for Very Strong level" }, { "baseStrength": "Pathogenic", "id": "1622503914", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503914", "label": "PS2", "strengthDescriptor": "Strong", "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). Use option 3 “Phenotype consistent with gene but not highly specific and high genetic heterogeneity” (maximum 0.5 points/proband)\n* Total of 2.00 - 3.75 points required for Strong level" }, { "baseStrength": "Pathogenic", "id": "1622503914", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503914", "label": "PS2", "strengthDescriptor": "Moderate", "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). Use option 3 “Phenotype consistent with gene but not highly specific and high genetic heterogeneity” (maximum 0.5 points/proband)\n* Total of 1.00 - 1.75 points required for Moderate level" }, { "baseStrength": "Pathogenic", "id": "1622503914", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503914", "label": "PS2", "strengthDescriptor": "Supporting", "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). Use option 3 “Phenotype consistent with gene but not highly specific and high genetic heterogeneity” (maximum 0.5 points/proband)\n* Total of 0.50 - 0.75 points required for Supporting level" }, { "baseStrength": "Pathogenic", "id": "1622503905", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503905", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n\n* Used if the gnomAD PopMax Filtering Allele Frequency (FAF) is ≤ 2.0 x 10-4." }, { "baseStrength": "Benign", "id": "1622503929", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503929", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Due to the high genetic heterogeneity and limited phenotypic specificities of retinal dystrophies, this rule should not be used.\nAdditionally, the presence of this variant could simply represent carrier status.\n" }, { "baseStrength": "Benign", "id": "1622503929", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503929", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable: Due to the high genetic heterogeneity and limited phenotypic specificities of retinal dystrophies, this rule should not be used.\nAdditionally, the presence of this variant could simply represent carrier status.\n" }, { "baseStrength": "Benign", "id": "1622503929", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503929", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: Due to the high genetic heterogeneity and limited phenotypic specificities of retinal dystrophies, this rule should not be used.\nAdditionally, the presence of this variant could simply represent carrier status.\n" }, { "baseStrength": "Benign", "id": "1622503929", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503929", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: Due to the high genetic heterogeneity and limited phenotypic specificities of retinal dystrophies, this rule should not be used.\nAdditionally, the presence of this variant could simply represent carrier status.\n" }, { "baseStrength": "Pathogenic", "id": "1622503921", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503921", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Use the PS2 code in lieu of using this code for de novo variants." }, { "baseStrength": "Pathogenic", "id": "1622503921", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503921", "label": "PM6", "strengthDescriptor": "Strong", "text": "Not Applicable: Use the PS2 code in lieu of using this code for de novo variants." }, { "baseStrength": "Pathogenic", "id": "1622503921", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503921", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Not Applicable: Use the PS2 code in lieu of using this code for de novo variants." }, { "baseStrength": "Pathogenic", "id": "1622503921", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503921", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Not Applicable: Use the PS2 code in lieu of using this code for de novo variants." }, { "baseStrength": "Pathogenic", "id": "1622503912", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503912", "label": "PP3", "strengthDescriptor": "Moderate", "text": "* For a missense variant use REVEL, requires a score of ≥ 0.774.\n* Splice variants use PP3 only at Supporting level." }, { "baseStrength": "Pathogenic", "id": "1622503912", "iri": "https://genboree.org/cspec/CriteriaCode/id/1622503912", "label": "PP3", "strengthDescriptor": "Supporting", "text": "* For a missense variant use REVEL, requires a score of 0.644 - 0.773.\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 RPE65-specific PVS1 Decision Tree **part (a)** for SpliceAI flowchart." } ], "diseases": [ { "id": "MONDO:0100368", "iri": "https://genboree.org/cspec/Disease/id/1558005557", "label": "RPE65-related recessive retinopathy" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467852566", "label": "RPE65" } ], "ruleSet": { "id": "1566365968", "iri": "https://genboree.org/cspec/RuleSet/id/1566365968" }, "svi": { "id": "GN120", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1566365955", "label": "ClinGen Leber Congenital Amaurosis/early onset Retinal Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPE65 Version 1.0.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1620858169", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858169", "label": "BP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620858169", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858169", "label": "BP4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620858169", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858169", "label": "BP4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620858169", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858169", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620858158", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858158", "label": "BP7", "strengthDescriptor": "Supporting", "text": "* Applicable to both synonymous variants and deep intronic variants affecting nucleotides at or beyond the +7 (donor) and -21 (acceptor) positions.\n* The variant should be predicted not to impact splicing by at least two out of three _in silico_ tools (freely available tools include GeneSplicer, MaxEntScan, NNSplice, SpliceAI, Splicing Sequences Finder (SSF), and varSEAK).\n* Given the potential for poor conservation of genes related to T cell and B cell development among vertebrates, nucleotide conservation is not required in order to apply BP7." }, { "baseStrength": "Pathogenic", "id": "1620858157", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858157", "label": "PM6", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620858157", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858157", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620858157", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858157", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620858152", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858152", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620858152", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858152", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620858152", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858152", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620858152", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858152", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620858150", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858150", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: The gnomAD v2.1.1 missense Z score for JAK3 (Z = 2.81) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in JAK3." }, { "baseStrength": "Pathogenic", "id": "1620858150", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858150", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: The gnomAD v2.1.1 missense Z score for JAK3 (Z = 2.81) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in JAK3." }, { "baseStrength": "Pathogenic", "id": "1620858150", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858150", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: The gnomAD v2.1.1 missense Z score for JAK3 (Z = 2.81) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in JAK3." }, { "baseStrength": "Pathogenic", "id": "1620858150", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858150", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: The gnomAD v2.1.1 missense Z score for JAK3 (Z = 2.81) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in JAK3." }, { "baseStrength": "Benign", "id": "1620858147", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858147", "label": "BS3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: There is not a well-established functional study which can rule out all damaging effects on protein function." }, { "baseStrength": "Benign", "id": "1620858147", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858147", "label": "BS3", "strengthDescriptor": "Strong", "text": "Not Applicable: There is not a well-established functional study which can rule out all damaging effects on protein function." }, { "baseStrength": "Benign", "id": "1620858147", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858147", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Not Applicable: There is not a well-established functional study which can rule out all damaging effects on protein function." }, { "baseStrength": "Benign", "id": "1620858147", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858147", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Not Applicable: There is not a well-established functional study which can rule out all damaging effects on protein function." }, { "baseStrength": "Pathogenic", "id": "1620858142", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858142", "label": "PM4", "strengthDescriptor": "Moderate", "text": "When applied to deletion variants, the deleted region must contain a known **pathogenic** or **likely pathogenic** variant that is not predicted/observed to alter splicing." }, { "baseStrength": "Pathogenic", "id": "1620858142", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858142", "label": "PM4", "strengthDescriptor": "Supporting", "text": "When applied to deletion variants, the deleted region must contain a known **VUS** variant that is not predicted/observed to alter splicing." }, { "baseStrength": "Benign", "id": "1620858162", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858162", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620858162", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858162", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620858162", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858162", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620858162", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858162", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620858151", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858151", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Only to be used when the variant is observed in the homozygous state in a healthy adult." }, { "baseStrength": "Benign", "id": "1620858149", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858149", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply. JAK3 missense variants are a known mechanism of disease.\n" }, { "baseStrength": "Benign", "id": "1620858149", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858149", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply. JAK3 missense variants are a known mechanism of disease.\n" }, { "baseStrength": "Benign", "id": "1620858149", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858149", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply. JAK3 missense variants are a known mechanism of disease.\n" }, { "baseStrength": "Benign", "id": "1620858149", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858149", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply. JAK3 missense variants are a known mechanism of disease.\n" }, { "baseStrength": "Pathogenic", "id": "1620858146", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858146", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Applicable if a previously established variant is classified as **pathogenic** by SCID VCEP specifications for _JAK3._ Previously established variant must be classified by SCID VCEP specifications for _JAK3._" }, { "baseStrength": "Pathogenic", "id": "1620858146", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858146", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Applicable if a previously established variant is classified as **likely pathogenic** by SCID VCEP specifications for _JAK3._ Previously established variant must be classified by SCID VCEP specifications for _JAK3._" }, { "baseStrength": "Benign", "id": "1620858168", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858168", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620858168", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858168", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620858168", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858168", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620858168", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858168", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620858167", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858167", "label": "PS1", "strengthDescriptor": "Strong", "text": "It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T.\n\nApplicable if the previously established variant is classified as **pathogenic** by SCID VCEP specifications for _JAK3._" }, { "baseStrength": "Pathogenic", "id": "1620858167", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858167", "label": "PS1", "strengthDescriptor": "Moderate", "text": "It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T\n\nApplicable if the previously established variant is classified as **likely pathogenic** by SCID VCEP specifications for _JAK3._" }, { "baseStrength": "Pathogenic", "id": "1620858166", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858166", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620858166", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858166", "label": "PS2", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620858166", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858166", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620858166", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858166", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620858160", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858160", "label": "PS3", "strengthDescriptor": "Strong", "text": "PS3 may potentially be applied at the default strength level of strong for evidence from an animal model expressing the variant of interest and recapitulating the JAK3-SCID phenotype. Animal models will be reviewed on a case-by-case basis by the VCEP to determine the appropriate strength level." }, { "baseStrength": "Pathogenic", "id": "1620858160", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858160", "label": "PS3", "strengthDescriptor": "Supporting", "text": "PS3\\_Supporting can be applied based on an abnormal result in an _in vitro_ kinase activity assay.\n\n* Approved assay instance: Roberts et al., 2004 (PMID: 14615376).\n\n_At least one previously observed proband with the JAK3 variant meeting PP4 is required to apply PS3 at any strength on the basis of a cellular model/in vitro study._" }, { "baseStrength": "Benign", "id": "1620858148", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858148", "label": "BS4", "strengthDescriptor": "Strong", "text": "Can be applied without additional specifications." }, { "baseStrength": "Benign", "id": "1620858145", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858145", "label": "BP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620858145", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858145", "label": "BP2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620858145", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858145", "label": "BP2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620858145", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858145", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620858165", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858165", "label": "PP4", "strengthDescriptor": "Strong", "text": "A patient score of ≥ 6 points1. \n\n1CNV (Copy number variation) testing is required to consider PP4\\_Strong in order to certify that the variant in question is the causative for the phenotype and not one CNV event corrected by gene therapy and not identified previously (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620858165", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858165", "label": "PP4", "strengthDescriptor": "Moderate", "text": "A patient score of 2-\\<6 points (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620858165", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858165", "label": "PP4", "strengthDescriptor": "Supporting", "text": "A patient score of 1-\\<2 points (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620858159", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858159", "label": "PP3", "strengthDescriptor": "Supporting", "text": "* Only applicable to synonymous or intronic variants predicted to impact splicing by SpliceAI with a delta score greater than or equal to 0.2.\n* **Do not apply to missense variants.**" }, { "baseStrength": "Pathogenic", "id": "1620858153", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858153", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _JAK3._" }, { "baseStrength": "Pathogenic", "id": "1620858153", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858153", "label": "PM3", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _JAK3._" }, { "baseStrength": "Pathogenic", "id": "1620858153", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858153", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _JAK3._" }, { "baseStrength": "Pathogenic", "id": "1620858153", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858153", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _JAK3._" }, { "baseStrength": "Benign", "id": "1620858164", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858164", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620858164", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858164", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620858164", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858164", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620858164", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858164", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Pathogenic", "id": "1620858163", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858163", "label": "PP1", "strengthDescriptor": "Strong", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Pathogenic", "id": "1620858163", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858163", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Pathogenic", "id": "1620858163", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858163", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Benign", "id": "1620858161", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858161", "label": "BS1", "strengthDescriptor": "Strong", "text": "gnomAD popmax filtering allele frequency >0.001001\n\n1Consider also bottleneck populations." }, { "baseStrength": "Benign", "id": "1620858156", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858156", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "gnomAD popmax filtering allele frequency >0.00447" }, { "baseStrength": "Pathogenic", "id": "1620858155", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858155", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042))." }, { "baseStrength": "Pathogenic", "id": "1620858155", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858155", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:\n\n* For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 24, or variants in the last 50 nucleotides of the penultimate exon after c.3157, codon 1053, in exon 23), at least one pathogenic variant **must be** present downstream in order to apply PVS1\\_Strong." }, { "baseStrength": "Pathogenic", "id": "1620858155", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858155", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:\n\n* For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 24, or variants in the last 50 nucleotides of the penultimate exon after c.3157, codon 1053, in exon 23), when at least one pathogenic variant is **not** present downstream downgrade to PVS1\\_Moderate." }, { "baseStrength": "Pathogenic", "id": "1620858154", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858154", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Defined to include missense alterations of two JH2 domain residues: R651W and C759R (PMID: 11668610)." }, { "baseStrength": "Pathogenic", "id": "1620858144", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858144", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620858144", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858144", "label": "PS4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620858144", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858144", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620858144", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858144", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620858143", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620858143", "label": "PM2", "strengthDescriptor": "Supporting", "text": "gnomAD popmax filtering allele frequency  \\<0.000115\n\n* An additional requirement is that **no homozygotes** have been observed in gnomAD." } ], "diseases": [ { "id": "MONDO:0010938", "iri": "https://genboree.org/cspec/Disease/id/467892668", "label": "T-B+ severe combined immunodeficiency due to JAK3 deficiency" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467831565", "label": "JAK3" } ], "ruleSet": { "id": "1567011294", "iri": "https://genboree.org/cspec/RuleSet/id/1567011294" }, "svi": { "id": "GN121", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1567011281", "label": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for JAK3 Version 1.0.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1620859083", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859083", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620859083", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859083", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620859083", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859083", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620859083", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859083", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Pathogenic", "id": "1620859076", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859076", "label": "PM6", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620859076", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859076", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620859076", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859076", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Benign", "id": "1620859075", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859075", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "gnomAD popmax filtering allele frequency >0.00872." }, { "baseStrength": "Pathogenic", "id": "1620859073", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859073", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Strength is dependent upon the location of the variant within specific functional domains (PMID: 26996199):\n\n* PM1\\_Moderate: missense variant located in the **NBD domain** (amino acids 394-460) and **DDBD domain** (amino acids 461-517)." }, { "baseStrength": "Pathogenic", "id": "1620859073", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859073", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Strength is dependent upon the location of the variant within specific functional domains (PMID: 26996199):\n\n* PM1\\_Supporting: missense variant located elsewhere in the **core domain** (amino acids 387-1011)" }, { "baseStrength": "Pathogenic", "id": "1620859071", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859071", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620859071", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859071", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620859071", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859071", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620859071", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859071", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620859070", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859070", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Only to be used when the variant is observed in the homozygous state in a healthy adult." }, { "baseStrength": "Benign", "id": "1620859068", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859068", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620859068", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859068", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620859068", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859068", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620859068", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859068", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Pathogenic", "id": "1620859062", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859062", "label": "PM2", "strengthDescriptor": "Supporting", "text": "gnomAD popmax filtering allele frequency  \\<0.000102 \n\n* An additional requirement is that **no homozygotes** have been observed in gnomAD." }, { "baseStrength": "Benign", "id": "1620859087", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859087", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620859087", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859087", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620859087", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859087", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620859087", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859087", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620859086", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859086", "label": "PS1", "strengthDescriptor": "Strong", "text": "It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T.\n\nApplicable if the previously established variant is classified as **pathogenic** by SCID VCEP specifications for _RAG1._" }, { "baseStrength": "Pathogenic", "id": "1620859086", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859086", "label": "PS1", "strengthDescriptor": "Moderate", "text": "It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T\n\nApplicable if the previously established variant is classified as **likely pathogenic** by SCID VCEP specifications for _RAG1._" }, { "baseStrength": "Pathogenic", "id": "1620859082", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859082", "label": "PP1", "strengthDescriptor": "Strong", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Pathogenic", "id": "1620859082", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859082", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Pathogenic", "id": "1620859082", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859082", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Benign", "id": "1620859080", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859080", "label": "BS1", "strengthDescriptor": "Strong", "text": "gnomAD popmax filtering allele frequency  >0.001951\n\n1 Consider also bottleneck populations." }, { "baseStrength": "Pathogenic", "id": "1620859079", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859079", "label": "PS3", "strengthDescriptor": "Strong", "text": "PS3 may potentially be applied at the default strength level of strong for evidence from an animal model expressing the variant of interest and recapitulating the RAG1-SCID phenotype." }, { "baseStrength": "Pathogenic", "id": "1620859079", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859079", "label": "PS3", "strengthDescriptor": "Moderate", "text": "The strength of evidence from cellular models/_in vitro_ studies is dependent upon the abnormal result in a V(D)J recombination assay:\n\n* PS3\\_Moderate: \\<25% of wild-type activity in Lee et al., 2014 (PMID: 24290284);\n\n_At least one previously observed proband with the expressed RAG1 variant meeting PP4 is required to apply PS3 at any strength._" }, { "baseStrength": "Pathogenic", "id": "1620859079", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859079", "label": "PS3", "strengthDescriptor": "Supporting", "text": "The strength of evidence from cellular models/_in vitro_ studies is dependent upon the abnormal result in a V(D)J recombination assay:\n\n* PS3\\_Supporting:\n * 25-60% of wild-type activity in Lee et al., 2014 (PMID: 24290284) **OR**\n * Reduced activity compared to wild type in Corneo et al., 2001 (PMID: 11313270);\n\n_At least one previously observed proband with the expressed RAG1 variant meeting PP4 is required to apply PS3 at any strength._" }, { "baseStrength": "Benign", "id": "1620859077", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859077", "label": "BP7", "strengthDescriptor": "Supporting", "text": "* Applicable to both synonymous variants and deep intronic variants affecting nucleotides at or beyond the +7 (donor) and -21 (acceptor) positions.\n* The variant should be predicted not to impact splicing by at least two out of three _in silico_ tools (freely available tools include GeneSplicer, MaxEntScan, NNSplice, SpliceAI, Splicing Sequences Finder (SSF), and varSEAK).\n* Given the potential for poor conservation of genes related to T cell and B cell development among vertebrates, nucleotide conservation is **not required** in order to apply BP7." }, { "baseStrength": "Benign", "id": "1620859067", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859067", "label": "BS4", "strengthDescriptor": "Strong", "text": "Can be applied without additional specifications." }, { "baseStrength": "Pathogenic", "id": "1620859063", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859063", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620859063", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859063", "label": "PS4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620859063", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859063", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620859063", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859063", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620859061", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859061", "label": "PM4", "strengthDescriptor": "Moderate", "text": "When applied to deletion variants, the deleted region must contain a known **pathogenic** or **likely pathogenic** variant that is not predicted/observed to alter splicing." }, { "baseStrength": "Pathogenic", "id": "1620859061", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859061", "label": "PM4", "strengthDescriptor": "Supporting", "text": "When applied to deletion variants, the deleted region must contain a known **VUS** variant that is not predicted/observed to alter splicing." }, { "baseStrength": "Benign", "id": "1620859088", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859088", "label": "BP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620859088", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859088", "label": "BP4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620859088", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859088", "label": "BP4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620859088", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859088", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620859078", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859078", "label": "PP3", "strengthDescriptor": "Supporting", "text": "* Only applicable to synonymous or intronic variants predicted to impact splicing by SpliceAI with a delta score greater than or equal to 0.2.\n* **Do not apply to missense variants.**" }, { "baseStrength": "Pathogenic", "id": "1620859085", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859085", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620859085", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859085", "label": "PS2", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620859085", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859085", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620859085", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859085", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Benign", "id": "1620859081", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859081", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620859081", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859081", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620859081", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859081", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620859081", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859081", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620859074", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859074", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with two specifications:\n\n* Given that the _RAG1_ protein is encoded by a single exon (based on MANE Select transcript NM\\_000448.3) and nonsense-mediated decay is not predicted for nonsense or frameshift variants, PVS1 cannot be applied at the default strength to RAG1 variants (indicated by the red boxes in the Flowchart attached), **except** in the case of full gene deletion **or** removing/altering critical domain for the protein (NBD domain, DDBD domain, and core domain, indicated by the purple in the Flowchart).\n* PVS1 can be applied to variants not predicted to undergo nonsense-mediated decay when removing/altering the critical NBD domain (aa 394-460), DDBD domain (aa 461-517), and core domain (aa 387-1011) based on recommendations from Walker et al., preprint." }, { "baseStrength": "Pathogenic", "id": "1620859074", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859074", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:\n\n* For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein, at least one pathogenic variant **must be** present downstream in order to apply PVS1\\_Strong." }, { "baseStrength": "Pathogenic", "id": "1620859074", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859074", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:\n\n* For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein, when at least one pathogenic variant is **not** present downstream, downgrade to PVS1\\_Moderate." }, { "baseStrength": "Pathogenic", "id": "1620859072", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859072", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _RAG1._" }, { "baseStrength": "Pathogenic", "id": "1620859072", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859072", "label": "PM3", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _RAG1._" }, { "baseStrength": "Pathogenic", "id": "1620859072", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859072", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _RAG1._" }, { "baseStrength": "Pathogenic", "id": "1620859072", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859072", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _RAG1._" }, { "baseStrength": "Pathogenic", "id": "1620859069", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859069", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for RAG1 (Z = 0.58) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in RAG1.\n" }, { "baseStrength": "Pathogenic", "id": "1620859069", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859069", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for RAG1 (Z = 0.58) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in RAG1.\n" }, { "baseStrength": "Pathogenic", "id": "1620859069", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859069", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for RAG1 (Z = 0.58) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in RAG1.\n" }, { "baseStrength": "Pathogenic", "id": "1620859069", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859069", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for RAG1 (Z = 0.58) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in RAG1.\n" }, { "baseStrength": "Benign", "id": "1620859066", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859066", "label": "BS3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: There is not a well-established functional study which can rule out all damaging effects on protein function." }, { "baseStrength": "Benign", "id": "1620859066", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859066", "label": "BS3", "strengthDescriptor": "Strong", "text": "Not Applicable: There is not a well-established functional study which can rule out all damaging effects on protein function." }, { "baseStrength": "Benign", "id": "1620859066", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859066", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Not Applicable: There is not a well-established functional study which can rule out all damaging effects on protein function." }, { "baseStrength": "Benign", "id": "1620859066", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859066", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Not Applicable: There is not a well-established functional study which can rule out all damaging effects on protein function." }, { "baseStrength": "Benign", "id": "1620859064", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859064", "label": "BP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620859064", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859064", "label": "BP2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620859064", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859064", "label": "BP2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620859064", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859064", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620859084", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859084", "label": "PP4", "strengthDescriptor": "Strong", "text": "A patient score of ≥ 4 points1. \n\n1CNV (Copy number variation) testing is required to consider PP4\\_Strong in order to certify that the variant in question is the causative for the phenotype and not one CNV event corrected by gene therapy and not identified previously (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620859084", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859084", "label": "PP4", "strengthDescriptor": "Moderate", "text": "A patient score of ≥2-\\<4 points (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620859084", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859084", "label": "PP4", "strengthDescriptor": "Supporting", "text": "A patient score of 1-\\<2 points (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620859065", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859065", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Applicable if a previously established variant is classified as **pathogenic** by SCID VCEP specifications for _RAG1._ Previously established variant must be classified by SCID VCEP specifications for _RAG1._" }, { "baseStrength": "Pathogenic", "id": "1620859065", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859065", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Applicable if a previously established variant is classified as **likely pathogenic** by SCID VCEP specifications for _RAG1._ Previously established variant must be classified by SCID VCEP specifications for _RAG1._" } ], "diseases": [ { "id": "MONDO:0000572", "iri": "https://genboree.org/cspec/Disease/id/467875862", "label": "recombinase activating gene 1 deficiency" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467847560", "label": "RAG1" } ], "ruleSet": { "id": "1567643924", "iri": "https://genboree.org/cspec/RuleSet/id/1567643924" }, "svi": { "id": "GN123", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1567643911", "label": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAG1 Version 1.0.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1620860005", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860005", "label": "BP7", "strengthDescriptor": "Supporting", "text": "* Applicable to both synonymous variants and deep intronic variants affecting nucleotides at or beyond the +7 (donor) and -21 (acceptor) positions.\n* The variant should be predicted not to impact splicing by at least two out of three _in silico_ tools (freely available tools include GeneSplicer, MaxEntScan, NNSplice, SpliceAI, Splicing Sequences Finder (SSF), and varSEAK).\n* Given the potential for poor conservation of genes related to T cell and B cell development among vertebrates, nucleotide conservation is **not required** in order to apply BP7." }, { "baseStrength": "Benign", "id": "1620860003", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860003", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "gnomAD popmax filtering allele frequency >0.00872" }, { "baseStrength": "Benign", "id": "1620859994", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859994", "label": "BS3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: There is not a well-established functional study which can rule out all damaging effects on protein function." }, { "baseStrength": "Benign", "id": "1620859994", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859994", "label": "BS3", "strengthDescriptor": "Strong", "text": "Not Applicable: There is not a well-established functional study which can rule out all damaging effects on protein function." }, { "baseStrength": "Benign", "id": "1620859994", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859994", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Not Applicable: There is not a well-established functional study which can rule out all damaging effects on protein function." }, { "baseStrength": "Benign", "id": "1620859994", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859994", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Not Applicable: There is not a well-established functional study which can rule out all damaging effects on protein function." }, { "baseStrength": "Pathogenic", "id": "1620859991", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859991", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620859991", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859991", "label": "PS4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620859991", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859991", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620859991", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859991", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620859989", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859989", "label": "PM4", "strengthDescriptor": "Moderate", "text": "When applied to deletion variants, the deleted region must contain a known **pathogenic** or **likely pathogenic** variant that is not predicted/observed to alter splicing." }, { "baseStrength": "Pathogenic", "id": "1620859989", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859989", "label": "PM4", "strengthDescriptor": "Supporting", "text": "When applied to deletion variants, the deleted region must contain a known **VUS** variant that is not predicted/observed to alter splicing." }, { "baseStrength": "Pathogenic", "id": "1620860014", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860014", "label": "PS1", "strengthDescriptor": "Strong", "text": "It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T.\n\nApplicable if the previously established variant is classified as **pathogenic** by SCID VCEP specifications for _RAG2._" }, { "baseStrength": "Pathogenic", "id": "1620860014", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860014", "label": "PS1", "strengthDescriptor": "Moderate", "text": "It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T\n\nApplicable if the previously established variant is classified as **likely pathogenic** by SCID VCEP specifications for _RAG2._" }, { "baseStrength": "Pathogenic", "id": "1620860013", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860013", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620860013", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860013", "label": "PS2", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620860013", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860013", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620860013", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860013", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620860010", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860010", "label": "PP1", "strengthDescriptor": "Strong", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Pathogenic", "id": "1620860010", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860010", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Pathogenic", "id": "1620860010", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860010", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Benign", "id": "1620860009", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860009", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620860009", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860009", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620860009", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860009", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620860009", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860009", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620860008", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860008", "label": "BS1", "strengthDescriptor": "Strong", "text": "gnomAD popmax filtering allele frequency  >0.001951\n\n1 Consider also bottleneck populations." }, { "baseStrength": "Pathogenic", "id": "1620860006", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860006", "label": "PP3", "strengthDescriptor": "Supporting", "text": "* Only applicable to synonymous or intronic variants predicted to impact splicing by SpliceAI with a delta score greater than or equal to 0.2.\n* **Do not apply to missense variants.**" }, { "baseStrength": "Pathogenic", "id": "1620860002", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860002", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with two specifications:\n\n* Given that the _RAG2_ protein is encoded by a single exon (based on MANE Select transcript NM\\_000536.4) and nonsense-mediated decay is not predicted for nonsense or frameshift variants, PVS1 cannot be applied at the default strength to RAG2 variants (indicated by the red boxes in the Flowchart), **except** in the case of full gene deletion **or** removing/altering critical domain: the PHD domain and core domain (indicated by the purple in the Flowchart). \n* PVS1 can be applied to variants not predicted to undergo nonsense-mediated decay when removing/altering the critical PHD domain (spanning amino acids 414-487) and core domain (amino acids 1-383)  based on recommendations from Walker et al., preprint." }, { "baseStrength": "Pathogenic", "id": "1620860002", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860002", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:\n\n* For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein, at least one pathogenic variant **must be** present downstream in order to apply PVS1\\_Strong." }, { "baseStrength": "Pathogenic", "id": "1620860002", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860002", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:\n\n* For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein, when at least one pathogenic variant is **not** present downstream, downgrade to PVS1\\_Moderate." }, { "baseStrength": "Pathogenic", "id": "1620860000", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860000", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _RAG2._" }, { "baseStrength": "Pathogenic", "id": "1620860000", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860000", "label": "PM3", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _RAG2._" }, { "baseStrength": "Pathogenic", "id": "1620860000", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860000", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _RAG2._" }, { "baseStrength": "Pathogenic", "id": "1620860000", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860000", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Use ClinGen SVI recommendations for _in trans_ criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for _RAG2._" }, { "baseStrength": "Benign", "id": "1620859998", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859998", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Only to be used when the variant is observed in the homozygous state in a healthy adult." }, { "baseStrength": "Benign", "id": "1620859996", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859996", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620859996", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859996", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620859996", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859996", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620859996", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859996", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Pathogenic", "id": "1620859990", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859990", "label": "PM2", "strengthDescriptor": "Supporting", "text": "gnomAD popmax filtering allele frequency \\<0.0000588  \n\n* An additional requirement is that **no homozygotes** have been observed in gnomAD." }, { "baseStrength": "Benign", "id": "1620860015", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860015", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620860015", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860015", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620860015", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860015", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620860015", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860015", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620860011", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860011", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620860011", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860011", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620860011", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860011", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Benign", "id": "1620860011", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860011", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply." }, { "baseStrength": "Pathogenic", "id": "1620859999", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859999", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620859999", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859999", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620859999", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859999", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620859999", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859999", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620859997", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859997", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for RAG2 (Z = 0.2) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in RAG2.\n" }, { "baseStrength": "Pathogenic", "id": "1620859997", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859997", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for RAG2 (Z = 0.2) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in RAG2.\n" }, { "baseStrength": "Pathogenic", "id": "1620859997", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859997", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for RAG2 (Z = 0.2) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in RAG2.\n" }, { "baseStrength": "Pathogenic", "id": "1620859997", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859997", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for RAG2 (Z = 0.2) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in RAG2.\n" }, { "baseStrength": "Benign", "id": "1620859995", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859995", "label": "BS4", "strengthDescriptor": "Strong", "text": "Can be applied without additional specifications." }, { "baseStrength": "Benign", "id": "1620859992", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859992", "label": "BP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620859992", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859992", "label": "BP2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620859992", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859992", "label": "BP2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620859992", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859992", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620860016", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860016", "label": "BP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620860016", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860016", "label": "BP4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620860016", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860016", "label": "BP4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1620860016", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860016", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "1620860007", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860007", "label": "PS3", "strengthDescriptor": "Strong", "text": "PS3 may potentially be applied at the default strength level of strong for evidence from an animal model expressing the variant of interest and recapitulating the RAG2-SCID phenotype." }, { "baseStrength": "Pathogenic", "id": "1620860007", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860007", "label": "PS3", "strengthDescriptor": "Moderate", "text": "Strength of evidence from cellular models/_in vitro_ studies is dependent upon abnormal result in a V(D)J recombination assay:\n\n* PS3\\_Moderate: \\<25% of wild-type activity in Tirosh et al., 2019 (PMID: 29772310)\n\n_At least one previously observed proband with the expressed RAG2 variant meeting PP4 is required to apply PS3 at any strength._" }, { "baseStrength": "Pathogenic", "id": "1620860007", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860007", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Strength of evidence from cellular models/_in vitro_ studies is dependent upon abnormal result in a V(D)J recombination assay:\n\n* PS3\\_Supporting: \n * 25-60% of wild-type activity in Tirosh et al., 2019 (PMID: 29772310) **OR**\n * Reduced activity compared to wild type in Couëdel et al., 2010 (PMID: 20234091)\n\n_At least one previously observed proband with the expressed RAG2 variant meeting PP4 is required to apply PS3 at any strength._" }, { "baseStrength": "Pathogenic", "id": "1620860004", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860004", "label": "PM6", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620860004", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860004", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620860004", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860004", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620860001", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860001", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Strength is dependent upon the location of the variant within specific functional domains (PMID: 26996199):\n\n* PM1\\_Moderate: missense variant located in the **PHD domain** (amino acids 414-487);" }, { "baseStrength": "Pathogenic", "id": "1620860001", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860001", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Strength is dependent upon the location of the variant within specific functional domains (PMID: 26996199):\n\n* PM1\\_Supporting: missense variant located in the **core domain** (amino acids 1-383);" }, { "baseStrength": "Pathogenic", "id": "1620859993", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859993", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Applicable if a previously established variant is classified as **pathogenic** by SCID VCEP specifications for _RAG2._ Previously established variant must be classified by SCID VCEP specifications for _RAG2._" }, { "baseStrength": "Pathogenic", "id": "1620859993", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620859993", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Applicable if a previously established variant is classified as **likely pathogenic** by SCID VCEP specifications for _RAG2._ Previously established variant must be classified by SCID VCEP specifications for _RAG2._" }, { "baseStrength": "Pathogenic", "id": "1620860012", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860012", "label": "PP4", "strengthDescriptor": "Strong", "text": "A patient score of ≥ 4 points1. \n\n1CNV (Copy number variation) testing is required to consider PP4\\_Strong in order to certify that the variant in question is the causative for the phenotype and not one CNV event corrected by gene therapy and not identified previously (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620860012", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860012", "label": "PP4", "strengthDescriptor": "Moderate", "text": "A patient score of ≥2-\\<4 points (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620860012", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860012", "label": "PP4", "strengthDescriptor": "Supporting", "text": "A patient score of 1-\\<2 points (see instructions below)." } ], "diseases": [ { "id": "MONDO:0000573", "iri": "https://genboree.org/cspec/Disease/id/467875860", "label": "recombinase activating gene 2 deficiency" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467847561", "label": "RAG2" } ], "ruleSet": { "id": "1567863469", "iri": "https://genboree.org/cspec/RuleSet/id/1567863469" }, "svi": { "id": "GN124", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1567863456", "label": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAG2 Version 1.0.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1744148754", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148754", "label": "BP4", "strengthDescriptor": "Supporting", "text": "REVEL ≤0.25 for missense variants or Splice AI ≤0.1 for non-canonical splice variants. No up/downgrading. If no REVEL or. Splice AI available, then CADD ≤ 10 can be used." }, { "baseStrength": "Pathogenic", "id": "1744148751", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148751", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Benign", "id": "1744148749", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148749", "label": "BP3", "strengthDescriptor": "Supporting", "text": "In frame-deletions/insertions in a repetitive region without a known function." }, { "baseStrength": "Benign", "id": "1744148732", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148732", "label": "BS3", "strengthDescriptor": "Strong", "text": "Use the BMPR2 functional assay document for acceptable assays and guidance. Note that p.Gln42Arg, Gly47Gln, Gln82His, Thr102Ala, Ser107Pro, Gly182Asp, Met186Val, Glu503Asp, Arg899X, and Arg899Pro have been demonstrated non-critical/not necessary for kinase activity based on a luciferase assay (apply BS3).\n\nNote that p.Cys34, Cys60, Cys66, Cys84, Cys94, Cys99, Cys116, Cys117, Cys118, Cys123, Gly210, Gly212, Lys230, Glu/Asn245, Asp333, Asn338, Asp351, Gly353 Glu386, Asp405, Gly410, Asp485, Gln486, Asp487, Ala488, Arg489, Ala490, Arg491, Arg491, and Leu492 have been demonstrated _critical_ (apply PM1\\_strong)." }, { "baseStrength": "Pathogenic", "id": "1744148729", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148729", "label": "PS4", "strengthDescriptor": "Strong", "text": "Prior observation of the variant in >4 unrelated patients with the same phenotype, and its absence in controls." }, { "baseStrength": "Pathogenic", "id": "1744148729", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148729", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Prior observation of the variant in >3 unrelated patients with the same phenotype, and its absence in controls." }, { "baseStrength": "Pathogenic", "id": "1744148729", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148729", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Prior observation of the variant in >1 unrelated patients with the same phenotype, and its absence in controls." }, { "baseStrength": "Pathogenic", "id": "1744148748", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148748", "label": "PP1", "strengthDescriptor": "Strong", "text": "Co-segregation with disease in ≥7 affected family members." }, { "baseStrength": "Pathogenic", "id": "1744148748", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148748", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Co-segregation with disease in ≥5 affected family members." }, { "baseStrength": "Pathogenic", "id": "1744148748", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148748", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Co-segregation with disease in ≥3 affected family members." }, { "baseStrength": "Benign", "id": "1744148747", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148747", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: BMPR2 is the major causal PAH gene." }, { "baseStrength": "Benign", "id": "1744148747", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148747", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable: BMPR2 is the major causal PAH gene." }, { "baseStrength": "Benign", "id": "1744148747", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148747", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: BMPR2 is the major causal PAH gene." }, { "baseStrength": "Benign", "id": "1744148747", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148747", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: BMPR2 is the major causal PAH gene." }, { "baseStrength": "Pathogenic", "id": "1744148744", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148744", "label": "PP3", "strengthDescriptor": "Supporting", "text": "REVEL ≥0.75 for missense variants or Splice AI ≥0.2 for non-canonical splice variants. No up/downgrading. If no REVEL score or SpliceAI prediction is available, then CADD ≥20 can be used. Note: can be applied additively with PS3 if applicable." }, { "baseStrength": "Benign", "id": "1744148743", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148743", "label": "BP7", "strengthDescriptor": "Strong", "text": "If BP7 is met and negative RNA splicing assay data is available, then apply BP7\\_strong. Acceptable splicing assays should have positive and negative controls, preferably from patients and matched unaffected individuals. Note that splicing assay results may be tissue-sensitive." }, { "baseStrength": "Benign", "id": "1744148743", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148743", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Applicable after assignment of BP4 for no adverse splicing predictions, and inclusive of exonic and intronic variants. Not applicable for synonymous variants located at the first base or the last three bases of an exon." }, { "baseStrength": "Pathogenic", "id": "1744148742", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148742", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Assumed de novo, but without confirmation of paternity and maternity." }, { "baseStrength": "Pathogenic", "id": "1744148740", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148740", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats:\n\n* Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n* Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n\n\\*\\*Use the PVS1 decision tree guide." }, { "baseStrength": "Pathogenic", "id": "1744148740", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148740", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Use the PVS1 decision tree guide." }, { "baseStrength": "Pathogenic", "id": "1744148740", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148740", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Use the PVS1 decision tree guide." }, { "baseStrength": "Pathogenic", "id": "1744148739", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148739", "label": "PM1", "strengthDescriptor": "Strong", "text": "Variant changes a _critical_ amino acid. Extracellular domain: p.Cys34, Cys60, Cys66, Cys84, Cys94, Cys99, Cys116, Cys117, Cys118, Cys123. Kinase domain: p.Gly210, Gly212, Lys230, Glu/Asn245, Asp333, Asn338, Asp351, Gly353 Glu386, Asp405, Gly410, Arg491. KD heterodimerization: p.Asp485, Gln486, Asp487, Ala488, Arg489, Ala490, Arg491, Leu492.\n\nNote that p.Gln42Arg, Gly47Gln, Gln82His, Thr102Ala, Ser107Pro, Gly182Asp, Met186Val, Glu503Asp, Arg899X, and Arg899Pro have been demonstrated _non-critical/not necessary_ for kinase activity based on a luciferase assay (apply BS3)." }, { "baseStrength": "Pathogenic", "id": "1744148739", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148739", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Variant changes an amino acid in the extracellular domain (aa 33-131) or kinase domain (aa 203-504) but without functional evidence indicating critical or non-critical.\n\nNote that p.Cys34, Cys60, Cys66, Cys84, Cys94, Cys99, Cys116, Cys117, Cys118, Cys123, Gly210, Gly212, Lys230, Glu/Asn245, Asp333, Asn338, Asp351, Gly353 Glu386, Asp405, Gly410, Asp485, Gln486, Asp487, Ala488, Arg489, Ala490, Arg491, Arg491, and Leu492 have been demonstrated _critical_ (apply PM1\\_strong).\n\nNote that p.Gln42Arg, Gly47Gln, Gln82His, Thr102Ala, Ser107Pro, Gly182Asp, Met186Val, Glu503Asp, Arg899X, and Arg899Pro have been demonstrated _non-critical/not necessary_ for kinase activity based on a luciferase assay (apply BS3)." }, { "baseStrength": "Pathogenic", "id": "1744148728", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148728", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Present at \\<0.01% among gnomAD controls, using the subpopulation with the highest frequency and at least 1,000 allele counts. Caveat: Population data for indels may be poorly called by next generation sequencing." }, { "baseStrength": "Pathogenic", "id": "1744148745", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148745", "label": "PS3", "strengthDescriptor": "Strong", "text": "Use the BMPR2 functional assay document for guidance on allowable assays. Known variant validation controls (i.e. established pathogenic and benign variants) are required. One exception is if the same functional assay has been performed for the same variant by two independent groups and demonstrated to have the same functional effect by both groups. Also applicable for non-canonical splice site variants when RNA splice site assay data is available demonstrating abnormal splicing; positive and negative controls are required, preferably from patients and matched unaffected individuals. Note that splicing assay results may be tissue-sensitive." }, { "baseStrength": "Pathogenic", "id": "1744148745", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148745", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Use the BMPR2 functional assay document for guidance on allowable assays. If no known variant validation controls (i.e. established pathogenic and benign variants) were used, then score at the supporting strength." }, { "baseStrength": "Pathogenic", "id": "1744148737", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148737", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1744148737", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148737", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1744148737", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148737", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1744148737", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148737", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1744148736", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148736", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in ≥3 homozygotes in gnomAD controls or reported in the literature (healthy adult individuals)." }, { "baseStrength": "Benign", "id": "1744148736", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148736", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Observed in ≥2 homozygotes in gnomAD controls or reported in the literature (healthy adult individuals)." }, { "baseStrength": "Pathogenic", "id": "1744148735", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148735", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: BMPR2 is not constrained for missense variants." }, { "baseStrength": "Pathogenic", "id": "1744148735", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148735", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: BMPR2 is not constrained for missense variants." }, { "baseStrength": "Pathogenic", "id": "1744148735", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148735", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: BMPR2 is not constrained for missense variants." }, { "baseStrength": "Pathogenic", "id": "1744148735", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148735", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: BMPR2 is not constrained for missense variants." }, { "baseStrength": "Benign", "id": "1744148734", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148734", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Both LOF and missense variants are known to cause PAH." }, { "baseStrength": "Benign", "id": "1744148734", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148734", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Both LOF and missense variants are known to cause PAH." }, { "baseStrength": "Benign", "id": "1744148734", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148734", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Both LOF and missense variants are known to cause PAH." }, { "baseStrength": "Benign", "id": "1744148734", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148734", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Both LOF and missense variants are known to cause PAH." }, { "baseStrength": "Pathogenic", "id": "1744148727", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148727", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." }, { "baseStrength": "Benign", "id": "1744148746", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148746", "label": "BS1", "strengthDescriptor": "Strong", "text": "Allele frequency >=0.1% among gnomAD controls, using the subpopulation with the highest frequency and at least 1,000 allele counts." }, { "baseStrength": "Benign", "id": "1744148741", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148741", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Allele frequency is above 1% in gnomAD, including any sub-population with at least 1,000 allele counts." }, { "baseStrength": "Pathogenic", "id": "1744148738", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148738", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: PAH is autosomal dominant." }, { "baseStrength": "Pathogenic", "id": "1744148738", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148738", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: PAH is autosomal dominant." }, { "baseStrength": "Pathogenic", "id": "1744148738", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148738", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: PAH is autosomal dominant." }, { "baseStrength": "Pathogenic", "id": "1744148738", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148738", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: PAH is autosomal dominant." }, { "baseStrength": "Pathogenic", "id": "1744148731", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148731", "label": "PM5", "strengthDescriptor": "Moderate", "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.  Also applicable for variants affecting the same splice site as a confirmed splice variant with similar or worse splicing in silico predictions" }, { "baseStrength": "Pathogenic", "id": "1744148731", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148731", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Novel missense change at an amino acid residue where a different missense change determined to be _likely pathogenic_ has been seen before." }, { "baseStrength": "Benign", "id": "1744148730", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148730", "label": "BP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: BMPR2 variants are not fully penetrant." }, { "baseStrength": "Benign", "id": "1744148730", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148730", "label": "BP2", "strengthDescriptor": "Strong", "text": "Not Applicable: BMPR2 variants are not fully penetrant." }, { "baseStrength": "Benign", "id": "1744148730", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148730", "label": "BP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: BMPR2 variants are not fully penetrant." }, { "baseStrength": "Benign", "id": "1744148730", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148730", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: BMPR2 variants are not fully penetrant." }, { "baseStrength": "Benign", "id": "1744148753", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148753", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1744148753", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148753", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1744148753", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148753", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1744148753", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148753", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1744148752", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148752", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as a previously established _pathogenic_ variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level." }, { "baseStrength": "Pathogenic", "id": "1744148752", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148752", "label": "PS1", "strengthDescriptor": "Moderate", "text": "Same amino acid change as a previously established _likely pathogenic_ variant regardless of nucleotide change." }, { "baseStrength": "Pathogenic", "id": "1744148750", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148750", "label": "PP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: PAH does not have a single genetic etiology." }, { "baseStrength": "Pathogenic", "id": "1744148750", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148750", "label": "PP4", "strengthDescriptor": "Strong", "text": "Not Applicable: PAH does not have a single genetic etiology." }, { "baseStrength": "Pathogenic", "id": "1744148750", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148750", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Not Applicable: PAH does not have a single genetic etiology." }, { "baseStrength": "Pathogenic", "id": "1744148750", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148750", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Not Applicable: PAH does not have a single genetic etiology." }, { "baseStrength": "Benign", "id": "1744148733", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744148733", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of variant segregation in affected members of a family." } ], "diseases": [ { "id": "MONDO:0015924", "iri": "https://genboree.org/cspec/Disease/id/467883888", "label": "pulmonary arterial hypertension" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467818781", "label": "BMPR2" } ], "ruleSet": { "id": "1568416535", "iri": "https://genboree.org/cspec/RuleSet/id/1568416535" }, "svi": { "id": "GN125", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1568416522", "label": "ClinGen Pulmonary Hypertension Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BMPR2 Version 1.1.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1620860940", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860940", "label": "BP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply. \n" }, { "baseStrength": "Benign", "id": "1620860940", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860940", "label": "BP4", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply. \n" }, { "baseStrength": "Benign", "id": "1620860940", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860940", "label": "BP4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply. \n" }, { "baseStrength": "Benign", "id": "1620860940", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860940", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply. \n" }, { "baseStrength": "Benign", "id": "1620860939", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860939", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620860939", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860939", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620860939", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860939", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620860939", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860939", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620860938", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860938", "label": "PS1", "strengthDescriptor": "Strong", "text": "It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T.\n\nApplicable if the previously established variant is classified as **pathogenic** by SCID VCEP specifications for _IL2RG_." }, { "baseStrength": "Pathogenic", "id": "1620860938", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860938", "label": "PS1", "strengthDescriptor": "Moderate", "text": "It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T\n\nApplicable if the previously established variant is classified as **likely pathogenic** by SCID VCEP specifications for _IL2RG._" }, { "baseStrength": "Pathogenic", "id": "1620860934", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860934", "label": "PP1", "strengthDescriptor": "Strong", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Pathogenic", "id": "1620860934", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860934", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Pathogenic", "id": "1620860934", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860934", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations." }, { "baseStrength": "Benign", "id": "1620860929", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860929", "label": "BP7", "strengthDescriptor": "Supporting", "text": "* Applicable to both synonymous variants and deep intronic variants affecting nucleotides at or beyond the +7 (donor) and -21 (acceptor) positions.\n* The variant should be predicted not to impact splicing by at least two out of three _in silico_ tools (freely available tools include GeneSplicer, MaxEntScan, NNSplice, SpliceAI, Splicing Sequences Finder (SSF), and varSEAK).\n* Given the potential for poor conservation of genes related to T cell and B cell development among vertebrates, nucleotide conservation is **not required** in order to apply BP7." }, { "baseStrength": "Pathogenic", "id": "1620860923", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860923", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620860923", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860923", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620860923", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860923", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620860923", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860923", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620860917", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860917", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Applicable if a previously established variant is classified as **pathogenic** by SCID VCEP specifications for _IL2RG._ Previously established variant must be classified by SCID VCEP specifications for _IL2RG._" }, { "baseStrength": "Pathogenic", "id": "1620860917", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860917", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Applicable if a previously established variant is classified as **likely pathogenic** by SCID VCEP specifications for _IL2RG._ Previously established variant must be classified by SCID VCEP specifications for _IL2RG._" }, { "baseStrength": "Pathogenic", "id": "1620860915", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860915", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Sum of case scores >16 points (see instructions below)" }, { "baseStrength": "Pathogenic", "id": "1620860915", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860915", "label": "PS4", "strengthDescriptor": "Strong", "text": "Sum of case scores 4.5-16 points (see instructions below)" }, { "baseStrength": "Pathogenic", "id": "1620860915", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860915", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Sum of case scores 2.5-4 points (see instructions below)" }, { "baseStrength": "Pathogenic", "id": "1620860915", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860915", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Sum of case scores 1-2 points (see instructions below)" }, { "baseStrength": "Pathogenic", "id": "1620860936", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860936", "label": "PP4", "strengthDescriptor": "Strong", "text": "A patient score of ≥ 8 points1. \n\n1CNV (Copy number variation) testing is required to consider PP4\\_Strong in order to certify that the variant in question is the causative for the phenotype and not one CNV event corrected by gene therapy and not identified previously (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620860936", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860936", "label": "PP4", "strengthDescriptor": "Moderate", "text": "A patient score of ≥2-7 points (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620860936", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860936", "label": "PP4", "strengthDescriptor": "Supporting", "text": "A patient score of 1-\\<2 points (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620860928", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860928", "label": "PM6", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620860928", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860928", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620860928", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860928", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620860926", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860926", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:\n\n* PVS1 at default strength (Very Strong) can be applied to variants not predicted to undergo nonsense-mediated decay but truncating the transmembrane domain (which begins at amino acid 255) or any distal region (i.e. cytoplasmic domain) due to the lack of functionality of the protein expressed with this defect." }, { "baseStrength": "Pathogenic", "id": "1620860926", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860926", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:\n\n* For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 8, or variants in the last 50 nucleotides of the penultimate exon after c.874, codon 292, in exon 7), at least one pathogenic variant **must be** present downstream in order to apply PVS1\\_Strong" }, { "baseStrength": "Pathogenic", "id": "1620860926", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860926", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:\n\n* For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 8, or variants in the last 50 nucleotides of the penultimate exon after c.874, codon 292, in exon 7), when at least one pathogenic variant is **not** present downstream downgrade to PVS1\\_Moderate." }, { "baseStrength": "Pathogenic", "id": "1620860925", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860925", "label": "PM1", "strengthDescriptor": "Strong", "text": "* Defined to include missense alterations of the following positions:\n * Affecting a conserved cysteine residue: Cys62 , Cys72 , Cys102, Cys115\n * Affecting CpG dinucleotides: c.684C (Arg224), c.690C (Arg226), c.691G (Arg691), c.868G (Arg285) (PMID: 7668284)\n * Affecting the WSxWS motif: Trp237, Ser238, Glu239, Trp240, Ser241\n * Affecting a transmembrane domain residue by introducing a charged or polar residue (Asn, Asp, Arg, Cys, His, Glu, Gln, Lys, Ser, Thr, Tyr): amino acids 263-283" }, { "baseStrength": "Benign", "id": "1620860919", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860919", "label": "BS4", "strengthDescriptor": "Strong", "text": "Can be applied without additional specifications." }, { "baseStrength": "Benign", "id": "1620860935", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860935", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply. \n" }, { "baseStrength": "Benign", "id": "1620860935", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860935", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply. \n" }, { "baseStrength": "Benign", "id": "1620860935", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860935", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply. \n" }, { "baseStrength": "Benign", "id": "1620860935", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860935", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply. \n" }, { "baseStrength": "Pathogenic", "id": "1620860931", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860931", "label": "PS3", "strengthDescriptor": "Strong", "text": "PS3 may potentially be applied at the default strength level of strong for evidence from an animal model expressing the variant of interest and recapitulating the IL2RG-SCID phenotype. Animal models will be reviewed on a case-by-case basis by the VCEP to determine the appropriate strength level." }, { "baseStrength": "Pathogenic", "id": "1620860931", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860931", "label": "PS3", "strengthDescriptor": "Supporting", "text": "PS3\\_Supporting can be applied based on an abnormal result in **at least** one approved _in vitro_ assay.\n\n* Approved assay instances:\n * Phosphorylation of JAK3/Co-Immunoprecipitation with JAK3\n * Sharfe et al., 1997 (PMID: 9399950)\n * Kumaki et al., 1999 (PMID: 9933465)\n * Arcas-García et al., 2020 (PMID: 31799703)\n * Cytokine binding\n * Sharfe et al., 1997 (PMID: 9399950)\n * Kumaki et al., 1995 (PMID: 7632950)\n * Surface expression of the gamma chain\n * Kumaki et al., 1995 (PMID: 7632950)\n * Interaction profiling-BioID\n * Tuovinen et al., 2020 (PMID: 32072341)\n\n_At least one previously observed proband with the IL2RG variant meeting PP4 is required to apply PS3 at any strength on the basis of a cellular model/in vitro study._" }, { "baseStrength": "Benign", "id": "1620860927", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860927", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "gnomAD popmax filtering allele frequency >0.01110." }, { "baseStrength": "Pathogenic", "id": "1620860937", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860937", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620860937", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860937", "label": "PS2", "strengthDescriptor": "Strong", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620860937", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860937", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620860937", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860937", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below)." }, { "baseStrength": "Pathogenic", "id": "1620860930", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860930", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Only applicable to synonymous or intronic variants predicted to impact splicing by SpliceAI with a delta score greater than or equal to 0.2.\n\n* **Do not apply to missense variants.**" }, { "baseStrength": "Pathogenic", "id": "1620860921", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860921", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for IL2RG (Z = 1.49) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in IL2RG.\n" }, { "baseStrength": "Pathogenic", "id": "1620860921", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860921", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for IL2RG (Z = 1.49) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in IL2RG.\n" }, { "baseStrength": "Pathogenic", "id": "1620860921", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860921", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for IL2RG (Z = 1.49) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in IL2RG.\n" }, { "baseStrength": "Pathogenic", "id": "1620860921", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860921", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply. The gnomAD v2.1.1 missense Z score for IL2RG (Z = 1.49) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in IL2RG.\n" }, { "baseStrength": "Benign", "id": "1620860933", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860933", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply. \n" }, { "baseStrength": "Benign", "id": "1620860933", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860933", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply. \n" }, { "baseStrength": "Benign", "id": "1620860933", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860933", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply. \n" }, { "baseStrength": "Benign", "id": "1620860933", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860933", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply. \n" }, { "baseStrength": "Benign", "id": "1620860932", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860932", "label": "BS1", "strengthDescriptor": "Strong", "text": "gnomAD popmax filtering allele frequency >0.002491\n\n1 Consider also bottleneck populations." }, { "baseStrength": "Pathogenic", "id": "1620860924", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860924", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply.\n" }, { "baseStrength": "Pathogenic", "id": "1620860924", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860924", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply.\n" }, { "baseStrength": "Pathogenic", "id": "1620860924", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860924", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply.\n" }, { "baseStrength": "Pathogenic", "id": "1620860924", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860924", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply.\n" }, { "baseStrength": "Benign", "id": "1620860922", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860922", "label": "BS2", "strengthDescriptor": "Strong", "text": "BS2\\_Strong: Observed in >=3 (3 or more) hemizygotes in gnomAD." }, { "baseStrength": "Benign", "id": "1620860922", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860922", "label": "BS2", "strengthDescriptor": "Supporting", "text": "BS2\\_Supporting: Can be applied at Supporting level of evidence if observed at least 2 hemizygotes in gnomAD." }, { "baseStrength": "Benign", "id": "1620860920", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860920", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply. IL2RG missense variants are a known mechanism of disease.\n" }, { "baseStrength": "Benign", "id": "1620860920", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860920", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply. IL2RG missense variants are a known mechanism of disease.\n" }, { "baseStrength": "Benign", "id": "1620860920", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860920", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply. IL2RG missense variants are a known mechanism of disease.\n" }, { "baseStrength": "Benign", "id": "1620860920", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860920", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply. IL2RG missense variants are a known mechanism of disease.\n" }, { "baseStrength": "Benign", "id": "1620860918", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860918", "label": "BS3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply.\n" }, { "baseStrength": "Benign", "id": "1620860918", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860918", "label": "BS3", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply.\n" }, { "baseStrength": "Benign", "id": "1620860918", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860918", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply.\n" }, { "baseStrength": "Benign", "id": "1620860918", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860918", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply.\n" }, { "baseStrength": "Benign", "id": "1620860916", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860916", "label": "BP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply. \n" }, { "baseStrength": "Benign", "id": "1620860916", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860916", "label": "BP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply. \n" }, { "baseStrength": "Benign", "id": "1620860916", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860916", "label": "BP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply. \n" }, { "baseStrength": "Benign", "id": "1620860916", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860916", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply. \n" }, { "baseStrength": "Pathogenic", "id": "1620860914", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860914", "label": "PM2", "strengthDescriptor": "Supporting", "text": "gnomAD popmax filtering allele frequency \\<0.000124 \n\n* Additional requirement that no **hemizygotes** have been observed in gnomAD." }, { "baseStrength": "Pathogenic", "id": "1620860913", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860913", "label": "PM4", "strengthDescriptor": "Moderate", "text": "When applied to deletion variants, the deleted region must contain a known **pathogenic** or **likely pathogenic** variant that is not predicted/observed to alter splicing." }, { "baseStrength": "Pathogenic", "id": "1620860913", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620860913", "label": "PM4", "strengthDescriptor": "Supporting", "text": "When applied to deletion variants, the deleted region must contain a known **VUS** variant that is not predicted/observed to alter splicing." } ], "diseases": [ { "id": "MONDO:0010315", "iri": "https://genboree.org/cspec/Disease/id/467873922", "label": "T-B+ severe combined immunodeficiency due to gamma chain deficiency" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467831036", "label": "IL2RG" } ], "ruleSet": { "id": "1571601262", "iri": "https://genboree.org/cspec/RuleSet/id/1571601262" }, "svi": { "id": "GN129", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1571601249", "label": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for IL2RG Version 1.0.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1744531101", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531101", "label": "BP4", "strengthDescriptor": "Supporting", "text": "* For missense variants: REVEL score ≤0.15 and SpliceAI score ≤0.1.\n* For synonymous and intronic variants: SpliceAI score ≤0.1." }, { "baseStrength": "Pathogenic", "id": "1744531097", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531097", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Patient's phenotype meets consensus clinical diagnostic (Curaçao) criteria for HHT, and sequencing and large deletion/duplication analysis was performed for both _ENG_ and _ACVRL1_ with any other identified variants ruled out." }, { "baseStrength": "Pathogenic", "id": "1744531091", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531091", "label": "PP3", "strengthDescriptor": "Supporting", "text": "* For missense variants: REVEL score ≥0.644 or SpliceAI score ≥0.2.\n* For synonymous and intronic variants: SpliceAI score ≥0.2." }, { "baseStrength": "Pathogenic", "id": "1744531086", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531086", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Apply if variant is located in a critical residue:\n\n* _ACVRL1_:\n * glycine-rich loop: G209-V216\n * phosphate anchor: K229\n * C-helix E pairing the phosphate anchor: E242\n * catalytic loop: R329-N335\n * metal-binding loop: D348-L351\n * _BMP10_ interaction cluster\n * (His40, Val54, Val56, Arg57, Glu58, Glu59, His66, Asn71, Leu72, His73, Glu75, Leu76, Arg78, Gly79, Arg80, Thr82, Glu83, Phe84, Val85, His87)" }, { "baseStrength": "Pathogenic", "id": "1744531084", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531084", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1744531084", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531084", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1744531084", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531084", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1744531084", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531084", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1744531083", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531083", "label": "BS2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Full penetrance at an early age is not observed in HHT." }, { "baseStrength": "Benign", "id": "1744531083", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531083", "label": "BS2", "strengthDescriptor": "Strong", "text": "Not Applicable: Full penetrance at an early age is not observed in HHT." }, { "baseStrength": "Benign", "id": "1744531083", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531083", "label": "BS2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Full penetrance at an early age is not observed in HHT." }, { "baseStrength": "Benign", "id": "1744531083", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531083", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Full penetrance at an early age is not observed in HHT." }, { "baseStrength": "Pathogenic", "id": "1744531078", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531078", "label": "PM5", "strengthDescriptor": "Strong", "text": "≥2 different missense changes at same codon have been determined to be likely pathogenic or pathogenic based on HHT VCEP rules." }, { "baseStrength": "Pathogenic", "id": "1744531078", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531078", "label": "PM5", "strengthDescriptor": "Moderate", "text": "A different missense change at same codon has been determined to be likely pathogenic or pathogenic based on HHT VCEP rules." }, { "baseStrength": "Pathogenic", "id": "1744531076", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531076", "label": "PS4", "strengthDescriptor": "Strong", "text": "4+ probands with phenotype consistent with HHT." }, { "baseStrength": "Pathogenic", "id": "1744531076", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531076", "label": "PS4", "strengthDescriptor": "Moderate", "text": " 2-3 probands with phenotype consistent with HHT." }, { "baseStrength": "Pathogenic", "id": "1744531076", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531076", "label": "PS4", "strengthDescriptor": "Supporting", "text": "1 proband with phenotype consistent with HHT." }, { "baseStrength": "Pathogenic", "id": "1744531075", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531075", "label": "PM2", "strengthDescriptor": "Supporting", "text": "\\<6 total alleles in gnomAD or \\<0.00004 (0.004%) in gnomAD subpopulations." }, { "baseStrength": "Pathogenic", "id": "1744531074", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531074", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." }, { "baseStrength": "Pathogenic", "id": "1744531098", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531098", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Benign", "id": "1744531094", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531094", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Apply if a likely pathogenic or pathogenic variant (based on HHT VCEP rules) is found in _ENG_." }, { "baseStrength": "Pathogenic", "id": "1744531089", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531089", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: De novo variants are rare in HHT. De novo variants should be confirmed not presumed for HHT." }, { "baseStrength": "Pathogenic", "id": "1744531089", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531089", "label": "PM6", "strengthDescriptor": "Strong", "text": "Not Applicable: De novo variants are rare in HHT. De novo variants should be confirmed not presumed for HHT." }, { "baseStrength": "Pathogenic", "id": "1744531089", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531089", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Not Applicable: De novo variants are rare in HHT. De novo variants should be confirmed not presumed for HHT." }, { "baseStrength": "Pathogenic", "id": "1744531089", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531089", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Not Applicable: De novo variants are rare in HHT. De novo variants should be confirmed not presumed for HHT." }, { "baseStrength": "Pathogenic", "id": "1744531085", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531085", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: HHT is autosomal dominant disorder." }, { "baseStrength": "Pathogenic", "id": "1744531085", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531085", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: HHT is autosomal dominant disorder." }, { "baseStrength": "Pathogenic", "id": "1744531085", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531085", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: HHT is autosomal dominant disorder." }, { "baseStrength": "Pathogenic", "id": "1744531085", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531085", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: HHT is autosomal dominant disorder." }, { "baseStrength": "Benign", "id": "1744531077", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531077", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Observed in trans with a pathogenic or likely pathogenic variant based on HHT VCEP rules." }, { "baseStrength": "Benign", "id": "1744531096", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531096", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1744531096", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531096", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1744531096", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531096", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1744531096", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531096", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1744531093", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531093", "label": "BS1", "strengthDescriptor": "Strong", "text": "\\>0.2% to \\<1% in general population databases (e.g. gnomAD) based on Popmax FAF, **or** if variant meets BS1\\_Supporting and has ≥2 homozygotes." }, { "baseStrength": "Benign", "id": "1744531093", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531093", "label": "BS1", "strengthDescriptor": "Supporting", "text": " >0.08% to 0.2% (based on gnomAD Popmax FAF)." }, { "baseStrength": "Benign", "id": "1744531088", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531088", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Allele frequency is ≥1% in general population databases (e.g. gnomAD) based on Popmax FAF." }, { "baseStrength": "Benign", "id": "1744531079", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531079", "label": "BS3", "strengthDescriptor": "Supporting", "text": "* mRNA splicing assays \n* Intracellular signaling assays: BRE/CAGA-luciferase, Gal4 Smad1/Smad3 for TGF-beta/BMP9 signaling\n* Binding assays: BMP9 binding, transcription factor Sp1, BMP9 protein-protein interaction (BLI)\n* Subcellular protein localization\n* Morphology: Morphology & actin cytoskeleton, tubulogenesis" }, { "baseStrength": "Benign", "id": "1744531100", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531100", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1744531100", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531100", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1744531100", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531100", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1744531100", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531100", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1744531095", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531095", "label": "PP1", "strengthDescriptor": "Strong", "text": "5+ meioses (1/32 likelihood)" }, { "baseStrength": "Pathogenic", "id": "1744531095", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531095", "label": "PP1", "strengthDescriptor": "Moderate", "text": "4 meioses (1/16 likelihood)" }, { "baseStrength": "Pathogenic", "id": "1744531095", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531095", "label": "PP1", "strengthDescriptor": "Supporting", "text": "3 meioses (1/8 likelihood)" }, { "baseStrength": "Pathogenic", "id": "1744531092", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531092", "label": "PS3", "strengthDescriptor": "Strong", "text": "* mRNA splicing assays can be used as strong functional evidence. \n * **Note:** level of evidence used may differ depending on whether the abnormal transcript is in-frame or out-of-frame, and whether there is complete or incomplete splicing impact.\n * Do not use PS3 for splice variants that meet PVS1." }, { "baseStrength": "Pathogenic", "id": "1744531092", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531092", "label": "PS3", "strengthDescriptor": "Moderate", "text": "See PS3\\_Supporting and Instructions below." }, { "baseStrength": "Pathogenic", "id": "1744531092", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531092", "label": "PS3", "strengthDescriptor": "Supporting", "text": "* Protein expression assays: Metabolic label & IP, WB & FACS HUVECs/BOECs, FACs activated monocytes, cDNA transfect, WB & ML HEK293T/COS/NIH3T3, cDNA transfect & luciferase HepG2\n * **Note:** Decreased protein expression can be used as supporting pathogenic evidence if experiment was not done in a single assay, and the corresponding densitometry of western blot reflects the conclusion drawn.\n* Intracellular signaling assays: BRE/CAGA-luciferase, Gal4 Smad1/Smad3 for TGF-beta/BMP9 signaling\n* Binding assays: BMP9 binding, transcription factor Sp1, BMP9 protein-protein interaction (BLI)\n* Subcellular protein localization\n* Morphology: Morphology & actin cytoskeleton, tubulogenesis\n* Somatic variant 2nd hit: In vivo evidence can be obtained as supporting functional evidence by identification of somatic variants in telangiectases´ biopsies using NGS, suggesting a second-hit mechanism leading to biallelic LOF (PMID: 31630786)." }, { "baseStrength": "Benign", "id": "1744531090", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531090", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous or intronic variant for which SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site. Can be used together with BP4 evidence." }, { "baseStrength": "Pathogenic", "id": "1744531087", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531087", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Use ACVRL1 PVS1 Decision Tree (see attachments)" }, { "baseStrength": "Pathogenic", "id": "1744531087", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531087", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Use ACVRL1 PVS1 Decision Tree (see attachments)" }, { "baseStrength": "Pathogenic", "id": "1744531087", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531087", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Use ACVRL1 PVS1 Decision Tree (see attachments)" }, { "baseStrength": "Benign", "id": "1744531081", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531081", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Missense variants commonly seen in HHT genes." }, { "baseStrength": "Benign", "id": "1744531081", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531081", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Missense variants commonly seen in HHT genes." }, { "baseStrength": "Benign", "id": "1744531081", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531081", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Missense variants commonly seen in HHT genes." }, { "baseStrength": "Benign", "id": "1744531081", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531081", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Missense variants commonly seen in HHT genes." }, { "baseStrength": "Pathogenic", "id": "1744531099", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531099", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level." }, { "baseStrength": "Pathogenic", "id": "1744531082", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531082", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply to ACVRL1 (Z-score 2.45)." }, { "baseStrength": "Pathogenic", "id": "1744531082", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531082", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply to ACVRL1 (Z-score 2.45)." }, { "baseStrength": "Pathogenic", "id": "1744531082", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531082", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply to ACVRL1 (Z-score 2.45)." }, { "baseStrength": "Pathogenic", "id": "1744531082", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531082", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply to ACVRL1 (Z-score 2.45)." }, { "baseStrength": "Benign", "id": "1744531080", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531080", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected members of a family." } ], "diseases": [ { "id": "MONDO:0010880", "iri": "https://genboree.org/cspec/Disease/id/467892150", "label": "telangiectasia, hereditary hemorrhagic, type 2" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467816325", "label": "ACVRL1" } ], "ruleSet": { "id": "1576018580", "iri": "https://genboree.org/cspec/RuleSet/id/1576018580" }, "svi": { "id": "GN135", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1576018567", "label": "ClinGen Hereditary Hemorrhagic Telangiectasia Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACVRL1 Version 1.1.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1744531862", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531862", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous or intronic variant for which SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site. Can be used together with BP4 evidence." }, { "baseStrength": "Pathogenic", "id": "1744531861", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531861", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: De novo variants are rare in HHT. De novo variants should be confirmed not presumed for HHT." }, { "baseStrength": "Pathogenic", "id": "1744531861", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531861", "label": "PM6", "strengthDescriptor": "Strong", "text": "Not Applicable: De novo variants are rare in HHT. De novo variants should be confirmed not presumed for HHT." }, { "baseStrength": "Pathogenic", "id": "1744531861", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531861", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Not Applicable: De novo variants are rare in HHT. De novo variants should be confirmed not presumed for HHT." }, { "baseStrength": "Pathogenic", "id": "1744531861", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531861", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Not Applicable: De novo variants are rare in HHT. De novo variants should be confirmed not presumed for HHT." }, { "baseStrength": "Pathogenic", "id": "1744531871", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531871", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level." }, { "baseStrength": "Pathogenic", "id": "1744531869", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531869", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Patient's phenotype meets consensus clinical diagnostic (Curaçao) criteria for HHT, and sequencing and large deletion/duplication analysis was performed for both _ENG_ and _ACVRL1_ with any other identified variants ruled out." }, { "baseStrength": "Benign", "id": "1744531851", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531851", "label": "BS3", "strengthDescriptor": "Supporting", "text": "* mRNA splicing assays \n* Intracellular signaling assays: BRE/CAGA-luciferase, Gal4 Smad1/Smad3 for TGF-beta/BMP9 signaling\n* Binding assays: BMP9 binding, transcription factor Sp1, BMP9 protein-protein interaction (BLI)\n* Subcellular protein localization\n* Morphology: Morphology & actin cytoskeleton, tubulogenesis" }, { "baseStrength": "Benign", "id": "1744531868", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531868", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1744531868", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531868", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1744531868", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531868", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1744531868", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531868", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "1744531866", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531866", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Apply if a likely pathogenic or pathogenic variant (based on HHT VCEP rules) is found in _ACVRL1_." }, { "baseStrength": "Pathogenic", "id": "1744531863", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531863", "label": "PP3", "strengthDescriptor": "Supporting", "text": "* For missense variants: REVEL score ≥0.644 or SpliceAI score ≥0.2.\n* For synonymous and intronic variants: SpliceAI score ≥0.2." }, { "baseStrength": "Pathogenic", "id": "1744531859", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531859", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Use ENG PVS1 Decision Tree (see attachments)" }, { "baseStrength": "Pathogenic", "id": "1744531859", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531859", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Use ENG PVS1 Decision Tree (see attachments)" }, { "baseStrength": "Pathogenic", "id": "1744531859", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531859", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Use ENG PVS1 Decision Tree (see attachments)" }, { "baseStrength": "Pathogenic", "id": "1744531857", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531857", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: HHT is autosomal dominant disorder." }, { "baseStrength": "Pathogenic", "id": "1744531857", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531857", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: HHT is autosomal dominant disorder." }, { "baseStrength": "Pathogenic", "id": "1744531857", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531857", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: HHT is autosomal dominant disorder." }, { "baseStrength": "Pathogenic", "id": "1744531857", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531857", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: HHT is autosomal dominant disorder." }, { "baseStrength": "Pathogenic", "id": "1744531856", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531856", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1744531856", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531856", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1744531856", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531856", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1744531856", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531856", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1744531848", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531848", "label": "PS4", "strengthDescriptor": "Strong", "text": "4+ probands with phenotype consistent with HHT." }, { "baseStrength": "Pathogenic", "id": "1744531848", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531848", "label": "PS4", "strengthDescriptor": "Moderate", "text": " 2-3 probands with phenotype consistent with HHT." }, { "baseStrength": "Pathogenic", "id": "1744531848", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531848", "label": "PS4", "strengthDescriptor": "Supporting", "text": "1 proband with phenotype consistent with HHT." }, { "baseStrength": "Benign", "id": "1744531873", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531873", "label": "BP4", "strengthDescriptor": "Supporting", "text": "* For missense variants: REVEL score ≤0.15 and SpliceAI score ≤0.1.\n* For synonymous and intronic variants: SpliceAI score ≤0.1." }, { "baseStrength": "Benign", "id": "1744531872", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531872", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1744531872", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531872", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1744531872", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531872", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1744531872", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531872", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1744531864", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531864", "label": "PS3", "strengthDescriptor": "Strong", "text": "* mRNA splicing assays can be used as strong functional evidence. \n * **Note:** level of evidence used may differ depending on whether the abnormal transcript is in-frame or out-of-frame, and whether there is complete or incomplete splicing impact.\n * Do not use PS3 for splice variants that meet PVS1." }, { "baseStrength": "Pathogenic", "id": "1744531864", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531864", "label": "PS3", "strengthDescriptor": "Moderate", "text": "See PS3\\_Supporting and Instructions below." }, { "baseStrength": "Pathogenic", "id": "1744531864", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531864", "label": "PS3", "strengthDescriptor": "Supporting", "text": "* Protein expression assays: Metabolic label & IP, WB & FACS HUVECs/BOECs, FACs activated monocytes, cDNA transfect, WB & ML HEK293T/COS/NIH3T3, cDNA transfect & luciferase HepG2\n * **Note:** Decreased protein expression can be used as supporting pathogenic evidence if experiment was not done in a single assay, and the corresponding densitometry of western blot reflects the conclusion drawn.\n* Intracellular signaling assays: BRE/CAGA-luciferase, Gal4 Smad1/Smad3 for TGF-beta/BMP9 signaling\n* Binding assays: BMP9 binding, transcription factor Sp1, BMP9 protein-protein interaction (BLI)\n* Subcellular protein localization\n* Morphology: Morphology & actin cytoskeleton, tubulogenesis\n* Somatic variant 2nd hit: In vivo evidence can be obtained as supporting functional evidence by identification of somatic variants in telangiectases´ biopsies using NGS, suggesting a second-hit mechanism leading to biallelic LOF (PMID: 31630786)." }, { "baseStrength": "Pathogenic", "id": "1744531854", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531854", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply to ENG (Z-score= 0.93). " }, { "baseStrength": "Pathogenic", "id": "1744531854", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531854", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply to ENG (Z-score= 0.93). " }, { "baseStrength": "Pathogenic", "id": "1744531854", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531854", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply to ENG (Z-score= 0.93). " }, { "baseStrength": "Pathogenic", "id": "1744531854", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531854", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply to ENG (Z-score= 0.93). " }, { "baseStrength": "Benign", "id": "1744531853", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531853", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Missense variants commonly seen in HHT genes" }, { "baseStrength": "Benign", "id": "1744531853", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531853", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Missense variants commonly seen in HHT genes" }, { "baseStrength": "Benign", "id": "1744531853", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531853", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Missense variants commonly seen in HHT genes" }, { "baseStrength": "Benign", "id": "1744531853", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531853", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Missense variants commonly seen in HHT genes" }, { "baseStrength": "Pathogenic", "id": "1744531847", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531847", "label": "PM2", "strengthDescriptor": "Supporting", "text": "\\<6 total alleles in gnomAD or \\<0.00004 (0.004%) in gnomAD subpopulations." }, { "baseStrength": "Pathogenic", "id": "1744531870", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531870", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "1744531867", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531867", "label": "PP1", "strengthDescriptor": "Strong", "text": "5+ meioses (1/32 likelihood)" }, { "baseStrength": "Pathogenic", "id": "1744531867", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531867", "label": "PP1", "strengthDescriptor": "Moderate", "text": "4 meioses (1/16 likelihood)" }, { "baseStrength": "Pathogenic", "id": "1744531867", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531867", "label": "PP1", "strengthDescriptor": "Supporting", "text": "3 meioses (1/8 likelihood)" }, { "baseStrength": "Benign", "id": "1744531865", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531865", "label": "BS1", "strengthDescriptor": "Strong", "text": "\\>0.2% to \\<1% in general population databases (e.g. gnomAD) based on Popmax FAF, **or** if variant meets BS1\\_Supporting and has ≥2 homozygotes." }, { "baseStrength": "Benign", "id": "1744531865", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531865", "label": "BS1", "strengthDescriptor": "Supporting", "text": " >0.08% to 0.2% (based on gnomAD Popmax FAF)." }, { "baseStrength": "Benign", "id": "1744531860", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531860", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Allele frequency is ≥1% in general population databases (e.g. gnomAD) based on Popmax FAF." }, { "baseStrength": "Pathogenic", "id": "1744531858", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531858", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Apply if variant is located in a critical residue:\n\n* ENG:\n * BMP9 binding sites: S278, F282 (PMIDs 28564608, 25312062)\n * Cysteine residues either previously reported to be likely pathogenic or pathogenic:\n * C207, C363, C382, C412, C549\n * Or cysteine residues known to be important for ENG function:\n * C350 (C350-C382 disulfide in ZP-N domain of ENG is required for secretion of its ZP module)\n * C394 (makes a disulfide bond with C412 which is reported to be a mutated residue)\n * C516 (involved in forming intermolecular disulfides that hold ENG homodimer together)\n * C582 (involved in forming intermolecular disulfides that hold ENG homodimer together)" }, { "baseStrength": "Benign", "id": "1744531855", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531855", "label": "BS2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Full penetrance at an early age is not observed in HHT." }, { "baseStrength": "Benign", "id": "1744531855", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531855", "label": "BS2", "strengthDescriptor": "Strong", "text": "Not Applicable: Full penetrance at an early age is not observed in HHT." }, { "baseStrength": "Benign", "id": "1744531855", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531855", "label": "BS2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Full penetrance at an early age is not observed in HHT." }, { "baseStrength": "Benign", "id": "1744531855", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531855", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Full penetrance at an early age is not observed in HHT." }, { "baseStrength": "Benign", "id": "1744531852", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531852", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected members of a family." }, { "baseStrength": "Pathogenic", "id": "1744531850", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531850", "label": "PM5", "strengthDescriptor": "Strong", "text": "≥2 different missense changes at same codon have been determined to be likely pathogenic or pathogenic based on HHT VCEP rules." }, { "baseStrength": "Pathogenic", "id": "1744531850", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531850", "label": "PM5", "strengthDescriptor": "Moderate", "text": "A different missense change at same codon has been determined to be likely pathogenic or pathogenic based on HHT VCEP rules." }, { "baseStrength": "Benign", "id": "1744531849", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531849", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Observed in trans with a pathogenic or likely pathogenic variant based on HHT VCEP rules." }, { "baseStrength": "Pathogenic", "id": "1744531846", "iri": "https://genboree.org/cspec/CriteriaCode/id/1744531846", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." } ], "diseases": [ { "id": "MONDO:0008535", "iri": "https://genboree.org/cspec/Disease/id/467878488", "label": "telangiectasia, hereditary hemorrhagic, type 1" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467825027", "label": "ENG" } ], "ruleSet": { "id": "1576926556", "iri": "https://genboree.org/cspec/RuleSet/id/1576926556" }, "svi": { "id": "GN136", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1576926543", "label": "ClinGen Hereditary Hemorrhagic Telangiectasia Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ENG Version 1.1.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "467903893", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903893", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Also applicable when in cis or trans with a likely pathogenic variant." }, { "baseStrength": "Benign", "id": "467903890", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903890", "label": "BS3", "strengthDescriptor": "Strong", "text": "Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing." }, { "baseStrength": "Benign", "id": "467903890", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903890", "label": "BS3", "strengthDescriptor": "Supporting", "text": "See HNF1A rules for full list of approved functional studies and guidelines for interpretation of data. \n(1) Luciferase assays for transactivation - \"No functional impact\" is defined as ≥ 75% activity of wildtype\n(2) EMSA for DNA binding - \"No functional impact\" is defined as ≥ 75% activity of wildtype.\n(3) Western blotting and indirect immunoflorescence for protein expression and localization - Determining appropriate thresholds for protein expression is more difficult due to variability in results between different experimental protocols. Altered protein expression can be indirectly captured through the read-out from a transactivation assay and reduced protein expression can provide an explanation for reduced transactivation." }, { "baseStrength": "Benign", "id": "467903888", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903888", "label": "BS1", "strengthDescriptor": "Strong", "text": "MAF ≥ 1:30,000 (≥0.0033% or 0.000033) in gnomAD 2.1.1\\* Popmax Filtering AF.\n\n\\*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used." }, { "baseStrength": "Pathogenic", "id": "467903885", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903885", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is above 0.2 (Wai et al. 2020 PMID: 32123317; Jaganathan et al. 2019 PMID: 30661751)." }, { "baseStrength": "Pathogenic", "id": "467903884", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903884", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Missense variants account for 55% of all published pathogenic variants in this gene (Colclough et al 2013), however the constraint score for HNF1A (gene) is 1.07, which is not significant; therefore, we do not support using this criterion at this time. The low constraint score is most likely due to high tolerance for missense variants in the transactivation domain (see PM1 section). There are significantly more pathogenic missense variants in the DNA binding and dimerization domains, which are much less tolerant to missense variation. We may update this in the future if we can generate domain-specific scores." }, { "baseStrength": "Pathogenic", "id": "467903884", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903884", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Missense variants account for 55% of all published pathogenic variants in this gene (Colclough et al 2013), however the constraint score for HNF1A (gene) is 1.07, which is not significant; therefore, we do not support using this criterion at this time. The low constraint score is most likely due to high tolerance for missense variants in the transactivation domain (see PM1 section). There are significantly more pathogenic missense variants in the DNA binding and dimerization domains, which are much less tolerant to missense variation. We may update this in the future if we can generate domain-specific scores." }, { "baseStrength": "Pathogenic", "id": "467903884", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903884", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Missense variants account for 55% of all published pathogenic variants in this gene (Colclough et al 2013), however the constraint score for HNF1A (gene) is 1.07, which is not significant; therefore, we do not support using this criterion at this time. The low constraint score is most likely due to high tolerance for missense variants in the transactivation domain (see PM1 section). There are significantly more pathogenic missense variants in the DNA binding and dimerization domains, which are much less tolerant to missense variation. We may update this in the future if we can generate domain-specific scores." }, { "baseStrength": "Pathogenic", "id": "467903884", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903884", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Missense variants account for 55% of all published pathogenic variants in this gene (Colclough et al 2013), however the constraint score for HNF1A (gene) is 1.07, which is not significant; therefore, we do not support using this criterion at this time. The low constraint score is most likely due to high tolerance for missense variants in the transactivation domain (see PM1 section). There are significantly more pathogenic missense variants in the DNA binding and dimerization domains, which are much less tolerant to missense variation. We may update this in the future if we can generate domain-specific scores." }, { "baseStrength": "Pathogenic", "id": "467903883", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903883", "label": "PP1", "strengthDescriptor": "Strong", "text": "Use thresholds suggested by Jarvik and Browning (PMID: 27236918)\n* Single Family : ≤ 1/32 (5 meioses) \n* >1 Family : ≤ 1/16 (4 meioses)" }, { "baseStrength": "Pathogenic", "id": "467903883", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903883", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Use thresholds suggested by Jarvik and Browning (PMID: 27236918)\n* Single Family : ≤ 1/16 (4 meioses)\n* >1 Family : ≤ 1/8 (3 meioses)" }, { "baseStrength": "Pathogenic", "id": "467903883", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903883", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Use thresholds suggested by Jarvik and Browning (PMID: 27236918)\n* Single Family : ≤ 1/8 (3 meioses) \n* >1 Family : ≤ ¼ (2 meioses)" }, { "baseStrength": "Pathogenic", "id": "467903878", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903878", "label": "PM2", "strengthDescriptor": "Supporting", "text": "gnomAD 2.1.1\\* Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in gnomAD European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population.  \n\n\\*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used." }, { "baseStrength": "Pathogenic", "id": "467903875", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903875", "label": "PS3", "strengthDescriptor": "Strong", "text": "Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing." }, { "baseStrength": "Pathogenic", "id": "467903875", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903875", "label": "PS3", "strengthDescriptor": "Moderate", "text": "Applicable for variants with luciferase assay data (evidence of decreased transactivation (<=40% of wild type) by the Gloyn/Oxford group (Althari et al 2020 https://pubmed.ncbi.nlm.nih.gov/32910913/)" }, { "baseStrength": "Pathogenic", "id": "467903875", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903875", "label": "PS3", "strengthDescriptor": "Supporting", "text": "See list of approved functional studies and guidelines for interpretation of data (below).\n(1) Luciferase assays for transactivation - \"Decreased function\" is defined as activity less than 40% of wildtype. Assays should include controls for WT, T2DM-risk, and known MODY variants. For additional specifications and recommendations, please see the HNF1A rules.\n(2) EMSA for DNA binding - \"Decreased function\" is defined as activity lesss than 405 of wildtype. We recommend that at least two of the following variants be used as positive controls for reduced DNA binding activity: c.335C>T (p.Pro112Leu), c.608G>A (p.Arg203His), c.787C>T (p.Arg263Cys) and c.686G>A (p.Arg229Gln) (PMID: 11162430, 12574234, 24915262). For additional specifications and recommendations, please see the HNF1A rules.\n(3) Western blotting and indirect immunoflorescence for protein expression and localization - Determining appropriate thresholds for protein expression is more difficult due to variability in results between experimental protocols. Altered protein expression can be indirectly captured through the read-out frame from transactivation assay, and reduced protein expression can provide an explanation for reduced transactivation. When exploring protein mis-localization, we recommend that the c.589_615del (p.Lys197_Lys205del) variant is included as a positive control for impaired nuclear localization (cytosolic retention)." }, { "baseStrength": "Pathogenic", "id": "638433451", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433451", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433451", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433451", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433451", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433451", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433451", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433451", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "467903897", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903897", "label": "BP7", "strengthDescriptor": "Supporting", "text": "Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way \\< 2.0." }, { "baseStrength": "Benign", "id": "467903896", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903896", "label": "BP5", "strengthDescriptor": "Supporting", "text": "A variant in other monogenic diabetes gene is P/LP." }, { "baseStrength": "Benign", "id": "467903895", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903895", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2 (Wai et al. 2020 PMID: 32123317; Jaganathan et al. 2019 PMID: 30661751)." }, { "baseStrength": "Benign", "id": "467903892", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903892", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "467903892", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903892", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "467903892", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903892", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "467903892", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903892", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "467903889", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903889", "label": "BS2", "strengthDescriptor": "Strong", "text": "Apply to normoglycemic individuals age 70 or older (i.e., genotype positive, phenotype negative)" }, { "baseStrength": "Benign", "id": "467903887", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903887", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "MAF ≥ 1:10,000 (≥ 0.01% or 0.0001) in gnomAD 2.1.1\\* Popmax Filtering AF.\n\n\\*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used." }, { "baseStrength": "Pathogenic", "id": "467903882", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903882", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "467903882", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903882", "label": "PM6", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "467903882", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903882", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "467903882", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903882", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "467903879", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903879", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "467903879", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903879", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "467903879", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903879", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "467903879", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903879", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "467903876", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903876", "label": "PS4", "strengthDescriptor": "Strong", "text": "Seven or more= Strong. Variant should meet PM2_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region). Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see below)." }, { "baseStrength": "Pathogenic", "id": "467903876", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903876", "label": "PS4", "strengthDescriptor": "Moderate", "text": "4-6 unrelated occurrences = Moderate. " }, { "baseStrength": "Pathogenic", "id": "467903881", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903881", "label": "PM5", "strengthDescriptor": "Strong", "text": "Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue" }, { "baseStrength": "Pathogenic", "id": "467903881", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903881", "label": "PM5", "strengthDescriptor": "Moderate", "text": "The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant." }, { "baseStrength": "Pathogenic", "id": "467903881", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903881", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance." }, { "baseStrength": "Pathogenic", "id": "467903880", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903880", "label": "PM4", "strengthDescriptor": "Moderate", "text": "For single amino acid deletions, use as supporting level of evidence." }, { "baseStrength": "Pathogenic", "id": "467903880", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903880", "label": "PM4", "strengthDescriptor": "Supporting", "text": "For single amino acid deletions/insertions, use as supporting level of evidence" }, { "baseStrength": "Pathogenic", "id": "467903874", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903874", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications." }, { "baseStrength": "Pathogenic", "id": "467903874", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903874", "label": "PS2", "strengthDescriptor": "Strong", "text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications." }, { "baseStrength": "Pathogenic", "id": "467903874", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903874", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications." }, { "baseStrength": "Pathogenic", "id": "467903874", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903874", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications." }, { "baseStrength": "Pathogenic", "id": "467903873", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903873", "label": "PS1", "strengthDescriptor": "Strong", "text": "No change" }, { "baseStrength": "Pathogenic", "id": "467903873", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903873", "label": "PS1", "strengthDescriptor": "Supporting", "text": "PS1 may also be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact." }, { "baseStrength": "Pathogenic", "id": "467903872", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903872", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Use HNF1A PVS1 decision tree.\n* Variants generating PTCs 3’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs.\n * PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY.\n* “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”\n * Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function.\n* Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118.\n* Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1." }, { "baseStrength": "Pathogenic", "id": "467903872", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903872", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Use HNF1A PVS1 decision tree.\n* Variants generating PTCs 3’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs.\n * PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY.\n* “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”\n * Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function.\n* Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118.\n* Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1." }, { "baseStrength": "Pathogenic", "id": "467903872", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903872", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "Use HNF1A PVS1 decision tree.\n* Variants generating PTCs 3’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs.\n * PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY.\n* “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”\n * Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function.\n* Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118.\n* Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1." }, { "baseStrength": "Benign", "id": "638433450", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433450", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433450", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433450", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433450", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433450", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433450", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433450", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "467903894", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903894", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "467903894", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903894", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "467903894", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903894", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "467903894", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903894", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "467903891", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903891", "label": "BS4", "strengthDescriptor": "Strong", "text": "Applicable to family members without variant who have MPC score >50% (i.e., genotype negative, phenotype positive)." }, { "baseStrength": "Pathogenic", "id": "467903886", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903886", "label": "PP4", "strengthDescriptor": "Moderate", "text": "MODY Probability Calculator (MPC) result ≥50% chance of testing positive https://www.diabetesgenes.org/mody-probability-calculator/) AND negative HNF4A testing AND presence of at least one additional feature characteristic of HNF1A-MODY:\n* Antibody negative and/or persistent C-peptide after five years post- T1DM diagnosis\n* Response to low-dose SU (extreme response- hypoglycemia)\n* Low hsCRP in patient with clinical diagnosis of T2DM\n* Biochemical/Molecular phenotypic evidence from patient cell lines\n* Hepatocellular adenomas" }, { "baseStrength": "Pathogenic", "id": "467903886", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903886", "label": "PP4", "strengthDescriptor": "Supporting", "text": "MODY Probability Calculator (MPC) result ≥50% chance of testing positive https://www.diabetesgenes.org/mody-probability-calculator/) AND negative HNF4A testing" }, { "baseStrength": "Pathogenic", "id": "467903877", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903877", "label": "PM1", "strengthDescriptor": "Moderate", "text": "This criterion can be used for variants in residues that directly bind DNA: Gln130, Arg131, Glu132, His143, Leu144, Ser145, Gln146, His147, Leu148, Asn149, Lys155, Thr156, Gln157, Lys158, Arg203, Phe204, Lys205, Trp206, Arg263, Val264, Tyr265, Asn270, Arg271, Arg272, Lys273 " }, { "baseStrength": "Pathogenic", "id": "467903877", "iri": "https://genboree.org/cspec/CriteriaCode/id/467903877", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Use for defined regions in the DNA binding and dimerization domains. \n* Dimerization: codons 1-32, NM_000545.8 \n* Subset of DNA binding domains: codons 107-174 and 201-280, NM_000545.8 \nIt can also be used for variants within certain transcription factor binding sites of the promoter. \n* –c.-187 to c.-195 (AP1 binding site) \n* –c.-209 to c.-227 (Overlapping HNF3 & NF-Y sites) \n* –c.-238 to c.-259 (HNF1A binding site) \n* –c.-276 to c.-288 (HNF4A binding site) \n " } ], "diseases": [ { "id": "MONDO:0015967", "iri": "https://genboree.org/cspec/Disease/id/467884025", "label": "monogenic diabetes" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467829599", "label": "HNF1A" } ], "ruleSet": { "id": "467903870", "iri": "https://genboree.org/cspec/RuleSet/id/467903870" }, "svi": { "id": "GN017", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/467903868", "label": "ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF1A Version 2.1.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "638433480", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433480", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433480", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433480", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433480", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433480", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433480", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433480", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "467907186", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907186", "label": "BP7", "strengthDescriptor": "Supporting", "text": "For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs, if the nucleotide is non-conserved award this point (PhyloP score <0.1)." }, { "baseStrength": "Benign", "id": "467907184", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907184", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Award BP4 for a synonymous, intronic positions (except canonical splice sites) or non-coding variants in the UTRs, if two out of three of the splicing prediction tools predicted no impact on splicing function.\nNot applicable for any variant type except for synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs,. This criterion can be applied when two of three splicing prediction tools predict no splicing change. The splicing prediction tools used are: varSEAK, spliceAI and MaxEntScan." }, { "baseStrength": "Benign", "id": "467907178", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907178", "label": "BS2", "strengthDescriptor": "Strong", "text": "Award BS2 if ≥3 homozygotes present in gnomAD or ≥3 heterozygous in well phenotyped family members.\nClinical laboratories are encouraged to accumulate more than 2 (≥3) instances of well phenotyped family members before applying this strong criterion. To be considered for this point, the variant should be either germline (most common), or somatic in a relevant tissue. Homozygous occurrences in gnomAD or ExAC can also be counted for this point (≥3)." }, { "baseStrength": "Pathogenic", "id": "467907175", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907175", "label": "PP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable since this criterion is accounted for under PS4." }, { "baseStrength": "Pathogenic", "id": "467907175", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907175", "label": "PP4", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable since this criterion is accounted for under PS4." }, { "baseStrength": "Pathogenic", "id": "467907175", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907175", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable since this criterion is accounted for under PS4." }, { "baseStrength": "Pathogenic", "id": "467907175", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907175", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable since this criterion is accounted for under PS4." }, { "baseStrength": "Pathogenic", "id": "467907174", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907174", "label": "PP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not applicable since these variants are GOF, and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms. Use of this criterion can be revisited if there emerges additional published experience with predictive algorithms specifically designed to detect gain of function mutations." }, { "baseStrength": "Pathogenic", "id": "467907174", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907174", "label": "PP3", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not applicable since these variants are GOF, and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms. Use of this criterion can be revisited if there emerges additional published experience with predictive algorithms specifically designed to detect gain of function mutations." }, { "baseStrength": "Pathogenic", "id": "467907174", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907174", "label": "PP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not applicable since these variants are GOF, and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms. Use of this criterion can be revisited if there emerges additional published experience with predictive algorithms specifically designed to detect gain of function mutations." }, { "baseStrength": "Pathogenic", "id": "467907174", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907174", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not applicable since these variants are GOF, and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms. Use of this criterion can be revisited if there emerges additional published experience with predictive algorithms specifically designed to detect gain of function mutations." }, { "baseStrength": "Pathogenic", "id": "467907169", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907169", "label": "PM4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Although there have been reported in-frame deletion/insertions in these genes which cause the overgrowth phenotype, they are exceptionally rare. Most insertion/deletions are associated with a LoF disease mechanism and so this point will still not be used even though we recognize that it is possible that a variant is an in-frame indel that results in a GoF mechanism." }, { "baseStrength": "Pathogenic", "id": "467907169", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907169", "label": "PM4", "strengthDescriptor": "Strong", "text": "Not Applicable: Although there have been reported in-frame deletion/insertions in these genes which cause the overgrowth phenotype, they are exceptionally rare. Most insertion/deletions are associated with a LoF disease mechanism and so this point will still not be used even though we recognize that it is possible that a variant is an in-frame indel that results in a GoF mechanism." }, { "baseStrength": "Pathogenic", "id": "467907169", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907169", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Although there have been reported in-frame deletion/insertions in these genes which cause the overgrowth phenotype, they are exceptionally rare. Most insertion/deletions are associated with a LoF disease mechanism and so this point will still not be used even though we recognize that it is possible that a variant is an in-frame indel that results in a GoF mechanism." }, { "baseStrength": "Pathogenic", "id": "467907169", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907169", "label": "PM4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Although there have been reported in-frame deletion/insertions in these genes which cause the overgrowth phenotype, they are exceptionally rare. Most insertion/deletions are associated with a LoF disease mechanism and so this point will still not be used even though we recognize that it is possible that a variant is an in-frame indel that results in a GoF mechanism." }, { "baseStrength": "Benign", "id": "467907176", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907176", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Allele frequency (>0.0926%). An allele frequency (>0.0926%) was approved.\n Note: this was adjusted from ACMG Guidelines due to maintaining the 5x threshold for benign (consistent with previously established guidelines)" }, { "baseStrength": "Pathogenic", "id": "467907166", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907166", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Residues affecting critical functional domains provided in Table 4 for each gene." }, { "baseStrength": "Pathogenic", "id": "467907164", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907164", "label": "PS3", "strengthDescriptor": "Strong", "text": "Follow recommendations set forth by the SVI in conjunction with specifications added by the BMVCEP for quality metrics and minimum validation controls required. (Supplemental Document 1) Animal models are considered in a different manner.\n\nAward PS4_Strong if the animal model generated with the variant of interest expressed in neural progenitors shows a complementary brain phenotype.\n\nAward PS3 if the functional assay meets the acceptability criteria delimited in (PMID: 31892348) with specifications added by the BMVCEP. Quality metrics and minimum validation controls required can be found in Supplementary Document 1.\n\nAnimal models are considered in a different manner. Award PS4_Strong if the animal model generated with the variant of interest expressed in neural progenitors show a complementary brain phenotype.\n\nCaveat: Studies of cell lines derived from the affected patient as the only source of functional characterization are by themselves insufficient to provide strong evidence of pathogenicity. This is because cells derived from patient affected tissue are likely to exhibit the desired phenotype since the patient tissue exhibits the phenotype. It is therefore impossible to determine whether the variant of interest was solely responsible for that phenotype. Instead, functional readout of patient-derived cells are now included in PS4." }, { "baseStrength": "Pathogenic", "id": "467907164", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907164", "label": "PS3", "strengthDescriptor": "Moderate", "text": "Follow recommendations set forth by the SVI in conjunction with specifications added by the BMVCEP for quality metrics and minimum validation controls required (PMID: 31892348). Animal models are considered in a different manner. Award PS4_Moderate if the animal model generated with the variant of interest expressed in non-neural tissues show an increased cancer burden." }, { "baseStrength": "Pathogenic", "id": "467907164", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907164", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Follow recommendations set forth by the SVI in conjunction with specifications added by the BMVCEP for quality metrics and minimum validation controls required (PMID: 31892348)." }, { "baseStrength": "Benign", "id": "467907177", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907177", "label": "BS1", "strengthDescriptor": "Strong", "text": "Allele frequency (>0.0185%). An allele frequency (>0.0185%) was approved. (Supplemental Table 3)." }, { "baseStrength": "Pathogenic", "id": "467907172", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907172", "label": "PP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable since disease-causing variants are germline mosaic, de novo or mosaic." }, { "baseStrength": "Pathogenic", "id": "467907172", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907172", "label": "PP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable since disease-causing variants are germline mosaic, de novo or mosaic." }, { "baseStrength": "Pathogenic", "id": "467907172", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907172", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable since disease-causing variants are germline mosaic, de novo or mosaic." }, { "baseStrength": "Pathogenic", "id": "467907172", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907172", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable since disease-causing variants are germline mosaic, de novo or mosaic." }, { "baseStrength": "Pathogenic", "id": "467907171", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907171", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This point is addressed according to PS2 and will not be used." }, { "baseStrength": "Pathogenic", "id": "467907171", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907171", "label": "PM6", "strengthDescriptor": "Strong", "text": "Not Applicable: This point is addressed according to PS2 and will not be used." }, { "baseStrength": "Pathogenic", "id": "467907171", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907171", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This point is addressed according to PS2 and will not be used." }, { "baseStrength": "Pathogenic", "id": "467907171", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907171", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This point is addressed according to PS2 and will not be used." }, { "baseStrength": "Pathogenic", "id": "467907170", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907170", "label": "PM5", "strengthDescriptor": "Moderate", "text": "No change." }, { "baseStrength": "Pathogenic", "id": "467907167", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907167", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Absent/rare from controls in an ethnically-matched cohort population sample ( ≥1)." }, { "baseStrength": "Pathogenic", "id": "467907163", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907163", "label": "PS2", "strengthDescriptor": "Strong", "text": "Award the PS2_Strong point if Criteria 1 AND Criteria 2 are fulfilled. \n\n Criteria 1. The variant is present at a detectable allele fraction but is absent from parental samples with confirmed maternity and paternity.\n\n Criteria 2. The variant is present at a detectable allele fraction in an affected tissue sample but is absent from or detected at a lower allelic fraction in another tissue (e.g. if present in 5% of brain tissue but absent from the blood or skin this point can be awarded).\n\nFor the sake of implementation, these criteria are intended to apply to high-confidence somatic mutations identified by the reporting CLIA laboratory. The expert panel recognizes that in practice there may be significant heterogeneity in the technical methods and thresholds used to identify such variants as 'high confidence', and flags the need to establish consensus statistical frameworks (e.g. Phred-scaled genotype qualities) or experimental approaches (e.g., confirmation of somatic variants by sequencing on orthogonal platforms) by which quality thresholds can be consistently applied." }, { "baseStrength": "Pathogenic", "id": "467907163", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907163", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Award the PS2_Moderate point if Criteria 1 is fulfilled, OR if parents are not available but Criteria 2 is fulfilled." }, { "baseStrength": "Pathogenic", "id": "467907161", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907161", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: LOF and/or haploinsufficiency have not been clearly identified as disease mechanisms underlying brain malformations related to these genes, so in general this rule is not applicable. The disease mechanism for these genes is gain of function (GOF)." }, { "baseStrength": "Pathogenic", "id": "467907161", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907161", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Not Applicable: LOF and/or haploinsufficiency have not been clearly identified as disease mechanisms underlying brain malformations related to these genes, so in general this rule is not applicable. The disease mechanism for these genes is gain of function (GOF)." }, { "baseStrength": "Pathogenic", "id": "467907161", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907161", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Not Applicable: LOF and/or haploinsufficiency have not been clearly identified as disease mechanisms underlying brain malformations related to these genes, so in general this rule is not applicable. The disease mechanism for these genes is gain of function (GOF)." }, { "baseStrength": "Pathogenic", "id": "467907161", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907161", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "Not Applicable: LOF and/or haploinsufficiency have not been clearly identified as disease mechanisms underlying brain malformations related to these genes, so in general this rule is not applicable. The disease mechanism for these genes is gain of function (GOF)." }, { "baseStrength": "Benign", "id": "467907185", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907185", "label": "BP5", "strengthDescriptor": "Supporting", "text": "No change." }, { "baseStrength": "Benign", "id": "467907183", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907183", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This is not applicable for the genes specified since the exon regions do not have repetitive regions without a known function." }, { "baseStrength": "Benign", "id": "467907183", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907183", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: This is not applicable for the genes specified since the exon regions do not have repetitive regions without a known function." }, { "baseStrength": "Benign", "id": "467907183", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907183", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: This is not applicable for the genes specified since the exon regions do not have repetitive regions without a known function." }, { "baseStrength": "Benign", "id": "467907183", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907183", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: This is not applicable for the genes specified since the exon regions do not have repetitive regions without a known function." }, { "baseStrength": "Benign", "id": "467907181", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907181", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable as LOF is not the disease mechanism." }, { "baseStrength": "Benign", "id": "467907181", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907181", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable as LOF is not the disease mechanism." }, { "baseStrength": "Benign", "id": "467907181", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907181", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable as LOF is not the disease mechanism." }, { "baseStrength": "Benign", "id": "467907181", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907181", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable as LOF is not the disease mechanism." }, { "baseStrength": "Benign", "id": "467907180", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907180", "label": "BS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable as these are de novo, germline mosaic or post-zygotic mutations." }, { "baseStrength": "Benign", "id": "467907180", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907180", "label": "BS4", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable as these are de novo, germline mosaic or post-zygotic mutations." }, { "baseStrength": "Benign", "id": "467907180", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907180", "label": "BS4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable as these are de novo, germline mosaic or post-zygotic mutations." }, { "baseStrength": "Benign", "id": "467907180", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907180", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable as these are de novo, germline mosaic or post-zygotic mutations." }, { "baseStrength": "Pathogenic", "id": "467907165", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907165", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant meets criteria for (PM2). Strength of evidence is determined by points according to (Table 2B). PS4\\_VeryStrong ≥ 16 points. For PS4, for cases reported in the literature, we recommend assigning each one to the SINGLE category below that is associated with the highest point value (Table 2A). The total score obtained for all reported cases with a particular variant will determine the strength of PS4 assigned according to the scale (Table 2B)*.\n\n_PS4\\_VeryStrong ≥ 16 points._\n\n*Applicable if the variant is absent/rare from controls according to PM2 to ensure the variant is not simply present due to beinging common in the general population." }, { "baseStrength": "Pathogenic", "id": "467907165", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907165", "label": "PS4", "strengthDescriptor": "Strong", "text": "Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2). Strength of evidence is determined by points according to (Table 2B). PS4_Strong = 3.5-15.75 points." }, { "baseStrength": "Pathogenic", "id": "467907165", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907165", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2). Strength of evidence is determined by points according to (Table 2B). PS4_Moderate = 1.5-3.25 points." }, { "baseStrength": "Pathogenic", "id": "467907165", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907165", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2). Strength of evidence is determined by points according to (Table 2B). PS4_Supporting = 0.5 – 1.25 points." }, { "baseStrength": "Pathogenic", "id": "638433481", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433481", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433481", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433481", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433481", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433481", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433481", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433481", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "467907182", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907182", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Observed in cis or trans with a known pathogenic variant in the same gene." }, { "baseStrength": "Benign", "id": "467907179", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907179", "label": "BS3", "strengthDescriptor": "Strong", "text": "Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required." }, { "baseStrength": "Benign", "id": "467907179", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907179", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required." }, { "baseStrength": "Pathogenic", "id": "467907173", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907173", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Missense constraint computed in ExAC/gnomAD was utilized. Award PP2 if the z-score > 3.09. (applicable to MTOR, PIK3CA and AKT3 but not PIK3R2)." }, { "baseStrength": "Pathogenic", "id": "467907168", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907168", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable since disease-causing variants are heterozygous." }, { "baseStrength": "Pathogenic", "id": "467907168", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907168", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable since disease-causing variants are heterozygous." }, { "baseStrength": "Pathogenic", "id": "467907168", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907168", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable since disease-causing variants are heterozygous." }, { "baseStrength": "Pathogenic", "id": "467907168", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907168", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable since disease-causing variants are heterozygous." }, { "baseStrength": "Pathogenic", "id": "467907162", "iri": "https://genboree.org/cspec/CriteriaCode/id/467907162", "label": "PS1", "strengthDescriptor": "Strong", "text": "No change." } ], "diseases": [ { "id": "MONDO:0016054", "iri": "https://genboree.org/cspec/Disease/id/467882125", "label": "obsolete cerebral malformation" }, { "id": "MONDO:0016054", "iri": "https://genboree.org/cspec/Disease/id/467882125", "label": "obsolete cerebral malformation" }, { "id": "MONDO:0016054", "iri": "https://genboree.org/cspec/Disease/id/467882125", "label": "obsolete cerebral malformation" }, { "id": "MONDO:0016054", "iri": "https://genboree.org/cspec/Disease/id/467882125", "label": "obsolete cerebral malformation" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467816839", "label": "AKT3" }, { "iri": "https://genboree.org/cspec/Gene/id/467840946", "label": "MTOR" }, { "iri": "https://genboree.org/cspec/Gene/id/467845243", "label": "PIK3CA" }, { "iri": "https://genboree.org/cspec/Gene/id/467845253", "label": "PIK3R2" } ], "ruleSet": { "id": "467907154", "iri": "https://genboree.org/cspec/RuleSet/id/467907154" }, "svi": { "id": "GN018", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/467907148", "label": "ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1.0" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "635003691", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003691", "label": "PM4", "strengthDescriptor": "Moderate", "text": "In-frame del/ins and truncating variants involving >10% of the protein and located within the conserved olfactomedin domain (AA 246-502)." }, { "baseStrength": "Pathogenic", "id": "635003691", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003691", "label": "PM4", "strengthDescriptor": "Supporting", "text": "In-frame del/ins and truncating variants involving ≤10% of the protein and located within the conserved olfactomedin domain (AA 246-502)." }, { "baseStrength": "Pathogenic", "id": "635003685", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003685", "label": "PS2", "strengthDescriptor": "Strong", "text": "≥2 confirmed de novo in JOAG.\nUse the proposed SVI point recommendations for “phenotype consistent with gene but not highly specific” for JOAG.\n * Both maternity and paternity need to be proven for confirmed de novo variants.\n * Parents need to be clinically assessed and not have a diagnosis of glaucoma." }, { "baseStrength": "Pathogenic", "id": "635003685", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003685", "label": "PS2", "strengthDescriptor": "Moderate", "text": "≥2 confirmed de novo in POAG or 1 confirmed de novo in JOAG\nUse proposed SVI point recommendations for “phenotype consistent with the gene but not highly specific and with high genetic heterogeneity” for POAG and “phenotype consistent with gene but not highly specific” for JOAG.\n * Both maternity and paternity need to be proven for confirmed de novo variants.\n * Parents need to be clinically assessed and not have a diagnosis of glaucoma." }, { "baseStrength": "Pathogenic", "id": "635003685", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003685", "label": "PS2", "strengthDescriptor": "Supporting", "text": "1 confirmed de novo in POAG.\nUse proposed SVI point recommendations for “phenotype consistent with the gene but not highly specific and with high genetic heterogeneity” for POAG. \n * Both maternity and paternity need to be proven for confirmed de novo variants. \n * Parents need to be clinically assessed and not have a diagnosis of glaucoma." }, { "baseStrength": "Pathogenic", "id": "638433511", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433511", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433511", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433511", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433511", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433511", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "638433511", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433511", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "635003703", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003703", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Both truncating and missense MYOC variants are causative." }, { "baseStrength": "Benign", "id": "635003703", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003703", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Both truncating and missense MYOC variants are causative." }, { "baseStrength": "Benign", "id": "635003703", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003703", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Both truncating and missense MYOC variants are causative." }, { "baseStrength": "Benign", "id": "635003703", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003703", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Both truncating and missense MYOC variants are causative." }, { "baseStrength": "Benign", "id": "635003702", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003702", "label": "BS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: The presence of phenocopies, the reduced age-related penetrance and the possibility that more than one pathogenic variant can contribute to the phenotype observed in families make non-segregation difficult to assess in the context of MYOC and POAG." }, { "baseStrength": "Benign", "id": "635003702", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003702", "label": "BS4", "strengthDescriptor": "Strong", "text": "Not Applicable: The presence of phenocopies, the reduced age-related penetrance and the possibility that more than one pathogenic variant can contribute to the phenotype observed in families make non-segregation difficult to assess in the context of MYOC and POAG." }, { "baseStrength": "Benign", "id": "635003702", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003702", "label": "BS4", "strengthDescriptor": "Moderate", "text": "Not Applicable: The presence of phenocopies, the reduced age-related penetrance and the possibility that more than one pathogenic variant can contribute to the phenotype observed in families make non-segregation difficult to assess in the context of MYOC and POAG." }, { "baseStrength": "Benign", "id": "635003702", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003702", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Not Applicable: The presence of phenocopies, the reduced age-related penetrance and the possibility that more than one pathogenic variant can contribute to the phenotype observed in families make non-segregation difficult to assess in the context of MYOC and POAG." }, { "baseStrength": "Pathogenic", "id": "635003693", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003693", "label": "PM6", "strengthDescriptor": "Moderate", "text": "≥2 assumed de novo in JOAG.\nUse proposed SVI point recommendations for “phenotype consistent with gene but not highly specific” for JOAG.\n * Both maternity and paternity need to be proven for confirmed de novo variants.\n * Parents need to be clinically assessed and not have a diagnosis of glaucoma." }, { "baseStrength": "Pathogenic", "id": "635003693", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003693", "label": "PM6", "strengthDescriptor": "Supporting", "text": "≥2 assumed de novo in POAG or 1 assumed de novo in JOAG\nUse proposed SVI point recommendations for “phenotype consistent with the gene but not highly specific and with high genetic heterogeneity” for POAG and “phenotype consistent with gene but not highly specific” for JOAG.\n * Both maternity and paternity need to be proven for confirmed de novo variants.\n * Parents need to be clinically assessed and not have a diagnosis of glaucoma." }, { "baseStrength": "Pathogenic", "id": "635003690", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003690", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: MYOC variants have an autosomal dominant mode of inheritance." }, { "baseStrength": "Pathogenic", "id": "635003690", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003690", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: MYOC variants have an autosomal dominant mode of inheritance." }, { "baseStrength": "Pathogenic", "id": "635003690", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003690", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: MYOC variants have an autosomal dominant mode of inheritance." }, { "baseStrength": "Pathogenic", "id": "635003690", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003690", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: MYOC variants have an autosomal dominant mode of inheritance." }, { "baseStrength": "Pathogenic", "id": "635003689", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003689", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Allele frequency ≤ 0.0001 in population databases.\n * The highest allele frequency in population databases should be used. \n * Only applies to populations of ≥ 10,000 alleles." }, { "baseStrength": "Pathogenic", "id": "635003688", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003688", "label": "PM1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: MYOC has no mutational hot spot and benign variants are present though the well-characterised olfactomedin domain in exon 3." }, { "baseStrength": "Pathogenic", "id": "635003688", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003688", "label": "PM1", "strengthDescriptor": "Strong", "text": "Not Applicable: MYOC has no mutational hot spot and benign variants are present though the well-characterised olfactomedin domain in exon 3." }, { "baseStrength": "Pathogenic", "id": "635003688", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003688", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Not Applicable: MYOC has no mutational hot spot and benign variants are present though the well-characterised olfactomedin domain in exon 3." }, { "baseStrength": "Pathogenic", "id": "635003688", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003688", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Not Applicable: MYOC has no mutational hot spot and benign variants are present though the well-characterised olfactomedin domain in exon 3." }, { "baseStrength": "Pathogenic", "id": "635003687", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003687", "label": "PS4", "strengthDescriptor": "Strong", "text": "≥ 15 probands from multiple independent studies.\n * Probands counted should be clinically assessed and have a diagnosis of JOAG or POAG.\n * PM2_Supporting must be met." }, { "baseStrength": "Pathogenic", "id": "635003687", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003687", "label": "PS4", "strengthDescriptor": "Moderate", "text": "≥ 6 probands from multiple independent studies.\n * Probands counted should be clinically assessed and have a diagnosis of JOAG or POAG.\n * PM2_Supporting must be met." }, { "baseStrength": "Pathogenic", "id": "635003687", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003687", "label": "PS4", "strengthDescriptor": "Supporting", "text": "≥ 2 probands from multiple independent studies.\n * Probands counted should be clinically assessed and have a diagnosis of JOAG or POAG.\n * PM2_Supporting must be met." }, { "baseStrength": "Benign", "id": "635003708", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003708", "label": "BP7", "strengthDescriptor": "Supporting", "text": "Applies to synonymous variants or noncoding variants with no impact on splicing (SpliceAI ≤ 0.2) and GERP <0 for conservation." }, { "baseStrength": "Benign", "id": "635003699", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003699", "label": "BS1", "strengthDescriptor": "Strong", "text": "Allele frequency ≥ 0.001 in population databases.\n * The highest allele frequency in population databases should be used. \n * Variant must be present in ≥ 5 alleles in any validated general continental population dataset of at least 2,000 observed alleles. \n * Does not apply to p.Gln368Ter." }, { "baseStrength": "Benign", "id": "635003698", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003698", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Allele frequency ≥ 0.01 in population databases.\n * The highest allele frequency in population databases should be used.\n * Variant must be present in ≥ 5 alleles in any validated general continental population dataset of at least 2,000 observed alleles." }, { "baseStrength": "Pathogenic", "id": "635003695", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003695", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Although pathogenic missense variants are common in MYOC, the gene also has a significant amount of benign missense variants as shown by the missense constraint z score in gnomAD (z = 0.52) supporting tolerance to variation." }, { "baseStrength": "Pathogenic", "id": "635003695", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003695", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Although pathogenic missense variants are common in MYOC, the gene also has a significant amount of benign missense variants as shown by the missense constraint z score in gnomAD (z = 0.52) supporting tolerance to variation." }, { "baseStrength": "Pathogenic", "id": "635003695", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003695", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Although pathogenic missense variants are common in MYOC, the gene also has a significant amount of benign missense variants as shown by the missense constraint z score in gnomAD (z = 0.52) supporting tolerance to variation." }, { "baseStrength": "Pathogenic", "id": "635003695", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003695", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Although pathogenic missense variants are common in MYOC, the gene also has a significant amount of benign missense variants as shown by the missense constraint z score in gnomAD (z = 0.52) supporting tolerance to variation." }, { "baseStrength": "Pathogenic", "id": "635003694", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003694", "label": "PP1", "strengthDescriptor": "Strong", "text": "≥7 meioses in >1 family.\n * BA1 and BS1 must not be met.\n * Only genotype positive/phenotype positive and obligate carriers/phenotype positive individuals should be counted as segregations.\n * Phenotype positive need to be clinically assessed and either have a diagnosis of glaucoma or suspicious signs of glaucoma." }, { "baseStrength": "Pathogenic", "id": "635003694", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003694", "label": "PP1", "strengthDescriptor": "Moderate", "text": "≥ 5 meioses.\n * BA1 and BS1 must not be met.\n * Only genotype positive/phenotype positive and obligate carriers/phenotype positive individuals should be counted as segregations.\n * Phenotype positive need to be clinically assessed and either have a diagnosis of glaucoma or suspicious signs of glaucoma." }, { "baseStrength": "Pathogenic", "id": "635003694", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003694", "label": "PP1", "strengthDescriptor": "Supporting", "text": "≥ 3 meioses.\n * BA1 and BS1 must not be met.\n * Only genotype positive/phenotype positive and obligate carriers/phenotype positive individuals should be counted as segregations.\n * Phenotype positive need to be clinically assessed and either have a diagnosis of glaucoma or suspicious signs of glaucoma." }, { "baseStrength": "Pathogenic", "id": "635003683", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003683", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: MYOC variants cause JOAG/POAG through a gain of function (GoF) disease mechanism and not loss of function (LoF). Truncating variants in exon 3 are expected to be pathogenic because they escape nonsense-mediated decay." }, { "baseStrength": "Pathogenic", "id": "635003683", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003683", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Not Applicable: MYOC variants cause JOAG/POAG through a gain of function (GoF) disease mechanism and not loss of function (LoF). Truncating variants in exon 3 are expected to be pathogenic because they escape nonsense-mediated decay." }, { "baseStrength": "Pathogenic", "id": "635003683", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003683", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Not Applicable: MYOC variants cause JOAG/POAG through a gain of function (GoF) disease mechanism and not loss of function (LoF). Truncating variants in exon 3 are expected to be pathogenic because they escape nonsense-mediated decay." }, { "baseStrength": "Pathogenic", "id": "635003683", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003683", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "Not Applicable: MYOC variants cause JOAG/POAG through a gain of function (GoF) disease mechanism and not loss of function (LoF). Truncating variants in exon 3 are expected to be pathogenic because they escape nonsense-mediated decay." }, { "baseStrength": "Benign", "id": "638433510", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433510", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433510", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433510", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433510", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433510", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "638433510", "iri": "https://genboree.org/cspec/CriteriaCode/id/638433510", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "635003706", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003706", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Applies to:\n * Missense variants with a REVEL score of ≤ 0.15.\n * Synonymous variants or noncoding variants with a CADD score of ≤ 10 AND SpliceAI ≤ 0.2" }, { "baseStrength": "Benign", "id": "635003701", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003701", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Applies to variants showing solubility or secretion in functional assays for studies with OddsPath <0.23 as per the SVI recommendations.\n* Only apply if the assay includes both negative and positive controls and includes technical and/or biological replicates.\n* If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.\n* Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.\n* If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another." }, { "baseStrength": "Benign", "id": "635003701", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003701", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Applies to variants showing solubility or secretion in functional assays for studies with OddsPath <0.48 as per the SVI recommendations.\n* Only apply if the assay includes both negative and positive controls and includes technical and/or biological replicates.\n* If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.\n* Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.\n* If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another." }, { "baseStrength": "Benign", "id": "635003700", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003700", "label": "BS2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: MYOC variants have an incomplete penetrance and late age of onset." }, { "baseStrength": "Benign", "id": "635003700", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003700", "label": "BS2", "strengthDescriptor": "Strong", "text": "Not Applicable: MYOC variants have an incomplete penetrance and late age of onset." }, { "baseStrength": "Benign", "id": "635003700", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003700", "label": "BS2", "strengthDescriptor": "Moderate", "text": "Not Applicable: MYOC variants have an incomplete penetrance and late age of onset." }, { "baseStrength": "Benign", "id": "635003700", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003700", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Not Applicable: MYOC variants have an incomplete penetrance and late age of onset." }, { "baseStrength": "Pathogenic", "id": "635003697", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003697", "label": "PP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: The phenotype associated with MYOC variants is not highly specific and there is genetic heterogeneity." }, { "baseStrength": "Pathogenic", "id": "635003697", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003697", "label": "PP4", "strengthDescriptor": "Strong", "text": "Not Applicable: The phenotype associated with MYOC variants is not highly specific and there is genetic heterogeneity." }, { "baseStrength": "Pathogenic", "id": "635003697", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003697", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Not Applicable: The phenotype associated with MYOC variants is not highly specific and there is genetic heterogeneity." }, { "baseStrength": "Pathogenic", "id": "635003697", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003697", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Not Applicable: The phenotype associated with MYOC variants is not highly specific and there is genetic heterogeneity." }, { "baseStrength": "Pathogenic", "id": "635003696", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003696", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Applies to missense variants with a REVEL score of ≥ 0.7." }, { "baseStrength": "Pathogenic", "id": "635003684", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003684", "label": "PS1", "strengthDescriptor": "Strong", "text": "* The novel change must not affect splicing (SpliceAI ≤ 0.2)." }, { "baseStrength": "Pathogenic", "id": "635003684", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003684", "label": "PS1", "strengthDescriptor": "Moderate", "text": "Same amino acid change as a previously established likely pathogenic variant\n * The novel change must not affect splicing (SpliceAI ≤ 0.2)." }, { "baseStrength": "Benign", "id": "635003707", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003707", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Multiple molecular diagnoses are possible and variants in different genes could have an additive effect." }, { "baseStrength": "Benign", "id": "635003707", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003707", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable: Multiple molecular diagnoses are possible and variants in different genes could have an additive effect." }, { "baseStrength": "Benign", "id": "635003707", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003707", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: Multiple molecular diagnoses are possible and variants in different genes could have an additive effect." }, { "baseStrength": "Benign", "id": "635003707", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003707", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: Multiple molecular diagnoses are possible and variants in different genes could have an additive effect." }, { "baseStrength": "Benign", "id": "635003705", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003705", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: MYOC does not have a repetitive region without a known function." }, { "baseStrength": "Benign", "id": "635003705", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003705", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: MYOC does not have a repetitive region without a known function." }, { "baseStrength": "Benign", "id": "635003705", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003705", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: MYOC does not have a repetitive region without a known function." }, { "baseStrength": "Benign", "id": "635003705", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003705", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: MYOC does not have a repetitive region without a known function." }, { "baseStrength": "Benign", "id": "635003704", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003704", "label": "BP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Biallelic variants (either compound heterozygotes or homozygotes) have been reported (with variable phenotype) and are not incompatible with life. Two missense variants in cis could act synergistically or the effect of a variant occurring after a truncating variant may not be predicted." }, { "baseStrength": "Benign", "id": "635003704", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003704", "label": "BP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Biallelic variants (either compound heterozygotes or homozygotes) have been reported (with variable phenotype) and are not incompatible with life. Two missense variants in cis could act synergistically or the effect of a variant occurring after a truncating variant may not be predicted." }, { "baseStrength": "Benign", "id": "635003704", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003704", "label": "BP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Biallelic variants (either compound heterozygotes or homozygotes) have been reported (with variable phenotype) and are not incompatible with life. Two missense variants in cis could act synergistically or the effect of a variant occurring after a truncating variant may not be predicted." }, { "baseStrength": "Benign", "id": "635003704", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003704", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Biallelic variants (either compound heterozygotes or homozygotes) have been reported (with variable phenotype) and are not incompatible with life. Two missense variants in cis could act synergistically or the effect of a variant occurring after a truncating variant may not be predicted." }, { "baseStrength": "Pathogenic", "id": "635003692", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003692", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Same residue as a previously established pathogenic variant (assessed independently of PM5) or 2 previously established likely pathogenic variants (both assessed independently of PM5)\n * The novel change must not affect splicing (SpliceAI ≤ 0.2), must meet PP3 and have a Grantham score equal or greater than the previously established P/LP variants." }, { "baseStrength": "Pathogenic", "id": "635003692", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003692", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Same residue as a previously established likely pathogenic variant (assessed independently of PM5).\n * The novel change must not affect splicing (SpliceAI ≤ 0.2), must meet PP3 and have a Grantham score equal or greater than the previously established P/LP variants." }, { "baseStrength": "Pathogenic", "id": "635003686", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003686", "label": "PS3", "strengthDescriptor": "Strong", "text": "Assays with OddsPath >18.7 as per the SVI recommendations.\n * Applies to the following functional studies: Solubility or secretion assays OR animal models that replicate the glaucoma phenotype.\n * PS3 should only be applied if the assay includes both negative and positive controls and includes technical and/or biological replicates.\n * If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.\n * Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.\n * If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another." }, { "baseStrength": "Pathogenic", "id": "635003686", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003686", "label": "PS3", "strengthDescriptor": "Moderate", "text": "Assays with OddsPath >4.3 as per the SVI recommendations\n * Applies to the following functional studies: Solubility or secretion assays OR animal models that replicate the glaucoma phenotype.\n * PS3 should only be applied if the assay includes both negative and positive controls and includes technical and/or biological replicates.\n * If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.\n * Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.\n * If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another." }, { "baseStrength": "Pathogenic", "id": "635003686", "iri": "https://genboree.org/cspec/CriteriaCode/id/635003686", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Assays with OddsPath >2.1 as per the SVI recommendations.\n * Applies to the following functional studies: Solubility or secretion assays OR animal models that replicate the glaucoma phenotype.\n * PS3 should only be applied if the assay includes both negative and positive controls and includes technical and/or biological replicates.\n * If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.\n * Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.\n * If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another." } ], "diseases": [ { "id": "MONDO:0007665", "iri": "https://genboree.org/cspec/Disease/id/467890796", "label": "obsolete glaucoma 1, open angle, E" }, { "id": "MONDO:0020367", "iri": "https://genboree.org/cspec/Disease/id/467891695", "label": "juvenile open angle glaucoma" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467841186", "label": "MYOC" } ], "ruleSet": { "id": "635003681", "iri": "https://genboree.org/cspec/RuleSet/id/635003681" }, "svi": { "id": "GN019", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/635003679", "label": "ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1" } }, { "codes": [ { "baseStrength": "Benign", "id": "639509018", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509018", "label": "BP7", "strengthDescriptor": "Strong", "text": "Can be considered for BP7\\_(RNA) with curator discretion of quality." }, { "baseStrength": "Benign", "id": "639509018", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509018", "label": "BP7", "strengthDescriptor": "Moderate", "text": "Can be considered for BP7\\_(RNA) with curator discretion of quality." }, { "baseStrength": "Benign", "id": "639509018", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509018", "label": "BP7", "strengthDescriptor": "Supporting", "text": "Can be considered for BP7\\_(RNA) with curator discretion of quality; Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -40 at donor and acceptor sites, respectively" }, { "baseStrength": "Benign", "id": "639509017", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509017", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "639509017", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509017", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "639509017", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509017", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "639509017", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509017", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "639509014", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509014", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "639509014", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509014", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "639509014", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509014", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "639509014", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509014", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "639509013", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509013", "label": "BP2", "strengthDescriptor": "Strong", "text": "Use ATM PM3/BP2 table." }, { "baseStrength": "Benign", "id": "639509013", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509013", "label": "BP2", "strengthDescriptor": "Moderate", "text": "Use ATM PM3/BP2 table." }, { "baseStrength": "Benign", "id": "639509013", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509013", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Use ATM PM3/BP2 table" }, { "baseStrength": "Benign", "id": "639509009", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509009", "label": "BS2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "639509009", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509009", "label": "BS2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "639509009", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509009", "label": "BS2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "639509009", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509009", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639508998", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508998", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Use ATM PM3/BP2 table." }, { "baseStrength": "Pathogenic", "id": "639508998", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508998", "label": "PM3", "strengthDescriptor": "Strong", "text": "Use ATM PM3/BP2 table." }, { "baseStrength": "Pathogenic", "id": "639508998", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508998", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Use ATM PM3/BP2 table." }, { "baseStrength": "Pathogenic", "id": "639508998", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508998", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Use ATM PM3/BP2 table" }, { "baseStrength": "Pathogenic", "id": "639508994", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508994", "label": "PS3", "strengthDescriptor": "Strong", "text": "Do not use as strong." }, { "baseStrength": "Pathogenic", "id": "639508994", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508994", "label": "PS3", "strengthDescriptor": "Moderate", "text": "Use when a variant fails to rescue both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity." }, { "baseStrength": "Pathogenic", "id": "639508994", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508994", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Use when a variant fails to rescue an ATM specifc feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency" }, { "baseStrength": "Pathogenic", "id": "639508993", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508993", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639508993", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508993", "label": "PS2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639508993", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508993", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639508993", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508993", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639508991", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508991", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Use ATM PVS1 Decision Tree" }, { "baseStrength": "Pathogenic", "id": "639508991", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508991", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Use ATM PVS1 Decision Tree." }, { "baseStrength": "Pathogenic", "id": "639508991", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508991", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Use ATM PVS1 Decision Tree." }, { "baseStrength": "Pathogenic", "id": "639508991", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508991", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "Use ATM PVS1 Decision Tree" }, { "baseStrength": "Benign", "id": "639509016", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509016", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "639509016", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509016", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "639509016", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509016", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "639509016", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509016", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "639509012", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509012", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "639509012", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509012", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "639509012", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509012", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "639509012", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509012", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639509004", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509004", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Protein: REVEL >.7333; RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing" }, { "baseStrength": "Pathogenic", "id": "639509000", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509000", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Use for genomic frameshift and truncating variants with PTC upstream of p.R3047. Apply also to splice variants as PM5\\_supporting for splice variants can only be applied for variants premature termination codons upstream of p.Arg3047 where PVS1\\_VS(RNA) is applied based on high quality observed splicing impact and must be NMD prone. Do not use for start-loss variants" }, { "baseStrength": "Pathogenic", "id": "639508999", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508999", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Use for stop-loss variants." }, { "baseStrength": "Benign", "id": "639509015", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509015", "label": "BP4", "strengthDescriptor": "Supporting", "text": "* **Protein** Analysis: Metapredictor REVEL score ≤.249\n* RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing \n * NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) \n * NOTE: BP4 for splice predictions may not be applied in conjunction with BP7\\_Variable(RNA) (a lack of observed RNA defect) Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism." }, { "baseStrength": "Benign", "id": "639509011", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509011", "label": "BS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: AD Condition: Co-segregation analysis in lowpenetrance genes can lead to false positive results (PMID 32773770)\n. AR Condition: informative instances of lack of co-segregation in A-T families are too rare to be considered for weight at this time and can also be considered for BP2 if biallelic unaffected patients are observed in an A-T family." }, { "baseStrength": "Benign", "id": "639509011", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509011", "label": "BS4", "strengthDescriptor": "Strong", "text": "Not Applicable: AD Condition: Co-segregation analysis in lowpenetrance genes can lead to false positive results (PMID 32773770)\n. AR Condition: informative instances of lack of co-segregation in A-T families are too rare to be considered for weight at this time and can also be considered for BP2 if biallelic unaffected patients are observed in an A-T family." }, { "baseStrength": "Benign", "id": "639509011", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509011", "label": "BS4", "strengthDescriptor": "Moderate", "text": "Not Applicable: AD Condition: Co-segregation analysis in lowpenetrance genes can lead to false positive results (PMID 32773770)\n. AR Condition: informative instances of lack of co-segregation in A-T families are too rare to be considered for weight at this time and can also be considered for BP2 if biallelic unaffected patients are observed in an A-T family." }, { "baseStrength": "Benign", "id": "639509011", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509011", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Not Applicable: AD Condition: Co-segregation analysis in lowpenetrance genes can lead to false positive results (PMID 32773770)\n. AR Condition: informative instances of lack of co-segregation in A-T families are too rare to be considered for weight at this time and can also be considered for BP2 if biallelic unaffected patients are observed in an A-T family." }, { "baseStrength": "Benign", "id": "639509007", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509007", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Filtering Allele Frequency >.5%." }, { "baseStrength": "Pathogenic", "id": "639509001", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509001", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639509001", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509001", "label": "PM6", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639509001", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509001", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639509001", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509001", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639508996", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508996", "label": "PM1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639508996", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508996", "label": "PM1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639508996", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508996", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639508996", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508996", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "639509010", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509010", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Use when a variant rescues both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity." }, { "baseStrength": "Benign", "id": "639509010", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509010", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Use when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity." }, { "baseStrength": "Benign", "id": "639509008", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509008", "label": "BS1", "strengthDescriptor": "Strong", "text": "Filtering Allele Frequency >.05%." }, { "baseStrength": "Pathogenic", "id": "639509006", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509006", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "639509006", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509006", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "639509006", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509006", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "639509006", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509006", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "639509002", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509002", "label": "PP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Informative pedigrees for segregation in families with AR Ataxia-Telangiectasia are not available. However, this VCEP would consider rules similar to the Glanzman and Hearing Loss VCEP rules if a pedigree becomes available." }, { "baseStrength": "Pathogenic", "id": "639509002", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509002", "label": "PP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Informative pedigrees for segregation in families with AR Ataxia-Telangiectasia are not available. However, this VCEP would consider rules similar to the Glanzman and Hearing Loss VCEP rules if a pedigree becomes available." }, { "baseStrength": "Pathogenic", "id": "639509002", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509002", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Informative pedigrees for segregation in families with AR Ataxia-Telangiectasia are not available. However, this VCEP would consider rules similar to the Glanzman and Hearing Loss VCEP rules if a pedigree becomes available." }, { "baseStrength": "Pathogenic", "id": "639509002", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509002", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Informative pedigrees for segregation in families with AR Ataxia-Telangiectasia are not available. However, this VCEP would consider rules similar to the Glanzman and Hearing Loss VCEP rules if a pedigree becomes available." }, { "baseStrength": "Pathogenic", "id": "639508997", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508997", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2\\_supporting would apply. n>1 in one or multiple subpopulations would not be considered rare and PM2\\_supporting would not apply" }, { "baseStrength": "Pathogenic", "id": "639508992", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508992", "label": "PS1", "strengthDescriptor": "Strong", "text": "Use for protein changes as long as splicing is ruled-out for both alterations. Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect." }, { "baseStrength": "Pathogenic", "id": "639508992", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508992", "label": "PS1", "strengthDescriptor": "Moderate", "text": "Use for protein changes as long as splicing is ruled-out for both alterations. Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect." }, { "baseStrength": "Pathogenic", "id": "639509005", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509005", "label": "PP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639509005", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509005", "label": "PP4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639509005", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509005", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639509005", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509005", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639509003", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509003", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Do not use: ATM does not have a defined low rate of missense benign variation." }, { "baseStrength": "Pathogenic", "id": "639509003", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509003", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Do not use: ATM does not have a defined low rate of missense benign variation." }, { "baseStrength": "Pathogenic", "id": "639509003", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509003", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Do not use: ATM does not have a defined low rate of missense benign variation." }, { "baseStrength": "Pathogenic", "id": "639509003", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509003", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Do not use: ATM does not have a defined low rate of missense benign variation." }, { "baseStrength": "Pathogenic", "id": "639508995", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508995", "label": "PS4", "strengthDescriptor": "Strong", "text": "Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk  ≥2 OR lower 95% CI ≥1.5)." }, { "baseStrength": "Pathogenic", "id": "639508995", "iri": "https://genboree.org/cspec/CriteriaCode/id/639508995", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Do not use for proband counting." } ], "diseases": [ { "id": "MONDO:0016419", "iri": "https://genboree.org/cspec/Disease/id/467880845", "label": "hereditary breast carcinoma" }, { "id": "MONDO:0008840", "iri": "https://genboree.org/cspec/Disease/id/467877731", "label": "ataxia telangiectasia" }, { "id": "MONDO:0018266", "iri": "https://genboree.org/cspec/Disease/id/467877093", "label": "ataxia - telangiectasia variant" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467818057", "label": "ATM" } ], "ruleSet": { "id": "639508987", "iri": "https://genboree.org/cspec/RuleSet/id/639508987" }, "svi": { "id": "GN020", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/639508985", "label": "ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.2.0" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "639509392", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509392", "label": "PP3", "strengthDescriptor": "Supporting", "text": "* Missense changes with a REVEL score >0.75 will meet PP3.\n* For in-frame deletions and insertions, use PROVEAN and Mutation Taster. Results must be consistent to count.\n* For non-canonical splice site variants, use Splice AI, MaxEntScn and NNSplice. Based on data from Jaganathan et al., 2019 (PMID: 30661751), Houdayer et al., 2012 (PMID: 22505045) and Tang et al., 2016 (PMID: 27313609), PP3 can be applied if there is, a SpliceAI “high score” (Δ Score ≥ 0.5 “confidently predicted splice variants”) (exclude any results with Δ Score ≤ 0.2 from consideration of pathogenicity, <0.2 are not “predicted to alter splicing”), >15% reduction using MaxEntScn and >5% reduction using NNSplice. Two out of the three predictors must be consistent to count.\n* For SpliceAI’s cryptic splice-site rules, the creation of a new splice-site with Δ Score ≥ 0.5 may be enough to produce a large proportion of aberrant transcripts.\n* If a new splice site is predicted to be generated, this rule can be applied if the newly generated splice site is significantly stronger than the wild type site (Δ Score ≥ 0.5 using SpliceAI; >15% difference using MaxEntScn).\n* Do not apply this rule for canonical splice site changes meeting PVS1." }, { "baseStrength": "Pathogenic", "id": "639509384", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509384", "label": "PM1", "strengthDescriptor": "Moderate", "text": "* Examples of mutational hot spots:\nIt has been cited that the CpG dinucleotides in the codon for arginine326 and arginine429 are mutational hot spots, since CrT (R326C and R429W) and GrA (R326H and R429Q) mutations of the CpG di- nucleotide are present in both codons. Article for reference is Clear Correlation of Genotype with Disease Phenotype in Very–Long-Chain Acyl-CoA Dehydrogenase Deficiency – by Andresen et al., 1999 (PMID 9973285).\n* Please refer to “Structural Basis for Substrate Fatty Acyl Chain Specificity: Crystal Structure of Human Very-Long-Chain acyl-CoA Dehydrogenase” by McAndrew et al., 2008 (PMID 18227065) (note – numbering in this reference is for the mature peptide without the mitochondrial signal peptide, so amino acid position numbers are lower by 40 than numbering based on NM-000018.4) and “Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches” by Gobin-Limballe et al., 2010 (PMID 20060901) for identifying important structural regions for proper enzyme function such as binding sites and active sites of the enzyme. Based on this and information from UniProt the following regions are designated to be important functional domains:\n * p.214-223, p.249-251, p.460-466, p.562: Nucleotide and substrate binding.\n * p.481-516: Membrane binding.\n * p.1-40: Mitochondrial signal peptide.\n* Curators may seek approval from the expert panel for identifying new hot spots or critical regions as discovered in literature searches, in uniport, HGMD, etc. for inclusion." }, { "baseStrength": "Pathogenic", "id": "639509379", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509379", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Loss of function is a known mechanism for VLCAD Deficiency. The specifications below are based on published guidance for assigning strength of evidence for PVS1 (Abou Tayoun et al., 2018; PMID: 30192042). There are multiple transcripts for ACADVL. The major isoform, NM\\_000018.4, encodes a 655 amino acid precursor protein that contains a 40 amino acid N-terminal target sequence that is removed during uptake (Aoyama et al., 1995; PMID: 7668252). In a joint project between NCBI and EMBL-EBI (MANE), NM\\_000018.4 was designated as the most relevant transcript. Nonsense or Frameshift:\n\n* Use caution when interpreting LOF variants at the 3’ end of the gene.\n* All nonsense and frameshift variants will meet PVS1 unless the variant is predicted to be missed by nonsense-mediated decay (NMD).\n* NMD is not predicted if the variant is in the last exon (exon 20) or in the last 50 nucleotides of the penultimate exon (exon 19). Canonical Splice Site (+1, +2, -1, -2):\n* All donor/acceptor sites follow the GT/AG rule, except for the donor splice site of intron 8, which begins with GC. PVS1 should not be applied for variants in the splice donor site of intron 8 since the impact of GC donor splice sites is not well understood.\n* For +1 or +2 GT donor splice site variants, the exon immediately 5’ of the variant is predicted to be skipped. For -1 or -2 AG acceptor splice site variants, the exon immediately 3’ of the variants is predicted to be skipped. For the predicted in frame/out of frame consequences for exon skipping in ACADVL (NM\\_000018.4), see Appendix 1. Deletions:\n* For single or multi-exon deletions that result in an out-of-frame consequence, use PVS1 unless NMD is not predicted to occur. If NMD is not predicted to occur, use PVS1\\_Moderate.\n* If a deletion results in an in-frame consequence, the deletion must encompass one or more exons in order to apply PVS1. Consult Appendix 1 and the PVS1 decision tree to assign a strength. Duplications:\n* Single and multi-exon duplications have not been reported in ACADVL. Consult the PVS1 decision tree to assign the strength. Initiation codon:\n* The next in-frame methionine is at position 6 (on transcript NM\\_000018). However, the first 40 amino acids comprise the leader sequence in the precursor peptide and are important for proper localization of the protein (Aoyama et al., 1995; PMID: 7668252). Therefore, initiator codon variants will meet PVS1\\_Strong.\n* If an in-frame deletion or splice variant disrupts a PM1 region, PVS1 can be modified to Strong instead of Moderate." }, { "baseStrength": "Benign", "id": "639509401", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509401", "label": "BP2", "strengthDescriptor": "Supporting", "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." }, { "baseStrength": "Pathogenic", "id": "639509393", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509393", "label": "PP4", "strengthDescriptor": "Moderate", "text": "* Abnormal tests that are consistent with VLCAD deficiency include deficient VLCAD enzyme activity in patient cells (leukocytes, fibroblasts, liver, heart, or skeletal muscle, or amniocytes), abnormal C14:1 acylcarnitine values from newborn screening (NBS), and abnormal acylcarnitine values from follow-up plasma analysis.\n* To award a given tier of evidence, at least one proband harboring the variant must meet at least one of the minimum requirements below. If multiple analyses are completed, only one result needs to be within the allowed ranges to meet this rule as values can fluctuate due to age or diet:\n* PP4\\_moderate (Must meet at least one of the below criteria):\n * VLCAD enzyme activity (β-Oxidation Flux) ≤20% of normal.\n * Clinical plasma acylcarnitine testing, not from newborn screen, is consistent with VLCADD\n * NBS C14:1 Levels ≥ 1.0 μM AND:\n * VLCAD enzyme activity (β-Oxidation Flux) 21-27% of normal OR Assertion of reduced VLCAD activity without specific levels OR Follow-Up Plasma Acylcarnitine analysis “consistent with VLCADD” without specific levels." }, { "baseStrength": "Pathogenic", "id": "639509393", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509393", "label": "PP4", "strengthDescriptor": "Supporting", "text": "* Abnormal tests that are consistent with VLCAD deficiency include deficient VLCAD enzyme activity in patient cells (leukocytes, fibroblasts, liver, heart, or skeletal muscle, or amniocytes), abnormal C14:1 acylcarnitine values from newborn screening (NBS), and abnormal acylcarnitine values from follow-up plasma analysis.\n* To award a given tier of evidence, at least one proband harboring the variant must meet at least one of the minimum requirements below. If multiple analyses are completed, only one result needs to be within the allowed ranges to meet this rule as values can fluctuate due to age or diet: \n* PP4_supporting (Must meet at least one of the below criteria):\n * VLCAD enzyme activity (β-Oxidation Flux) 21-27% of normal.\n * Assertion of reduced VLCAD activity without specific levels.\n * NBS C14:1 Levels from >0.8 μM.\n * Assertion of abnormal NBS “consistent with VLCADD” without specific levels AND: Follow-Up Plasma Acylcarnitine analysis “consistent with VLCADD” without specific levels." }, { "baseStrength": "Pathogenic", "id": "639509387", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509387", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." }, { "baseStrength": "Pathogenic", "id": "639509383", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509383", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639509383", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509383", "label": "PS4", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639509383", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509383", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639509383", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509383", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "639509404", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509404", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: An individual could be a carrier of a pathogenic variant in ACADVL and have another disorder." }, { "baseStrength": "Benign", "id": "639509404", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509404", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable: An individual could be a carrier of a pathogenic variant in ACADVL and have another disorder." }, { "baseStrength": "Benign", "id": "639509404", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509404", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: An individual could be a carrier of a pathogenic variant in ACADVL and have another disorder." }, { "baseStrength": "Benign", "id": "639509404", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509404", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: An individual could be a carrier of a pathogenic variant in ACADVL and have another disorder." }, { "baseStrength": "Benign", "id": "639509396", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509396", "label": "BS1", "strengthDescriptor": "Strong", "text": "* Variants with a highest population minor allele frequency (MAF) ≥0.0035 (0.35%) in any continental population with >2000 alleles in gnomAD will meet BS1.\n* See Appendix 2 for calculations." }, { "baseStrength": "Pathogenic", "id": "639509388", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509388", "label": "PM5", "strengthDescriptor": "Moderate", "text": "* These variant interpretation guidelines should be used to determine the classification of the other missense change in order to determine whether this rule can be applied.\n* Use PM5_Supporting if the other variant is Likely Pathogenic." }, { "baseStrength": "Pathogenic", "id": "639509386", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509386", "label": "PM3", "strengthDescriptor": "Moderate", "text": "* Details of the cDNA change must be used to describe any variants used as evidence for PM3. If the variant is described only as an amino acid change, this is not sufficient. Probands must also meet PP4 criteria to be counted.\n* If more than one case has the same genotype and the variants are not confirmed in trans, then only one case should be used for assigning points to avoid overcounting evidence if the variants are actually in cis and hence inherited together in multiple individuals or potentially counting the same case twice. If the variants are confirmed to be in trans, more than one individual with the same genotype can be counted as long as the reports do not represent the same case.\n* Following SVI guidance for PM3, use the scoring system below to determine the strength of evidence for PM3.\n* These variant interpretation guidelines should be used to determine the classification of the “other variant” in order to determine the appropriate number of points to assign.\n* For a variant to be “confirmed in trans” in a compound heterozygous patient, parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed. Otherwise, the phase of the variants is unknown. Parental testing is not required for homozygous cases." }, { "baseStrength": "Pathogenic", "id": "639509385", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509385", "label": "PM2", "strengthDescriptor": "Supporting", "text": "* Variants with a highest population minor allele frequency (MAF) \\<0.001 (0.1%) in any continental population with >2000 alleles in gnomAD will meet PM2\\_supporting.\n* The 0.001 cutoff is based on a disease frequency of 1:100,000, genetic heterogeneity of 100%, penetrance of 75%, and maximum allelic contribution of 20%, based on the most common pathogenic ACADVL variant, c.848T>C (p.Val283Ala): gnomAD MAF: 0.002238 (289/129106; 1 homozygote; European Non-Finnish) and overall frequency: 0.001224 (346/282744; 2 homozygotes). This variant would not meet PM2\\_supporting, but it is assumed that the most common variants have already been identified so a conservative cutoff was chosen. The result of the calculation is 0.00073, which was multiplied by 1.5 to account for mild clinical presentation.\n* See Appendix 2 for calculations.\n* It is acceptable for an ACADVL variant to be present in controls because VLCAD deficiency is a recessive condition. It is also possible for homozygous ACADVL variants to be present in population databases due to later onset of the condition. If homozygous variants are present, the number should be noted and discussed with an expert.\n* SVI guidance: use PM2 as Supporting (not Moderate) based on absence or rarity not being in the odds range expected for a moderate piece of evidence. This EP will track the impact of not using Moderate for PM2." }, { "baseStrength": "Pathogenic", "id": "639509381", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509381", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639509381", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509381", "label": "PS2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639509381", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509381", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "639509381", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509381", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "639509400", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509400", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This rule does not apply. There are known pathogenic missense variants in ACADVL." }, { "baseStrength": "Benign", "id": "639509400", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509400", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: This rule does not apply. There are known pathogenic missense variants in ACADVL." }, { "baseStrength": "Benign", "id": "639509400", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509400", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: This rule does not apply. There are known pathogenic missense variants in ACADVL." }, { "baseStrength": "Benign", "id": "639509400", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509400", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: This rule does not apply. There are known pathogenic missense variants in ACADVL." }, { "baseStrength": "Benign", "id": "639509395", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509395", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "* Variants with a highest population minor allele frequency (MAF) ≥0.007 (0.7%) in any continental population with >2000 alleles in gnomAD will meet BA1.\n* See Appendix 2 for calculations." }, { "baseStrength": "Pathogenic", "id": "639509390", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509390", "label": "PP1", "strengthDescriptor": "Supporting", "text": "* Following SVI guidance, use the scoring system below to determine the strength of evidence for PP1.\n* For segregation counting, do not count probands as a segregation.\no Affected segregations = # affected individuals in the family with the variants - 1.\n* Affected segregations are defined as affected family members (typically siblings) who harbor the variant in question and a second variant on the remaining allele.\n* Unaffected segregations are defined as unaffected family members, typically siblings, who are at risk to inherit the two variants identified in the proband. These individuals should be either wild-type for both variants identified in the proband, or a heterozygous carrier for a single variant.\n* Unaffected, carrier parents DO NOT count as unaffected segregations.\n* There may be scenarios where individuals other than siblings could be counted as segregations, such as in families where one parent is affected with the autosomal recessive disorder, in large families with multiple branches, or in consanguineous families." }, { "baseStrength": "Pathogenic", "id": "639509389", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509389", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Assumed de novo, but without confirmation of paternity and maternity." }, { "baseStrength": "Pathogenic", "id": "639509380", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509380", "label": "PS1", "strengthDescriptor": "Strong", "text": "* Exact same donor/acceptor with a different nucleotide change (PMID: 37352859)" }, { "baseStrength": "Pathogenic", "id": "639509380", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509380", "label": "PS1", "strengthDescriptor": "Moderate", "text": "* Exact same donor/acceptor with a different nucleotide change (PMID: 37352859)" }, { "baseStrength": "Pathogenic", "id": "639509380", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509380", "label": "PS1", "strengthDescriptor": "Supporting", "text": "* Exact same donor/acceptor with a different nucleotide change (PMID: 37352859)" }, { "baseStrength": "Benign", "id": "639509406", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509406", "label": "BP7", "strengthDescriptor": "Supporting", "text": "* Can be used with BP4 code.\n* Defined “not highly conserved” regions in BP7 as those with PhastCons score \\<1 and/or PhyloP score \\<0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.\n* BP7 to be applied to intronic variants at or beyond -21 and +7 (PMID: 37352859)." }, { "baseStrength": "Benign", "id": "639509405", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509405", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "639509405", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509405", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "639509405", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509405", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "639509405", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509405", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "639509403", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509403", "label": "BP4", "strengthDescriptor": "Supporting", "text": "* Missense changes with a REVEL score <0.5 will meet BP4.\n* For in-frame deletions and insertions, use PROVEAN and Mutation Taster. Results must be consistent to count.\n For non-canonical splice site variants, use Splice AI, MaxEntScn and NNSplice. Based on data from Jaganathan et al., 2019 (PMID: 30661751), Houdayer et al., 2012 (PMID: 22505045) and Tang et al., 2016 (PMID: 27313609), PP3 can be applied if there is a with Δ Score ≤ 0.2 , <10% reduction using MaxEntScn and <2% reduction using NNSplice. Two out of the three predictors must be consistent to count.\n* Do not apply this rule if there is evidence for creation of a cryptic splice site.\n* Can be used with BP7 code." }, { "baseStrength": "Benign", "id": "639509402", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509402", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: There are no known repetitive regions without known function in ACADVL." }, { "baseStrength": "Benign", "id": "639509402", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509402", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: There are no known repetitive regions without known function in ACADVL." }, { "baseStrength": "Benign", "id": "639509402", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509402", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: There are no known repetitive regions without known function in ACADVL." }, { "baseStrength": "Benign", "id": "639509402", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509402", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: There are no known repetitive regions without known function in ACADVL." }, { "baseStrength": "Benign", "id": "639509399", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509399", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected members of a family." }, { "baseStrength": "Benign", "id": "639509398", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509398", "label": "BS3", "strengthDescriptor": "Strong", "text": "In vitro expression:\n * >50% enzyme activity\nSplicing assays:\n * For non-canonical splicing variants, use BS3 if there is evidence demonstrating normal splicing with no evidence of abnormal splicing (RT-PCR and/or RNA sequencing).\n * These studies can be performed using patient-derived cells or heterologous cultured cells.\n * Any variants meeting the requirement for in vitro expression or splicing assays can meet BS3, but if the variant meets the description for both, BS3 should only be counted once." }, { "baseStrength": "Benign", "id": "639509397", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509397", "label": "BS2", "strengthDescriptor": "Strong", "text": "Test" }, { "baseStrength": "Pathogenic", "id": "639509394", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509394", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "639509394", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509394", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "639509394", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509394", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "639509394", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509394", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "639509391", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509391", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This rule does not apply as there are benign and pathogenic missense variants in ACADVL." }, { "baseStrength": "Pathogenic", "id": "639509391", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509391", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: This rule does not apply as there are benign and pathogenic missense variants in ACADVL." }, { "baseStrength": "Pathogenic", "id": "639509391", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509391", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: This rule does not apply as there are benign and pathogenic missense variants in ACADVL." }, { "baseStrength": "Pathogenic", "id": "639509391", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509391", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: This rule does not apply as there are benign and pathogenic missense variants in ACADVL." }, { "baseStrength": "Pathogenic", "id": "639509382", "iri": "https://genboree.org/cspec/CriteriaCode/id/639509382", "label": "PS3", "strengthDescriptor": "Strong", "text": "* Functional evidence from non-patient derived material with only a single variant best reflects the variant-level phenotype. Apply patient-derived evidence in PP4.\n* Apply criteria at the level determined by validation parameters (see flowchart below). VLCAD assays available now do not meet the criteria that is being proposed now regarding the types of controls etc. but the published VLCAD assays are well established with many positive and negative controls being run.\n* Hesse et al., 2018 (PMID 30194637) reviewed enzymatic testing in lymphocytes as a confirmatory tool in newborns identified by screening. Molecular testing was performed after in most patients.\n* If an enzyme activity assay has >20% activity it cannot be weighted above PS3_supporting regardless of flowchart results." } ], "diseases": [ { "id": "MONDO:0008723", "iri": "https://genboree.org/cspec/Disease/id/467878321", "label": "very long chain acyl-CoA dehydrogenase deficiency" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467816115", "label": "ACADVL" } ], "ruleSet": { "id": "639509377", "iri": "https://genboree.org/cspec/RuleSet/id/639509377" }, "svi": { "id": "GN021", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/639509375", "label": "ClinGen ACADVL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACADVL Version 1.1.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "643243129", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243129", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243129", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243129", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243129", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243129", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243129", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243129", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243126", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243126", "label": "BS4", "strengthDescriptor": "Strong", "text": "* Caution is warranted when the phenotype is not highly specific. Lack of segregation should then be clear in >1 affected family member." }, { "baseStrength": "Benign", "id": "643243122", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243122", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Allele frequency above 0.1% in ExAc and gnomAD\n* Use the ethnic population with the highest allele frequency.\n* Caveat: Do not use Finnish, Ashkenazi Jewish, or “Other” populations in gnomAD.\n* Minimum amount of studied alleles should be 2000." }, { "baseStrength": "Pathogenic", "id": "643243116", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243116", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "4 points" }, { "baseStrength": "Pathogenic", "id": "643243116", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243116", "label": "PM6", "strengthDescriptor": "Strong", "text": "2-3 points." }, { "baseStrength": "Pathogenic", "id": "643243116", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243116", "label": "PM6", "strengthDescriptor": "Moderate", "text": "1 point." }, { "baseStrength": "Pathogenic", "id": "643243116", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243116", "label": "PM6", "strengthDescriptor": "Supporting", "text": "0.5 points." }, { "baseStrength": "Pathogenic", "id": "643243113", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243113", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "643243113", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243113", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "643243113", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243113", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "643243113", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243113", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243125", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243125", "label": "BS3", "strengthDescriptor": "Strong", "text": "Use the ‘Funtional Assay SVI Documentation’ (https://clinicalgenome.org/working-groups/sequence-variant-interpretation/).\nFor step 2 assessment.\n* Functional studies deemed appropriate:\n * cDNA analyses showing altered FBN1 sequence.\n * Functional studies showing altered FBN1 protein or RNA expression, proteolysis, folding, assembly, trafficking, secretion, Ca2+ binding, matrix deposition (cfr Dave Hollister assay), microfibril fragmentation/catabolism in an in vitro engineered system.\n* Functional studies NOT deemed appropriate: non-specific altered TGF-beta signaling or histological hallmarks of medial degeneration, which are associated with many other types of variants in genes that are associated with MFS or HTAAD in general.\nFor step 3 assessment: Studies should be performed in the presence of NMD inhibitor." }, { "baseStrength": "Pathogenic", "id": "643243117", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243117", "label": "PP1", "strengthDescriptor": "Strong", "text": "≥5 affected individuals.\n" }, { "baseStrength": "Pathogenic", "id": "643243117", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243117", "label": "PP1", "strengthDescriptor": "Moderate", "text": "4 affected individuals.\n" }, { "baseStrength": "Pathogenic", "id": "643243117", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243117", "label": "PP1", "strengthDescriptor": "Supporting", "text": "2-3 affected individuals.\n" }, { "baseStrength": "Pathogenic", "id": "643243115", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243115", "label": "PM5", "strengthDescriptor": "Moderate", "text": "* Add caveat: Use argument with caution when the original missense variant created a cysteine especially in a cbEGFlike domain (cfr PM1_strong) as this may increase the\npathogenicity level of this variant improperly.\n* Add caveat: original variant should be pathogenic according to the (modified) ACMG guidelines for variant classification." }, { "baseStrength": "Benign", "id": "643243133", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243133", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\nBP7 applicable as described." }, { "baseStrength": "Benign", "id": "643243131", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243131", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease." }, { "baseStrength": "Benign", "id": "643243127", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243127", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243127", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243127", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243127", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243127", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243127", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243127", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "643243119", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243119", "label": "PP3", "strengthDescriptor": "Supporting", "text": "* Recommended prediction program for missense variants: REVEL. Use 0.75 as a discriminatory cut-off value.\n* Recommended prediction programs for splice variants: GeneSplicer, MaxEntscan, and NNSPLICE. The outcome of all 3 prediction programs need to be in concordance." }, { "baseStrength": "Pathogenic", "id": "643243114", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243114", "label": "PM4", "strengthDescriptor": "Moderate", "text": "* Add caveat: cannot be applied simultaneously with PVS1 (at any strength level)" }, { "baseStrength": "Pathogenic", "id": "643243112", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243112", "label": "PM2", "strengthDescriptor": "Supporting", "text": "* Threshold: <5.0E-6 (<0.0005%).\n* Use the highest ethnic population allele frequency.\n* Caveat: PVS1 + PM2_Supportive may reach Likely Pathogenic.\n* Caveat: Do not use Finnish, Ashkenazi Jewish, or “Other” populations in gnomAD.\n* Minimum amount of studied alleles should be 2000." }, { "baseStrength": "Pathogenic", "id": "643243111", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243111", "label": "PM1", "strengthDescriptor": "Strong", "text": "* Cys residues in cbEGF-like domains\n* Add caveat: PM5/PS1 should not be used when this argument applies." }, { "baseStrength": "Pathogenic", "id": "643243111", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243111", "label": "PM1", "strengthDescriptor": "Moderate", "text": "* Cys in EGF-like domain, Cys in TB domain, Cys in hybrid domain, (D/N)-X-(D/N)-(E/Q)-Xm-(D/N)-Xn-(Y/F) substitution in cbEGF-like domain, invariant calcium-binding or hydroxylation residue in cbEGF-like domain, critical Gly between Cys2-Cys3 in cbEGF-like domain, Gly between Cys3-Cys4 if there is an upstream cbEGF domain, Cys-creating variants.\n* Add caveat: N to S substitution in the second N of de consensus sequence and G to A might be tolerated, PM1 should not be used in these cases." }, { "baseStrength": "Pathogenic", "id": "643243107", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243107", "label": "PS1", "strengthDescriptor": "Strong", "text": "* Beware of changes that impact splicing rather than the amino acid. Splicing predictions should remain the same for WT and mutant alleles.\n* Original variant should be pathogenic according to the (modified) ACMG guidelines for variant classification." }, { "baseStrength": "Benign", "id": "643243130", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243130", "label": "BP4", "strengthDescriptor": "Supporting", "text": "* Recommended prediction program for missense variants: REVEL. Use 0.326 as a discriminatory cut-off value.\n* Recommended prediction programs for splice variants: GeneSplicer, MaxEntscan, and NNSPLICE. The outcome of all 3 prediction programs need to be in concordance." }, { "baseStrength": "Benign", "id": "643243128", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243128", "label": "BP2", "strengthDescriptor": "Supporting", "text": "* Observed in trans in multiple cases (+2) with co-occuring pathogenic variants and phenotype is not more severe than when seen in isolation.\n* Observed in cis with a pathogenic variant, if the pathogenic variant has been seen in isolation in a patient with the disease phenotype." }, { "baseStrength": "Benign", "id": "643243124", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243124", "label": "BS2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243124", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243124", "label": "BS2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243124", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243124", "label": "BS2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243124", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243124", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243123", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243123", "label": "BS1", "strengthDescriptor": "Strong", "text": "Allele frequency greater than expected for disease (>0.005%).\n* Use the ethnic population with the highest allele frequency.\n* Caveat: Do not use Finnish, Ashkenazi Jewish, or “Other” populations in gnomAD.\n* Minimum amount of studied alleles should be 2000." }, { "baseStrength": "Pathogenic", "id": "643243110", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243110", "label": "PS4", "strengthDescriptor": "Strong", "text": "* If ≥ 4 points.\n" }, { "baseStrength": "Pathogenic", "id": "643243110", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243110", "label": "PS4", "strengthDescriptor": "Moderate", "text": "* If 2-3.5 points.\n" }, { "baseStrength": "Pathogenic", "id": "643243110", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243110", "label": "PS4", "strengthDescriptor": "Supporting", "text": "* If 1-1.5 points.\n" }, { "baseStrength": "Pathogenic", "id": "643243109", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243109", "label": "PS3", "strengthDescriptor": "Strong", "text": "Follow the ‘Funtional Assay SVI Documentation’" }, { "baseStrength": "Pathogenic", "id": "643243109", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243109", "label": "PS3", "strengthDescriptor": "Moderate", "text": "Follow the ‘Funtional Assay SVI Documentation’" }, { "baseStrength": "Pathogenic", "id": "643243109", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243109", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Use the ‘Funtional Assay SVI Documentation’. " }, { "baseStrength": "Benign", "id": "643243132", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243132", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243132", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243132", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243132", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243132", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243132", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243132", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243121", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243121", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243121", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243121", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243121", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243121", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243121", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243121", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243120", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243120", "label": "PP4", "strengthDescriptor": "Supporting", "text": "* Use if patient fulfils revised Ghent criteria.\n* Can be used if any of the family members have a highly specific phenotype." }, { "baseStrength": "Pathogenic", "id": "643243118", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243118", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Add caveat: if this argument is used pro-pathogenicity, there must be other arguments supporting pathogenicity, and no arguments supporting a benign assertion." }, { "baseStrength": "Pathogenic", "id": "643243108", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243108", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Four points" }, { "baseStrength": "Pathogenic", "id": "643243108", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243108", "label": "PS2", "strengthDescriptor": "Strong", "text": "Two-three points" }, { "baseStrength": "Pathogenic", "id": "643243108", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243108", "label": "PS2", "strengthDescriptor": "Moderate", "text": "One point" }, { "baseStrength": "Pathogenic", "id": "643243108", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243108", "label": "PS2", "strengthDescriptor": "Supporting", "text": "0.5 points" }, { "baseStrength": "Pathogenic", "id": "643243106", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243106", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": " * Nonsense/frameshift variants predicted to undergo NMD (not affecting last exon or 55 last nt of penultimate exon).\n * 1,2 splice site variants leading to exon skipping or use of a cryptic splice site disrupting the reading frame and predicted to undergo NMD.\n * Full gene deletion.\n * Single to multi-exon deletion disrupting the reading frame and predicted to undergo NMD.\n * Duplication (>=1 exon in size and completely contained within gene) proven in tandem and disrupting the reading frame and predicted to undergo NMD." }, { "baseStrength": "Pathogenic", "id": "643243106", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243106", "label": "PVS1", "strengthDescriptor": "Strong", "text": " * Nonsense/frameshift variants predicted to escape NMD (affecting last exon, last 55nt of the penultimate exon).\n * 1,2 splice site variants leading to exon skipping or use of a cryptic splice site disrupting the reading frame and predicted to escape NMD.\n * 1,2 splice site variants leading to exon skipping or use of a cryptic splice site but preserving the reading frame.\n * Single to multi-exon deletion disrupting the reading frame and predicted to escape NMD.\n * Single to multi-exon deletion preserving the reading frame.\n * Duplication (>=1 exon in size and completely contained within gene) presumed in tandem and presumably disrupting the reading frame and predicted to escape NMD." }, { "baseStrength": "Pathogenic", "id": "643243106", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243106", "label": "PVS1", "strengthDescriptor": "Moderate", "text": " * Initiation codon variant with 1 or more pathogenic variant(s) upstream of closest potential in-frame start codon." } ], "diseases": [ { "id": "MONDO:0007947", "iri": "https://genboree.org/cspec/Disease/id/467897451", "label": "Marfan syndrome" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467826222", "label": "FBN1" } ], "ruleSet": { "id": "643243099", "iri": "https://genboree.org/cspec/RuleSet/id/643243099" }, "svi": { "id": "GN022", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243092", "label": "ClinGen FBN1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1" } }, { "codes": [ { "baseStrength": "Benign", "id": "643243160", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243160", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243160", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243160", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243160", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243160", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243160", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243160", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243151", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243151", "label": "BS1", "strengthDescriptor": "Very Strong", "text": "MAF of ≥0.003 (0.3%) for autosomal recessive. Likely benign, provided there is no conflicting evidence." }, { "baseStrength": "Benign", "id": "643243151", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243151", "label": "BS1", "strengthDescriptor": "Supporting", "text": "MAF of ≥0.0007 (0.07%) for autosomal recessive." }, { "baseStrength": "Pathogenic", "id": "643243143", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243143", "label": "PM5", "strengthDescriptor": "Strong", "text": "Missense change at same codon as two different pathogenic missense variants.\nLocated at an amino acid residue with known pathogenic variation (at least 2 other variants at the same site meet pathogenic criteria for based on independent data).\n* Caveat: Assess whether the variants in question could have an impact at the DNA level, such as through splicing impacts." }, { "baseStrength": "Pathogenic", "id": "643243143", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243143", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Missense change at same codon as another pathogenic missense variant.\nNo changes. Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group." }, { "baseStrength": "Pathogenic", "id": "643243142", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243142", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length change due to an in-frame deletion or insertion that are not located in repetitive regions.\nNo changes. Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group." }, { "baseStrength": "Pathogenic", "id": "643243138", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243138", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Fisher Exact or Chi-Squared analysis shows statistical increase in cases over controls." }, { "baseStrength": "Pathogenic", "id": "643243135", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243135", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as an established pathogenic variant; OR splice variants at same nucleotide and with similar impact prediction as previously reported pathogenic variant.\n* Established variant must meet criteria for pathogenicity by the HL specifications.\n* Can also use PS1 for splice variants located in the splice consensus sequence, at the same nucleotide position as a previously reported pathogenic variant.\n * Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T.\n* No additional hearing loss specifications for missense variants. Follow recommendations as outlined in Richard 2015 and/or the Sequence Variant Interpretation working group within ClinGen.\n* Caveat (from ACMG/AMP guidelines): Assess the possibility that the variant may act directly through the DNA change (e.g. through splicing disruption as assessed by at least computational analysis) instead of through the amino acid change)." }, { "baseStrength": "Pathogenic", "id": "643243134", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243134", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Null variant in a gene with established LOF as a disease mechanism; see PVS1_Strong, PVS1_Moderate, PVS1_Supporting for reduced evidence applications.\nPVS1 should also be considered for both of the genes OTOF and MYO15A with variants falling in two exons being exceptions to this rule: OTOF: NM_194248.2 Exon 46 (c.5841 to c.5994; PMID: 19250381) and MYO15A: NM_016239.3 Exon 8 (c.4033 to c. 4038; PMID: 10552926) and Exon 26 (c.5911 to c.5964; PMID: 30096381 and high frequency LOF variant https://gnomad.broadinstitute.org/variant/17-18046894-G-A?dataset=gnomad_r2_1)" }, { "baseStrength": "Pathogenic", "id": "643243134", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243134", "label": "PVS1", "strengthDescriptor": "Strong", "text": "See PVS1 flow chart for PVS1_Strong variants in gene where LOF is a known mechanism of disease." }, { "baseStrength": "Pathogenic", "id": "643243134", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243134", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "See PVS1 flowchart for PVS1_Moderate variants in gene where LOF is a known mechanism of disease." }, { "baseStrength": "Pathogenic", "id": "643243134", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243134", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "See PVS1 flowchart for PVS1_Supporting variants in gene where LOF is a known mechanism of disease." }, { "baseStrength": "Benign", "id": "643243157", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243157", "label": "BP3", "strengthDescriptor": "Supporting", "text": "In-frame indels in repeat region without known function.\n* No changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group." }, { "baseStrength": "Pathogenic", "id": "643243149", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243149", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243149", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243149", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243149", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243149", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243149", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243149", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243148", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243148", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Patient's phenotype highly specific for gene or fully sequenced gene set (see specifications in Table 7).\n* The HL-EP applied this rule to HL syndromes if all causative genes have been sequenced and the detection rate at least doubles when the added clinical feature is present.\n* See table below for applicable gene-disease phenotypes.\n* Advise against using PP4 for patients with nonsyndromic or apparently nonsyndromic hearing loss, given genetic heterogeneity." }, { "baseStrength": "Pathogenic", "id": "643243146", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243146", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Advise against using this rule because there are few such genes that this would apply to, particularly genes associated to autosomal recessive hearing loss." }, { "baseStrength": "Pathogenic", "id": "643243146", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243146", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Advise against using this rule because there are few such genes that this would apply to, particularly genes associated to autosomal recessive hearing loss." }, { "baseStrength": "Pathogenic", "id": "643243146", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243146", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Advise against using this rule because there are few such genes that this would apply to, particularly genes associated to autosomal recessive hearing loss." }, { "baseStrength": "Pathogenic", "id": "643243146", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243146", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Advise against using this rule because there are few such genes that this would apply to, particularly genes associated to autosomal recessive hearing loss." }, { "baseStrength": "Benign", "id": "643243155", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243155", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243155", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243155", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243155", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243155", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243155", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243155", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Pathogenic", "id": "643243144", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243144", "label": "PM6", "strengthDescriptor": "Moderate", "text": "See PS2 above." }, { "baseStrength": "Pathogenic", "id": "643243139", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243139", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Mutational hot spot or well-studied functional domain without benign variation (None defined for OTOF and MYO15A)." }, { "baseStrength": "Pathogenic", "id": "643243136", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243136", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "4 points per tables 5a and 5b:\nExamples: 2 proven de novo occurrences; OR\n1 proven + 2 assumed de novo occurrences; OR\n4 assumed de novo occurrences." }, { "baseStrength": "Pathogenic", "id": "643243136", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243136", "label": "PS2", "strengthDescriptor": "Strong", "text": "2 points per tables 5a and 5b:\nExamples: 1 proven de novo occurrence; OR 2 assumed de novo occurrences.\n\n* OTOF and MYO15A are associated with autosomal recessive conditions. Therefore, de novo variants are expected to be an unlikely occurrence. It is recommended that de novo evidence is only awarded when phase with another variant (VUS, Likely Pathogenic, or Pathogenic) can be confirmed in trans. This is to avoid inappropriately awarding de novo evidence, which would lead to potentially incorrect classification.\n\n* Follow recommendations as specified by the Sequence Variant Interpretation working group within ClinGen, as outlined below\n \n* Determine number of points per proband using table 1 below. Sum the total number of points for all probands, and determine the strength of the evidence by using table 2.\n\n * Please note, the phenotype for de novo occurrences for MYO15A and OTOF are not considered “highly specific”." }, { "baseStrength": "Pathogenic", "id": "643243136", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243136", "label": "PS2", "strengthDescriptor": "Moderate", "text": "1 point per tables 5a and 5b:\nExamples: 1 proven de novo occurrence (phenotype consistent but not specific to gene); OR\n1 assumed de novo occurrence; OR 2 assumed de novo occurrences (phenotype/gene not specific)." }, { "baseStrength": "Pathogenic", "id": "643243136", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243136", "label": "PS2", "strengthDescriptor": "Supporting", "text": "0.5 points per tables 5a and 5b:\nExample: 1 assumed de novo occurrence (phenotype/gene not specific)." }, { "baseStrength": "Benign", "id": "643243161", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243161", "label": "BP7", "strengthDescriptor": "Supporting", "text": "Silent variant with no predicted impact to splicing.\n* No changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group." }, { "baseStrength": "Benign", "id": "643243159", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243159", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Autosomal recessive: Do not use. An individual could be carrier of pathogenic variant and have an alternate cause. Therefore, BP5 shouldn’t be used as evidence for benign in this case." }, { "baseStrength": "Benign", "id": "643243159", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243159", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable: Autosomal recessive: Do not use. An individual could be carrier of pathogenic variant and have an alternate cause. Therefore, BP5 shouldn’t be used as evidence for benign in this case." }, { "baseStrength": "Benign", "id": "643243159", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243159", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: Autosomal recessive: Do not use. An individual could be carrier of pathogenic variant and have an alternate cause. Therefore, BP5 shouldn’t be used as evidence for benign in this case." }, { "baseStrength": "Benign", "id": "643243159", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243159", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: Autosomal recessive: Do not use. An individual could be carrier of pathogenic variant and have an alternate cause. Therefore, BP5 shouldn’t be used as evidence for benign in this case." }, { "baseStrength": "Benign", "id": "643243156", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243156", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Observed in trans with a dominant variant/observed in cis with a pathogenic variant (use with caution).\n* Use with caution. For genes that are associated with both dominant and recessive hearing loss, consider whether an earlier onset/more severe phenotype could be present if variant is identified in trans with a dominant variant." }, { "baseStrength": "Pathogenic", "id": "643243147", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243147", "label": "PP3", "strengthDescriptor": "Supporting", "text": "REVEL score ≥0.7, or predicted impact to splicing using MaxEntScan.\n* Use REVEL and MAXENTSCAN\n * For missense variants, award PP3 if REVEL score is ≥0.7\n * If splicing is predicted to be impacted, either creation of a cryptic splice site, or disruption of a native splice site, award PP3\n* For splice variants (except for canonical -/+1 or 2), use MAXENTSCAN.\n * For -/+ 1 or 2 splice variants, do not use PP3 if you are using PVS1" }, { "baseStrength": "Pathogenic", "id": "643243140", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243140", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Absent/Rare in population databases (absent or ≤0.00007 (0.007%) for autosomal recessive)." }, { "baseStrength": "Benign", "id": "643243158", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243158", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Computational evidence suggests no impact; REVEL score ≤0.15 or no impact to splicing in MaxEntScan.\n* Use REVEL, award BP4 if score is 0.15 or lower. Make sure to also check MAXENTSCAN to rule out the creation of a cryptic splice site." }, { "baseStrength": "Benign", "id": "643243154", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243154", "label": "BS4", "strengthDescriptor": "Strong", "text": "Non-segregation with disease.\n* Phenotype+/genotype-\n * Strong evidence for benign.\n * Be cautious when using this as the possibility for phenocopy is high. The hearing loss phenotype should be consistent within the family to consider it a non-segregation, though intra-familial variability has been reported. Factors to consider are:\n * Age of onset (ie. congenital/early childhood vs. adult onset)\n * Hearing loss prevalence increases significantly with age. A congenital hearing loss in a child and a late onset hearing loss in a grandparent would not be a consistent phenotype.\n * Severity (ie - mild vs. profound)\n * Minor differences may exist among family members.\n * Keep in mind that progression in older individuals may account for a discrepancy between individuals.\n * Audiogram shape\n * May not be completely consistent among family members even with same etiology.\n- Genotype+/phenotype-\n* Confounding variables to applying this rule: Age-related penetrance, variable expressivity, etc.\n* If the gene is associated with later onset and individual with the non-segregation is beyond the expected age that the hearing loss would occur, consider applying BS4_Supporting\n.\n* Recommend only using for fully penetrant genes (typically genes associated with AR hearing loss)\no Must be confident that patient is truly unaffected and a hearing loss is not missed or subclinical. Be cautious if only phenotyping was newborn hearing screening. Diagnostic audiometric testing (auditory brainstem response (ABR) or audiogram should be required).\n\n* Any evidence for reduced penetrance, do not use BS4." }, { "baseStrength": "Benign", "id": "643243153", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243153", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Functional study shows no deleterious effect (none are defined for OTOF and MYO15A).\n* Recommend that functional evidence is not used as strong evidence, due to the absence of well-established functional studies for hearing loss genes.\n\n* No specific assays are listed for OTOF or MYO15A. However, BS3_Supporting can be used for functional analyses if\n * The assay has been validated by a known pathogenic and benign variant AND\n * There is plausible reason that the function the assay is testing relates to the phenotype AND\n * The assay conditions are likely to mimic the physiological environment.\n" }, { "baseStrength": "Benign", "id": "643243152", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243152", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observation of variant (biallelic with known pathogenic variant for recessive) in controls inconsistent with disease penetrance.\n* Advise caution when using this rule, since most of hearing loss is autosomal recessive, and autosomal dominant hearing loss could display reduced penetrance or variable expression.\n* However, if biallelic observations in controls are inconsistent with disease penetrance, this may be applicable. Ensure age of the unaffected individual is appropriate. MYO15A and OTOF are expected to cause congenital or childhood onset hearing loss. Therefore, an adult (ie >18 years) may be an appropriate individual to consider application of this criteria. Please see additional considerations listed under BS4 “Genotype+/phenotype-”." }, { "baseStrength": "Benign", "id": "643243150", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243150", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "MAF of ≥0.005 (0.5%) for autosomal recessive." }, { "baseStrength": "Pathogenic", "id": "643243145", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243145", "label": "PP1", "strengthDescriptor": "Strong", "text": "Segregation in three affected relatives for recessive." }, { "baseStrength": "Pathogenic", "id": "643243145", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243145", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Segregation in two affected relatives for recessive." }, { "baseStrength": "Pathogenic", "id": "643243145", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243145", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Segregation in one affected relative for recessive." }, { "baseStrength": "Pathogenic", "id": "643243141", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243141", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "4 points awarded from tables 7a and 7b.\nExample: Detected in trans in ≥4 probands with a pathogenic variant (recessive)." }, { "baseStrength": "Pathogenic", "id": "643243141", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243141", "label": "PM3", "strengthDescriptor": "Strong", "text": "2 points awarded from tables 7a and 7b.\nExample: Detected in trans in 2 probands with a pathogenic variant (recessive)." }, { "baseStrength": "Pathogenic", "id": "643243141", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243141", "label": "PM3", "strengthDescriptor": "Moderate", "text": "1 point awarded from tables 7a and 7b\nExample: Detected in trans with a pathogenic variant (recessive)." }, { "baseStrength": "Pathogenic", "id": "643243141", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243141", "label": "PM3", "strengthDescriptor": "Supporting", "text": "0.5 points awarded from tables 7a and 7b\nExamples: \nTwo variants that meet PM2_Supporting detected in trans; OR\na homozygous variant meeting PM2_Supporting." }, { "baseStrength": "Pathogenic", "id": "643243137", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243137", "label": "PS3", "strengthDescriptor": "Strong", "text": "Knock-in mouse model demonstrates the phenotype.\n* Recommend that functional evidence, except for a variant specific mouse model, is not used as strong evidence, due to the absence of well-established functional studies for hearing loss genes.\n* There are no specific assays for OTOF or MYO15A. However, PS3_Supporting can be applied for other functional analyses if\n * The assay has been validated by a known pathogenic and benign variant AND\n * There is plausible reason that the function the assay is testing relates to the phenotype AND\n * The assay conditions are likely to mimic the physiological environment." }, { "baseStrength": "Pathogenic", "id": "643243137", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243137", "label": "PS3", "strengthDescriptor": "Moderate", "text": "Validated functional studies show a deleterious effect (none are defined for OTOF and MYO15A)." }, { "baseStrength": "Pathogenic", "id": "643243137", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243137", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Functional studies with limited validation show a deleterious effect." } ], "diseases": [ { "id": "MONDO:0019497", "iri": "https://genboree.org/cspec/Disease/id/135642106", "label": "nonsyndromic genetic hearing loss" }, { "id": "MONDO:0019497", "iri": "https://genboree.org/cspec/Disease/id/135642106", "label": "nonsyndromic genetic hearing loss" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467841177", "label": "MYO15A" }, { "iri": "https://genboree.org/cspec/Gene/id/467844034", "label": "OTOF" } ], "ruleSet": { "id": "643243100", "iri": "https://genboree.org/cspec/RuleSet/id/643243100" }, "svi": { "id": "GN023", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243093", "label": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for OTOF and MYO15A Version 1" } }, { "codes": [ { "baseStrength": "Benign", "id": "643243189", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243189", "label": "BP7", "strengthDescriptor": "Supporting", "text": "Silent variant\nOR Intronic variant at or beyond +7 to -21 positions\nOR Other intronic or non-coding variant if the variant is the reference nucleotide in ≥1 primate and/or ≥4 mammalian species.\nCaveat: Variant must meet BP4 to apply BP7" }, { "baseStrength": "Benign", "id": "643243188", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243188", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243188", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243188", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243188", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243188", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243188", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243188", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243183", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243183", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This rule code does not apply to this gene, as truncating variants account for only a portion of disease-causing variants." }, { "baseStrength": "Benign", "id": "643243183", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243183", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: This rule code does not apply to this gene, as truncating variants account for only a portion of disease-causing variants." }, { "baseStrength": "Benign", "id": "643243183", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243183", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: This rule code does not apply to this gene, as truncating variants account for only a portion of disease-causing variants." }, { "baseStrength": "Benign", "id": "643243183", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243183", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: This rule code does not apply to this gene, as truncating variants account for only a portion of disease-causing variants." }, { "baseStrength": "Benign", "id": "643243180", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243180", "label": "BS2", "strengthDescriptor": "Strong", "text": "40+ unrelated females from a single source are tumor-free through age 50 (caveat: ratio of BS2-eligible females to PS4-eligible probands must be ≥ 40:1) \nOR 2+ observations of homozygosity in healthy individuals\nOR 1+ observation(s) of homozygosity in a healthy individual with status confirmed by parental testing." }, { "baseStrength": "Benign", "id": "643243180", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243180", "label": "BS2", "strengthDescriptor": "Supporting", "text": "10+ unrelated females from a single source are tumor-free through age 50 (caveat: ratio of BS2-eligible females to PS4-eligible probands must be ≥ 10:1) \nOR 2+ observations of homozygosity in individuals lacking clinical information" }, { "baseStrength": "Pathogenic", "id": "643243162", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243162", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Follow SVI guidance, using DICER1-specific information. Per the PVS1 workflow guidance provided in Tayoun et al. 2018[1](#pmid_30192042), the following will apply:\n\n* Nonsense or frameshift variants:\n* PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD); the predicted NMD cutoff for DICER1 occurs at p.Pro1850.\n* PVS1\\_Moderate applies to variants resulting in protein truncation 3’ of this cutoff\n* Canonical splice variants (+/- 1,2 intronic positions): PVS1 applies with the following exceptions:\n* Exon 10 SDS/SAS: PVS1\\_Strong (in-frame but exon includes >10% protein)\n* Exons 5, 15, 18, 22 SDS/SAS: PVS1\\_Moderate (in-frame and each \\<10% of protein)\n* Exon 27 SAS: PVS1\\_Moderate (final exon)\n* Exon 1: no criteria (non-coding)\n* Variants that disrupt the translation start site (p.M1?): no criteria applied given p.M1 is not highly conserved, there are three in-frame possible alternate start codons (p.Met11, p.Met17, p.Met24), and multiple lab cases of p.Met1? without DICER1 phenotype. SDS = splice donor site; SAS = splice acceptor site. Refer to PS3 weight guidelines when a variant meets criterion for application of both PVS1 and PS3. A disease-specific PVS1 decision tree incorporating the above bullets is also included at the end of this document as an additional curation tool." }, { "baseStrength": "Benign", "id": "643243186", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243186", "label": "BP4", "strengthDescriptor": "Supporting", "text": "For missense variants, REVEL score \\< 0.50 and agreement in splicing predictors that no splicing effects are predicted. For synonymous/intronic/non-coding variants concordance of MaxEntScan and SpliceAI." }, { "baseStrength": "Benign", "id": "643243178", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243178", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Frequency >0.003 (0.3%) in gnomAD subpopulations. Subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present." }, { "baseStrength": "Pathogenic", "id": "643243172", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243172", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Combined with PS2. Use PS2 instead of PM6." }, { "baseStrength": "Pathogenic", "id": "643243172", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243172", "label": "PM6", "strengthDescriptor": "Strong", "text": "Not Applicable: Combined with PS2. Use PS2 instead of PM6." }, { "baseStrength": "Pathogenic", "id": "643243172", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243172", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Not Applicable: Combined with PS2. Use PS2 instead of PM6." }, { "baseStrength": "Pathogenic", "id": "643243172", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243172", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Not Applicable: Combined with PS2. Use PS2 instead of PM6." }, { "baseStrength": "Pathogenic", "id": "643243170", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243170", "label": "PM4", "strengthDescriptor": "Moderate", "text": "In-frame indels with a residue within the RNase IIIb domain (p.Y1682 – p.S1846)." }, { "baseStrength": "Pathogenic", "id": "643243170", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243170", "label": "PM4", "strengthDescriptor": "Supporting", "text": "In-frame indels outside of the RNase IIIb domain (p.Y1682 – p.S1846) and repeat regions (p.D606-p.D609; p.E1418-p.E1420; p.E1422-p.E1425)." }, { "baseStrength": "Pathogenic", "id": "643243169", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243169", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Autosomal dominant." }, { "baseStrength": "Pathogenic", "id": "643243169", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243169", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: Autosomal dominant." }, { "baseStrength": "Pathogenic", "id": "643243169", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243169", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Autosomal dominant." }, { "baseStrength": "Pathogenic", "id": "643243169", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243169", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Autosomal dominant." }, { "baseStrength": "Pathogenic", "id": "643243165", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243165", "label": "PS3", "strengthDescriptor": "Strong", "text": "RNA assay shows splicing impact that is out-of-frame, in-frame ≥193 residues, or in-frame with RNase IIIb disruption. (PS3\\_Moderate if PVS1\\_Strong is applied)." }, { "baseStrength": "Pathogenic", "id": "643243165", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243165", "label": "PS3", "strengthDescriptor": "Moderate", "text": "RNA assay shows in-frame splicing impact with change in protein length \\<193 residues AND RNase IIIb domain not disrupted." }, { "baseStrength": "Pathogenic", "id": "643243165", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243165", "label": "PS3", "strengthDescriptor": "Supporting", "text": "In vitro cleavage assay shows failure or severely reduced capacity to produce either 5p or 3p microRNAs from a premiRNA (positive and negative controls also performed)." }, { "baseStrength": "Benign", "id": "643243187", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243187", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Given the broad spectrum of DICER1-related neoplasms and the General recommendation lack of evidence of other high-penetrance germline variants that could account for such neoplasms (except perhaps for some already low-specificity phenotypes such as Wilms tumor), this rule should not be used at this time." }, { "baseStrength": "Benign", "id": "643243187", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243187", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable: Given the broad spectrum of DICER1-related neoplasms and the General recommendation lack of evidence of other high-penetrance germline variants that could account for such neoplasms (except perhaps for some already low-specificity phenotypes such as Wilms tumor), this rule should not be used at this time." }, { "baseStrength": "Benign", "id": "643243187", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243187", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: Given the broad spectrum of DICER1-related neoplasms and the General recommendation lack of evidence of other high-penetrance germline variants that could account for such neoplasms (except perhaps for some already low-specificity phenotypes such as Wilms tumor), this rule should not be used at this time." }, { "baseStrength": "Benign", "id": "643243187", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243187", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: Given the broad spectrum of DICER1-related neoplasms and the General recommendation lack of evidence of other high-penetrance germline variants that could account for such neoplasms (except perhaps for some already low-specificity phenotypes such as Wilms tumor), this rule should not be used at this time." }, { "baseStrength": "Benign", "id": "643243182", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243182", "label": "BS4", "strengthDescriptor": "Strong", "text": "Family members should be phenotype-positive (must be high- or moderatespecificity phenotype; see phenotype table), genotype-negative 1st, 2nd, or 3rd degree relatives of the proband." }, { "baseStrength": "Pathogenic", "id": "643243177", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243177", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243177", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243177", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243177", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243177", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243177", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243177", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243173", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243173", "label": "PP1", "strengthDescriptor": "Strong", "text": "≥7 meioses across ≥2 families" }, { "baseStrength": "Pathogenic", "id": "643243173", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243173", "label": "PP1", "strengthDescriptor": "Moderate", "text": "5 – 6 meioses across ≥1 family" }, { "baseStrength": "Pathogenic", "id": "643243173", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243173", "label": "PP1", "strengthDescriptor": "Supporting", "text": "3 – 4 meioses across ≥1 family" }, { "baseStrength": "Pathogenic", "id": "643243168", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243168", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Allele frequency \\<0.000005 across gnomAD with no more than one allele in any subpopulation and at least 20x coverage." }, { "baseStrength": "Pathogenic", "id": "643243163", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243163", "label": "PS1", "strengthDescriptor": "Strong", "text": "For same AA change, must confirm there is no difference in splicing using RNA data or in-silico modeling data (concordance of MaxEntScan and SpliceAI). For non-canonical intronic splicing variants at same nucleotide should have equal or worse splicing impact.\nThis rule code can only be used to compare variants asserted as pathogenic by the ClinGen DICER1 VCEP. Likely pathogenic changes do not apply." }, { "baseStrength": "Benign", "id": "643243181", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243181", "label": "BS3", "strengthDescriptor": "Strong", "text": "For intronic or synonymous variants, no splicing impact observed via RNA assay. (Should be observed more than once.)" }, { "baseStrength": "Benign", "id": "643243181", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243181", "label": "BS3", "strengthDescriptor": "Supporting", "text": "An in vitro cleavage assay must demonstrate the variant produces both 5p and 3p microRNAs from a pre-miRNA (positive and negative controls also performed). An example of an appropriate assay to which criteria could be applied is Wu et al. 2018[7](#pmid_28862265)." }, { "baseStrength": "Pathogenic", "id": "643243176", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243176", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Somatic tumor testing identifies somatic hotspot second hit and no additional somatic LOF variants. Tumor testing[6](#pmid_30311369) of a neoplasm with known DICER1 association in a proband who carries the germline variant under evaluation reveals the following:\n\n* A previously reported somatic second hit of DICER1 in an RNase IIIb-disrupting “hotspot” codon (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, or p.E1813) AND\n* Retention of the germline DICER1 variant under evaluation. PP4 is NOT applicable if:\n* The germline variant is a missense variant in one of the seven RNase IIIb “hotspot” codons (see PM1), OR\n* Somatic sequencing reveals additional DICER1 non-hotspot variants (could be consistent with sporadic tumorigenesis)." }, { "baseStrength": "Pathogenic", "id": "643243174", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243174", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: While DICER1 does meet recommended cutoff for missense constraint z score of ≥3.09 established by the SVI (4.23 on gnomAD) the VCEP recommends this rule not be used for DICER1 due to the presence of various missense variants throughout the gene that are clinically interpreted as benign (9) or likely benign (30) in ClinVar." }, { "baseStrength": "Pathogenic", "id": "643243174", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243174", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: While DICER1 does meet recommended cutoff for missense constraint z score of ≥3.09 established by the SVI (4.23 on gnomAD) the VCEP recommends this rule not be used for DICER1 due to the presence of various missense variants throughout the gene that are clinically interpreted as benign (9) or likely benign (30) in ClinVar." }, { "baseStrength": "Pathogenic", "id": "643243174", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243174", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: While DICER1 does meet recommended cutoff for missense constraint z score of ≥3.09 established by the SVI (4.23 on gnomAD) the VCEP recommends this rule not be used for DICER1 due to the presence of various missense variants throughout the gene that are clinically interpreted as benign (9) or likely benign (30) in ClinVar." }, { "baseStrength": "Pathogenic", "id": "643243174", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243174", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: While DICER1 does meet recommended cutoff for missense constraint z score of ≥3.09 established by the SVI (4.23 on gnomAD) the VCEP recommends this rule not be used for DICER1 due to the presence of various missense variants throughout the gene that are clinically interpreted as benign (9) or likely benign (30) in ClinVar." }, { "baseStrength": "Pathogenic", "id": "643243171", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243171", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Missense variant under evaluation should have equal or worse Grantham score. Splicing should be ruled out with either RNA data or agreement in splicing predictors (MaxEntScan and SpliceAI) that show no splicing effects. The other variant must be interpreted as pathogenic by the ClinGen DICER1 VCEP. Likely pathogenic changes do not apply. This rule cannot be applied in combination with PM1 or PS1." }, { "baseStrength": "Pathogenic", "id": "643243167", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243167", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Putative missense variants at residues affecting metal ion-binding: codons p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813" }, { "baseStrength": "Pathogenic", "id": "643243167", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243167", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Putative missense variants at residues in the RNase IIIb domain (p.Y1682 – p.S1846), besides the metal ion-binding residues (see PM1)." }, { "baseStrength": "Pathogenic", "id": "643243164", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243164", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "≥4 de novo points" }, { "baseStrength": "Pathogenic", "id": "643243164", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243164", "label": "PS2", "strengthDescriptor": "Strong", "text": "≥2 but less than 4 de novo points" }, { "baseStrength": "Pathogenic", "id": "643243164", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243164", "label": "PS2", "strengthDescriptor": "Moderate", "text": "≥1 but less than 2 de novo points" }, { "baseStrength": "Pathogenic", "id": "643243164", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243164", "label": "PS2", "strengthDescriptor": "Supporting", "text": "≥0.5 but less than 1 de novo points" }, { "baseStrength": "Benign", "id": "643243185", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243185", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable at this time." }, { "baseStrength": "Benign", "id": "643243185", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243185", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable at this time." }, { "baseStrength": "Benign", "id": "643243185", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243185", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable at this time." }, { "baseStrength": "Benign", "id": "643243185", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243185", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable at this time." }, { "baseStrength": "Benign", "id": "643243184", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243184", "label": "BP2", "strengthDescriptor": "Supporting", "text": "≥1 observation in trans with P/LP DICER1 variant or ≥3\nobservations in cis or phase unknown with 2+ different\nP/LP DICER1 variants." }, { "baseStrength": "Benign", "id": "643243179", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243179", "label": "BS1", "strengthDescriptor": "Strong", "text": "Frequency >0.0003 (0.03%) in gnomAD subpopulations. Subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present." }, { "baseStrength": "Pathogenic", "id": "643243175", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243175", "label": "PP3", "strengthDescriptor": "Supporting", "text": "For missense variants, REVEL score ≥ 0.75 OR agreement in splicing predictors predict splicing effects. For splicing variants, concordance of MaxEntScan and SpliceAI." }, { "baseStrength": "Pathogenic", "id": "643243166", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243166", "label": "PS4", "strengthDescriptor": "Strong", "text": "≥4 phenotype points" }, { "baseStrength": "Pathogenic", "id": "643243166", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243166", "label": "PS4", "strengthDescriptor": "Moderate", "text": "2 – 3.5 phenotype points" }, { "baseStrength": "Pathogenic", "id": "643243166", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243166", "label": "PS4", "strengthDescriptor": "Supporting", "text": "1 – 1.5 phenotype points" } ], "diseases": [ { "id": "MONDO:0100216", "iri": "https://genboree.org/cspec/Disease/id/1571068601", "label": "DICER1-related tumor predisposition" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467823568", "label": "DICER1" } ], "ruleSet": { "id": "643243101", "iri": "https://genboree.org/cspec/RuleSet/id/643243101" }, "svi": { "id": "GN024", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243094", "label": "ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.3.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "643243208", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243208", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in the homozygous state in a healthy adult." }, { "baseStrength": "Pathogenic", "id": "643243198", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243198", "label": "PM4", "strengthDescriptor": "Moderate", "text": "CCDS VCEP notes: Stop loss variants in GATM have not been reported, as far as we are aware. \n\nGATM specifications: Use this rule “as is” for in frame deletions and insertions of 2 or more amino acids, but downgrade to PM4\\_Supporting for single amino acid deletions and insertions." }, { "baseStrength": "Pathogenic", "id": "643243198", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243198", "label": "PM4", "strengthDescriptor": "Supporting", "text": "Downgrade to PM4\\_Supporting for in frame deletion/insertion of a single amino acid." }, { "baseStrength": "Pathogenic", "id": "643243196", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243196", "label": "PM2", "strengthDescriptor": "Supporting", "text": "**Allele frequency \\<0.000055 (\\<0.0055%) in all populations in gnomAD.**\n\nCCDS VCEP notes: It is acceptable for a GATM variant to be present in controls, if heterozygous, because AGAT-D is a recessive disorder. Homozygotes should not be seen in a population database, such as gnomAD, because the penetrance of this condition in individuals with biallelic pathogenic variants is expected to be 100%. \n\nGATM specifications:\n\n* All subpopulations in gnomAD must have a maximum allele frequency less than 0.000055 (based on the prevalence of the most common suspected pathogenic variants, c.484+1G>T and p.Arg169Ter) (see Appendix 3). Note – PM2 will NOT be used at moderate strength; PM2 will only be applied as a Supporting criterion.\n* If homozygotes are observed, the variant will meet BS2 (assuming 100% penetrance for an individual with 2 pathogenic variants in trans)." }, { "baseStrength": "Pathogenic", "id": "643243191", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243191", "label": "PS1", "strengthDescriptor": "Strong", "text": "* This criterion is applicable as described.\n* If the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing." }, { "baseStrength": "Benign", "id": "643243210", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243210", "label": "BS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Lack of segregation in a family. Caveat: The presence of phenocopies for common phenotypes." }, { "baseStrength": "Benign", "id": "643243210", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243210", "label": "BS4", "strengthDescriptor": "Strong", "text": "Not Applicable: Lack of segregation in a family. Caveat: The presence of phenocopies for common phenotypes." }, { "baseStrength": "Benign", "id": "643243210", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243210", "label": "BS4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Lack of segregation in a family. Caveat: The presence of phenocopies for common phenotypes." }, { "baseStrength": "Benign", "id": "643243210", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243210", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Lack of segregation in a family. Caveat: The presence of phenocopies for common phenotypes." }, { "baseStrength": "Benign", "id": "643243209", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243209", "label": "BS3", "strengthDescriptor": "Supporting", "text": "**\\>30% normal GAA activity when the variant is expressed in a heterologous cell type.** \nGATM specifications: \nIn vitro assays in which a variant is expressed in AGAT-deficient cultured cells (e.g. AGAT-deficient fibroblasts) or in-fusion High-Fidelity cloning of GATM transcript and site directed mutagenesis to generate missense variant overexpressed in HeLa cells and measurement of AGAT activity in cells for wild-type and missense variant. Any variant with enzyme activity at or above 30% of normal in DesRoches et al, 2016, PMID 27233232, meets BS3\\_Supporting." }, { "baseStrength": "Pathogenic", "id": "643243204", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243204", "label": "PP4", "strengthDescriptor": "Strong", "text": "4 or more points based on any combination of the following. Two or more data types are required to meet Strong: \n• Low urine guanidinoacetate with or without low or low normal creatine (1 point) \n• Low plasma guanidinoacetate with or without low or low normal creatine (2 points) \n• Significantly decreased creatine peak in brain magnetic resonance spectroscopy (3 points) \n• AGAT enzyme activity \\<5% of normal (3 points)\n\n\\* Variant must meet PM2\\_Supporting for PP4 to apply at any strength. \n\\* For PP4 to be applied at strong, full GATM gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading." }, { "baseStrength": "Pathogenic", "id": "643243204", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243204", "label": "PP4", "strengthDescriptor": "Moderate", "text": "3 points based on any combination of the following. Two or more data types are recommended to reach moderate: \n• Low urine guanidinoacetate with or without low or low normal creatine (1 point) \n• Low plasma guanidinoacetate with or without low or low normal creatine (2 points) \n• Significantly decreased creatine peak in brain magnetic resonance spectroscopy (3 points) \n• AGAT enzyme activity \\<5% of normal (3 points)\n\nVariant must meet PM2\\_Supporting for PP4 to apply at any strength." }, { "baseStrength": "Pathogenic", "id": "643243204", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243204", "label": "PP4", "strengthDescriptor": "Supporting", "text": "1-2 points based on: \n• Low urine guanidinoacetate with or without low or low normal creatine (1 point) \n• Low plasma guanidinoacetate with or without low or low normal creatine (2 points) \nVariant must meet PM2\\_Supporting for PP4 to apply at any strength." }, { "baseStrength": "Pathogenic", "id": "643243203", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243203", "label": "PP3", "strengthDescriptor": "Moderate", "text": "Non-canonical splice site variant predicted to be more deleterious, by SpliceAI and varSEAK, than a previously observed pathogenic variant at the same nucleotide." }, { "baseStrength": "Pathogenic", "id": "643243203", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243203", "label": "PP3", "strengthDescriptor": "Supporting", "text": "* REVEL score >0.75 for missense variants.\n* In frame deletion or insertion predicted deleterious by PROVEAN and MutationTaster.\n* Predicted impact on splicing by SpliceAI and varSEAK. GATM specifications:\n* For missense changes, those with a REVEL score more than 0.75 will meet PP3.\n* For in frame insertions and deletions, use PROVEAN and Mutation Taster. Results must be consistent to count.\n* For non-canonical splice site variants (e.g., +3, -3), use SpliceAI (([https://spliceailookup.broadinstitute.org/](https://spliceailookup.broadinstitute.org/) ) and varSEAK ([https://varseak.bio/](https://varseak.bio/)). Results must be consistent to apply this criterion.\n* For SpliceAI, any donor loss or acceptor loss with a score >0.5. For varSEAK, any variant with splicing class 4 or 5. Evidence for creation of a cryptic splice site should also be assessed.\n* Do not apply this rule for canonical splice site changes meeting PVS1." }, { "baseStrength": "Pathogenic", "id": "643243202", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243202", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: CCDS VCEP notes for PP2:\nDoes not apply; there are benign and pathogenic missense variants in GATM." }, { "baseStrength": "Pathogenic", "id": "643243202", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243202", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: CCDS VCEP notes for PP2:\nDoes not apply; there are benign and pathogenic missense variants in GATM." }, { "baseStrength": "Pathogenic", "id": "643243202", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243202", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: CCDS VCEP notes for PP2:\nDoes not apply; there are benign and pathogenic missense variants in GATM." }, { "baseStrength": "Pathogenic", "id": "643243202", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243202", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: CCDS VCEP notes for PP2:\nDoes not apply; there are benign and pathogenic missense variants in GATM." }, { "baseStrength": "Pathogenic", "id": "643243199", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243199", "label": "PM5", "strengthDescriptor": "Moderate", "text": "If the pathogenicity of another missense change at the same amino acid residue is unknown, determine its pathogenicity using these specifications in order to determine if this criterion can be used. If the variant is pathogenic, use PM5. If the variant is likely pathogenic, use PM5\\_Supporting." }, { "baseStrength": "Pathogenic", "id": "643243199", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243199", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Missense change at an amino acid residue where a different missense change determined to be likely pathogenic has been seen before." }, { "baseStrength": "Pathogenic", "id": "643243193", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243193", "label": "PS3", "strengthDescriptor": "Strong", "text": "**RT-PCR evidence of mis-splicing for non-canonical intronic variants with no evidence of normal splice products.**\n\nGATM specifications: \nAny variant meeting the description for either in vitro expression or splicing assays can meet PS3 at the strengths given. If a variant meets the description for both e.g., a splice site variant with no evidence of abnormal splicing and deficient AGAT activity in vitro, PS3 must only be applied once.\n\n**Splicing assays** \nFor non-canonical splicing variants, use PS3 if there is RT-PCR and/or RNA sequencing evidence demonstrating only abnormal splice products, with no evidence of normal splicing. \n\\* Evidence of abnormal splicing includes transcripts of alternative length or with specific intron or exon inclusion/exclusion. These studies can be performed on mRNA extracted from patient-derived cells, or by inserting the mutant genomic DNA into plasmid vectors and introducing these into human or other mammalian host cells. \n\\* Note that in patients who are compound heterozygotes for a splicing variant and another variants type that does not disrupt splicing, such as a missense variant, evidence of normal splicing is expected. However, the presence of normal splice products could complicate the assessment of the impact of the splice variant. Therefore, if there is any evidence of normal splice products, either when using RNA from patient cells or in an in vitro expression system, use PS3\\_Supporting. \n\\* PP3 may also be used for non-canonical splice variants meeting PS3 or PS3\\_Supporting." }, { "baseStrength": "Pathogenic", "id": "643243193", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243193", "label": "PS3", "strengthDescriptor": "Supporting", "text": "**\\<15% control activity when variant is expressed in HeLa cells, as reported in PMID 27233232.** \n**RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.**\n\nGATM specifications: \nAny variant meeting the description for either in vitro expression or splicing assays can meet PS3 at the strengths given. If a variant meets the description for both e.g., a splice site variant with no evidence of abnormal splicing and deficient AGAT activity in vitro, PS3 must only be applied once.  \n\n**In vitro expression** \nAGAT activity data from an in vitro assay in which GATM variants were overexpressed in HeLa cells has been published (DesRoches et al, 2016; PMID 27233232). Any variant with AGAT activity at or below 15% of normal in this paper meets PS3\\_Supporting (see [Appendix 2](https://docs.google.com/spreadsheets/d/1ANaK1am_4svqc0h0m3qaEqLmjqTfJ0pG/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) for further details on AGAT functional assays).  \n\n**Splicing assays** \nFor non-canonical splicing variants, use PS3 if there is RT-PCR and/or RNA sequencing evidence demonstrating only abnormal splice products, with no evidence of normal splicing. \n\\* Evidence of abnormal splicing includes transcripts of alternative length or with specific intron or exon inclusion/exclusion. These studies can be performed on mRNA extracted from patient-derived cells, or by inserting the mutant genomic DNA into plasmid vectors and introducing these into human or other mammalian host cells. \n\\* Note that in patients who are compound heterozygotes for a splicing variant and another variants type that does not disrupt splicing, such as a missense variant, evidence of normal splicing is expected. However, the presence of normal splice products could complicate the assessment of the impact of the splice variant. Therefore, if there is any evidence of normal splice products, either when using RNA from patient cells or in an in vitro expression system, use PS3\\_Supporting. \n\\* PP3 may also be used for non-canonical splice variants meeting PS3 or PS3\\_Supporting." }, { "baseStrength": "Pathogenic", "id": "643243190", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243190", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "**Nonsense-mediated decay predicted.**\n\nCCDS VCEP notes: \nLoss of function (LOF) of GATM is a known mechanism of disease for arginine:glycine amidinotransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D (https://databases.lovd.nl/shared/variants/GATM/unique). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).\n\nGATM specifications: \n**Nonsense and frameshift variants** \n\\* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, PVS1\\_Strong or PVS1\\_Moderate will be applied depending on whether >10% or \\<10% of the protein is lost.\n\n**Splice site variants (+1, +2, -1, -2)** \n\\* All canonical splice site pairs in GATM are GT-AG. \n\\* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. \n\\* For the predicted in frame/out of frame consequences of exon skipping and considerations for strength of PVS1, see [Appendix 1](https://docs.google.com/spreadsheets/d/16DkEaIPdtcYuQ5dqOw9bP3VwEVO4gqJK/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true). \n\\* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \n\\* To apply PVS1, splice site variants must have no detectable nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. Otherwise, the PVS1 strength should be reduced accordingly. \n\\* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.\n\n**Deletions (single or multi exon)** \n\\* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1\\_Strong if >10% of the protein is predicted to be removed, and use PVS1\\_Moderate if \\<10% of the protein is predicted to be removed. \n\\* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\\_Strong if more than 10% of the protein is removed and PVS1\\_Moderate if \\<10% of the protein is removed. \n\\* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \n\\* [Appendix 1](https://docs.google.com/spreadsheets/d/16DkEaIPdtcYuQ5dqOw9bP3VwEVO4gqJK/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) can be used to predict the consequences of single exon deletions.\n\n**Duplications** \n\\* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications." }, { "baseStrength": "Pathogenic", "id": "643243190", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243190", "label": "PVS1", "strengthDescriptor": "Strong", "text": "**In frame loss of >10% of the protein.** \nCCDS VCEP notes: \nLoss of function (LOF) of GATM is a known mechanism of disease for arginine:glycine amidinotransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D (https://databases.lovd.nl/shared/variants/GATM/unique). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).\n\nGATM specifications: \n**Nonsense and frameshift variants** \n\\* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, PVS1\\_Strong or PVS1\\_Moderate will be applied depending on whether >10% or \\<10% of the protein is lost.\n\n**Splice site variants (+1, +2, -1, -2)** \n\\* All canonical splice site pairs in GATM are GT-AG. \n\\* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. \n\\*Use SpliceAI and varSEAK to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing.  \n\\* For considerations for strength at which PVS1 may be applied see [Appendix 1](https://docs.google.com/spreadsheets/d/16DkEaIPdtcYuQ5dqOw9bP3VwEVO4gqJK/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true). \n\\* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \n\\* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.\n\n**Deletions (single or multi exon)** \n\\* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1\\_Strong if >10% of the protein is predicted to be removed, and use PVS1\\_Moderate if \\<10% of the protein is predicted to be removed. \n\\* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\\_Strong if more than 10% of the protein is removed and PVS1\\_Moderate if \\<10% of the protein is removed. \n\\* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \n\\* [Appendix 1](https://docs.google.com/spreadsheets/d/16DkEaIPdtcYuQ5dqOw9bP3VwEVO4gqJK/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) can be used to predict the consequences of single exon deletions.\n\n**Duplications** \n\\* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications." }, { "baseStrength": "Pathogenic", "id": "643243190", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243190", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "**Single exon or larger deletion resulting in loss of \\<10% of the protein, and initiator codon variants.**\n\nCCDS VCEP notes: \nLoss of function (LOF) of GATM is a known mechanism of disease for arginine:glycine amidinotransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D (https://databases.lovd.nl/shared/variants/GATM/unique). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).  \n\nGATM specifications:\n\n**Nonsense and frameshift variants** \n\\* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, PVS1\\_Moderate will be applied.\n\n**Splice site variants (+1, +2, -1, -2)** \n\\* All canonical splice site pairs in GATM are GT-AG. \n\\* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. \n\\*Use SpliceAI and varSEAK to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing.  \n\\* For considerations for strength at which PVS1 may be applied see [Appendix 1](https://docs.google.com/spreadsheets/d/16DkEaIPdtcYuQ5dqOw9bP3VwEVO4gqJK/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true). \n\\* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \n\\* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.\n\n**Initiator codon variants** \n\\* To our knowledge, initiator codon variants have not been reported in GATM (01/2019) but may occur. \n\\* All initiator codon variants will meet PVS1\\_Moderate. The next in-frame methionine is at amino acid position 130 (based on NP\\_001473).\n\n**Deletions (single or multi exon)** \n\\* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1\\_Strong if >10% of the protein is predicted to be removed, and use PVS1\\_Moderate if \\<10% of the protein is predicted to be removed. \n\\* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\\_Strong if more than 10% of the protein is removed and PVS1\\_Moderate if \\<10% of the protein is removed. \n\\* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \n\\* [Appendix 1](https://docs.google.com/spreadsheets/d/16DkEaIPdtcYuQ5dqOw9bP3VwEVO4gqJK/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) can be used to predict the consequences of single exon deletions.\n\n**Duplications** \n\\* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications." }, { "baseStrength": "Benign", "id": "643243217", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243217", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved." }, { "baseStrength": "Benign", "id": "643243206", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243206", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "**Allele frequency >0.0005 (0.05%) in gnomAD in any continental population in gnomAD with >2000 alleles.**\n\n* Any variant with a frequency >0.0005 (max allelic contribution = 100% and max genetic contribution = 100% based on estimated prevalence of 1 in 3,450,000 (PMID 27233232), and penetrance of 100%) in a continental population with >2000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).\n* Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383)." }, { "baseStrength": "Pathogenic", "id": "643243201", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243201", "label": "PP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: CCDS VCEP notes for PP1: Sibships large enough to use meet this criterion are extremely rare. In addition, because GATM is the only gene involved in AGAT-D, ALL patients are expected to be bi-allelic, regardless of whether the pathogenic variants can be, or have been, detected. A variant under assessment may not be the true pathogenic variant but instead in linkage disequilibrium with an unidentified pathogenic variant. For this reason, this criterion does not facilitate assessment of pathogenicity." }, { "baseStrength": "Pathogenic", "id": "643243201", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243201", "label": "PP1", "strengthDescriptor": "Strong", "text": "Not Applicable: CCDS VCEP notes for PP1: Sibships large enough to use meet this criterion are extremely rare. In addition, because GATM is the only gene involved in AGAT-D, ALL patients are expected to be bi-allelic, regardless of whether the pathogenic variants can be, or have been, detected. A variant under assessment may not be the true pathogenic variant but instead in linkage disequilibrium with an unidentified pathogenic variant. For this reason, this criterion does not facilitate assessment of pathogenicity." }, { "baseStrength": "Pathogenic", "id": "643243201", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243201", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: CCDS VCEP notes for PP1: Sibships large enough to use meet this criterion are extremely rare. In addition, because GATM is the only gene involved in AGAT-D, ALL patients are expected to be bi-allelic, regardless of whether the pathogenic variants can be, or have been, detected. A variant under assessment may not be the true pathogenic variant but instead in linkage disequilibrium with an unidentified pathogenic variant. For this reason, this criterion does not facilitate assessment of pathogenicity." }, { "baseStrength": "Pathogenic", "id": "643243201", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243201", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: CCDS VCEP notes for PP1: Sibships large enough to use meet this criterion are extremely rare. In addition, because GATM is the only gene involved in AGAT-D, ALL patients are expected to be bi-allelic, regardless of whether the pathogenic variants can be, or have been, detected. A variant under assessment may not be the true pathogenic variant but instead in linkage disequilibrium with an unidentified pathogenic variant. For this reason, this criterion does not facilitate assessment of pathogenicity." }, { "baseStrength": "Pathogenic", "id": "643243194", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243194", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: CCDS VCEP notes for PS4:\nThis rule is typically used for autosomal dominant disorders, with PM3 used as a case-counting mechanism for autosomal recessive conditions." }, { "baseStrength": "Pathogenic", "id": "643243194", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243194", "label": "PS4", "strengthDescriptor": "Strong", "text": "Not Applicable: CCDS VCEP notes for PS4:\nThis rule is typically used for autosomal dominant disorders, with PM3 used as a case-counting mechanism for autosomal recessive conditions." }, { "baseStrength": "Pathogenic", "id": "643243194", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243194", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Not Applicable: CCDS VCEP notes for PS4:\nThis rule is typically used for autosomal dominant disorders, with PM3 used as a case-counting mechanism for autosomal recessive conditions." }, { "baseStrength": "Pathogenic", "id": "643243194", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243194", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Not Applicable: CCDS VCEP notes for PS4:\nThis rule is typically used for autosomal dominant disorders, with PM3 used as a case-counting mechanism for autosomal recessive conditions." }, { "baseStrength": "Pathogenic", "id": "643243192", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243192", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to non-maternity.\nCCDS VCEP notes for PS2 and PM6: De novo variants have not been reported in patients with AGAT deficiency, to our knowledge. Furthermore, the observation that a variant in GATM has arisen de novo does not support its causality because AGAT deficiency is an autosomal recessive disorder. The occurrence of de novo variants is more supportive in autosomal dominant and X-linked disorders. Any de novo variants in GATM, should they be observed, will be assessed based on the variant type, functional evidence, and in trans data as described." }, { "baseStrength": "Pathogenic", "id": "643243192", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243192", "label": "PS2", "strengthDescriptor": "Strong", "text": "Not Applicable: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to non-maternity.\nCCDS VCEP notes for PS2 and PM6: De novo variants have not been reported in patients with AGAT deficiency, to our knowledge. Furthermore, the observation that a variant in GATM has arisen de novo does not support its causality because AGAT deficiency is an autosomal recessive disorder. The occurrence of de novo variants is more supportive in autosomal dominant and X-linked disorders. Any de novo variants in GATM, should they be observed, will be assessed based on the variant type, functional evidence, and in trans data as described." }, { "baseStrength": "Pathogenic", "id": "643243192", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243192", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Not Applicable: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to non-maternity.\nCCDS VCEP notes for PS2 and PM6: De novo variants have not been reported in patients with AGAT deficiency, to our knowledge. Furthermore, the observation that a variant in GATM has arisen de novo does not support its causality because AGAT deficiency is an autosomal recessive disorder. The occurrence of de novo variants is more supportive in autosomal dominant and X-linked disorders. Any de novo variants in GATM, should they be observed, will be assessed based on the variant type, functional evidence, and in trans data as described." }, { "baseStrength": "Pathogenic", "id": "643243192", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243192", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Not Applicable: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to non-maternity.\nCCDS VCEP notes for PS2 and PM6: De novo variants have not been reported in patients with AGAT deficiency, to our knowledge. Furthermore, the observation that a variant in GATM has arisen de novo does not support its causality because AGAT deficiency is an autosomal recessive disorder. The occurrence of de novo variants is more supportive in autosomal dominant and X-linked disorders. Any de novo variants in GATM, should they be observed, will be assessed based on the variant type, functional evidence, and in trans data as described." }, { "baseStrength": "Benign", "id": "643243216", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243216", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243216", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243216", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243216", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243216", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243216", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243216", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243214", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243214", "label": "BP4", "strengthDescriptor": "Supporting", "text": "* REVEL score <0.15 for missense variants.\n* In frame deletion or insertion predicted benign by PROVEAN and MutationTaster.\n* No predicted impact on splicing by SpliceAI and varSEAK.\nGATM specifications:\n* For missense changes, REVEL score <0.15.\n* For in frame insertions and deletions, use PROVEAN and Mutation Taster. Results must be consistent to count.\n* For non-canonical splice site variants, use SpliceAI (https://spliceailookup.broadinstitute.org/ ) and varSEAK (https://varseak.bio/) to assess the impact of variants that are not +/-1 or 2 canonical splice site variants. For SpliceAI, this criterion can be applied for scores <0.2, and for varSEAK class 1 and 2. If there is any evidence for possible creation of a cryptic splice site, this criterion should not be applied." }, { "baseStrength": "Benign", "id": "643243213", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243213", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: In-frame deletions/insertions in a repetitive region without a known function." }, { "baseStrength": "Benign", "id": "643243213", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243213", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: In-frame deletions/insertions in a repetitive region without a known function." }, { "baseStrength": "Benign", "id": "643243213", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243213", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: In-frame deletions/insertions in a repetitive region without a known function." }, { "baseStrength": "Benign", "id": "643243213", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243213", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: In-frame deletions/insertions in a repetitive region without a known function." }, { "baseStrength": "Benign", "id": "643243212", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243212", "label": "BP2", "strengthDescriptor": "Supporting", "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.\nGATM specifications:\nObserved in cis with a pathogenic variant (to take AR inheritance into account)." }, { "baseStrength": "Benign", "id": "643243211", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243211", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Missense variant in a gene for which primarily truncating variants are known to cause disease." }, { "baseStrength": "Benign", "id": "643243211", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243211", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Missense variant in a gene for which primarily truncating variants are known to cause disease." }, { "baseStrength": "Benign", "id": "643243211", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243211", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Missense variant in a gene for which primarily truncating variants are known to cause disease." }, { "baseStrength": "Benign", "id": "643243211", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243211", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Missense variant in a gene for which primarily truncating variants are known to cause disease." }, { "baseStrength": "Benign", "id": "643243207", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243207", "label": "BS1", "strengthDescriptor": "Strong", "text": "**Allele frequency >0.0001 (0.01%) in gnomAD in any continental population in gnomAD with >2000 alleles.**\n\n* Any variant with a frequency >0.0001 (max allelic contribution = 25% and max genetic contribution = 100% based on estimated prevalence of 1 in 3,450,000, (PMID 27233232), and penetrance of 100%) in a continental population with >2000 (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383) (see Appendix 3).\n* Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383)." }, { "baseStrength": "Pathogenic", "id": "643243197", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243197", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous." }, { "baseStrength": "Pathogenic", "id": "643243197", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243197", "label": "PM3", "strengthDescriptor": "Strong", "text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous." }, { "baseStrength": "Pathogenic", "id": "643243197", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243197", "label": "PM3", "strengthDescriptor": "Moderate", "text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous." }, { "baseStrength": "Pathogenic", "id": "643243197", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243197", "label": "PM3", "strengthDescriptor": "Supporting", "text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous." }, { "baseStrength": "Pathogenic", "id": "643243195", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243195", "label": "PM1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation." }, { "baseStrength": "Pathogenic", "id": "643243195", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243195", "label": "PM1", "strengthDescriptor": "Strong", "text": "Not Applicable: Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation." }, { "baseStrength": "Pathogenic", "id": "643243195", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243195", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation." }, { "baseStrength": "Pathogenic", "id": "643243195", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243195", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation." }, { "baseStrength": "Benign", "id": "643243215", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243215", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Variant found in a case with an alternate molecular basis for disease.\nCCDS VCEP notes for BP5: An individual could be a carrier of a pathogenic variant in GATM and have another disorder" }, { "baseStrength": "Benign", "id": "643243215", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243215", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable: Variant found in a case with an alternate molecular basis for disease.\nCCDS VCEP notes for BP5: An individual could be a carrier of a pathogenic variant in GATM and have another disorder" }, { "baseStrength": "Benign", "id": "643243215", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243215", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: Variant found in a case with an alternate molecular basis for disease.\nCCDS VCEP notes for BP5: An individual could be a carrier of a pathogenic variant in GATM and have another disorder" }, { "baseStrength": "Benign", "id": "643243215", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243215", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: Variant found in a case with an alternate molecular basis for disease.\nCCDS VCEP notes for BP5: An individual could be a carrier of a pathogenic variant in GATM and have another disorder" }, { "baseStrength": "Pathogenic", "id": "643243205", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243205", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243205", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243205", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243205", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243205", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243205", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243205", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243200", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243200", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: CCDS VCEP notes for PS2 and PM6: De novo variants have not been reported in patients with AGAT deficiency, to our knowledge. Furthermore, the observation that a variant in GATM has arisen de novo does not support its causality because AGAT deficiency is an autosomal recessive disorder. The occurrence of de novo variants is more supportive in autosomal dominant and X-linked disorders. Any de novo variants in GATM, should they be observed, will be assessed based on the variant type, functional evidence, and in trans data as described." }, { "baseStrength": "Pathogenic", "id": "643243200", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243200", "label": "PM6", "strengthDescriptor": "Strong", "text": "Not Applicable: CCDS VCEP notes for PS2 and PM6: De novo variants have not been reported in patients with AGAT deficiency, to our knowledge. Furthermore, the observation that a variant in GATM has arisen de novo does not support its causality because AGAT deficiency is an autosomal recessive disorder. The occurrence of de novo variants is more supportive in autosomal dominant and X-linked disorders. Any de novo variants in GATM, should they be observed, will be assessed based on the variant type, functional evidence, and in trans data as described." }, { "baseStrength": "Pathogenic", "id": "643243200", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243200", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Not Applicable: CCDS VCEP notes for PS2 and PM6: De novo variants have not been reported in patients with AGAT deficiency, to our knowledge. Furthermore, the observation that a variant in GATM has arisen de novo does not support its causality because AGAT deficiency is an autosomal recessive disorder. The occurrence of de novo variants is more supportive in autosomal dominant and X-linked disorders. Any de novo variants in GATM, should they be observed, will be assessed based on the variant type, functional evidence, and in trans data as described." }, { "baseStrength": "Pathogenic", "id": "643243200", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243200", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Not Applicable: CCDS VCEP notes for PS2 and PM6: De novo variants have not been reported in patients with AGAT deficiency, to our knowledge. Furthermore, the observation that a variant in GATM has arisen de novo does not support its causality because AGAT deficiency is an autosomal recessive disorder. The occurrence of de novo variants is more supportive in autosomal dominant and X-linked disorders. Any de novo variants in GATM, should they be observed, will be assessed based on the variant type, functional evidence, and in trans data as described." } ], "diseases": [ { "id": "MONDO:0012996", "iri": "https://genboree.org/cspec/Disease/id/467873716", "label": "AGAT deficiency" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467827462", "label": "GATM" } ], "ruleSet": { "id": "643243102", "iri": "https://genboree.org/cspec/RuleSet/id/643243102" }, "svi": { "id": "GN025", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243095", "label": "ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GATM Version 1.1.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "643243245", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243245", "label": "BP7", "strengthDescriptor": "Supporting", "text": "Apply this criterion as described." }, { "baseStrength": "Benign", "id": "643243237", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243237", "label": "BS3", "strengthDescriptor": "Supporting", "text": "\\>30% normal GAA activity when the variant is expressed in a heterologous cell type. \nGAMT specifications: \nIn vitro assays in which a variant is expressed in GAMT-deficient cultured cells (e.g. GAMT-deficient fibroblasts) or in-fusion High-Fidelity cloning of GAMT transcript and site directed mutagenesis to generate missense variant overexpressed in HeLa cells and measurement of GAMT activity in cells for wild-type and missense variant. Any variant with enzyme activity at or above 30% of normal in the following publications meets BS3\\_Supporting (Mercimek-Mahmutoglu et al, 2014; PMID 24415674; Mercimek-Mahmutoglu et al, 2016, PMID 26319512; DesRoches et al, 2016, PMID 26003046)." }, { "baseStrength": "Benign", "id": "643243235", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243235", "label": "BS1", "strengthDescriptor": "Strong", "text": "Allele frequency >0.001 (0.1%) in gnomAD in any continental population in gnomAD with >2000 alleles. \n\nGAMT specifications:\n\n* Any variant with a frequency >0.001 (based on the estimated prevalence 1 in 114,000 (PMID: 24071436) in gnomAD (max allelic contribution = 40%; max genetic contribution = 100%).\n* Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383)." }, { "baseStrength": "Benign", "id": "643243234", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243234", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Allele frequency >0.003 (0.3%) in gnomAD in any continental population in gnomAD with >2000 alleles.\n\nGAMT specifications:\n\n* Any variant with a frequency >0.003 (based on the estimated prevalence 1 in 114,000, PMID 24071436) in gnomAD (max allelic contribution = 100%; max genetic contribution = 100%).\n* Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383)." }, { "baseStrength": "Pathogenic", "id": "643243233", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243233", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243233", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243233", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243233", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243233", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243233", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243233", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243226", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243226", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Stop loss variants in GAMT have not been reported, as far as we are aware.\n\nGAMT specifications: Use this rule “as is” for in frame deletions and insertions of 2 or more amino acids, but downgrade to PM4\\_Supporting for single amino acid deletions and insertions." }, { "baseStrength": "Pathogenic", "id": "643243226", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243226", "label": "PM4", "strengthDescriptor": "Supporting", "text": " Downgrade to PM4\\_Supporting for single amino acid deletions and insertions." }, { "baseStrength": "Pathogenic", "id": "643243225", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243225", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous." }, { "baseStrength": "Pathogenic", "id": "643243225", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243225", "label": "PM3", "strengthDescriptor": "Strong", "text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous." }, { "baseStrength": "Pathogenic", "id": "643243225", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243225", "label": "PM3", "strengthDescriptor": "Moderate", "text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous." }, { "baseStrength": "Pathogenic", "id": "643243225", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243225", "label": "PM3", "strengthDescriptor": "Supporting", "text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous." }, { "baseStrength": "Pathogenic", "id": "643243223", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243223", "label": "PM1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation." }, { "baseStrength": "Pathogenic", "id": "643243223", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243223", "label": "PM1", "strengthDescriptor": "Strong", "text": "Not Applicable: Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation." }, { "baseStrength": "Pathogenic", "id": "643243223", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243223", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation." }, { "baseStrength": "Pathogenic", "id": "643243223", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243223", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation." }, { "baseStrength": "Pathogenic", "id": "643243222", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243222", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\nCCDS VCEP notes for PS4:\nThis rule is typically used for autosomal dominant disorders, with PM3 used as a case-counting mechanism for autosomal recessive conditions." }, { "baseStrength": "Pathogenic", "id": "643243222", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243222", "label": "PS4", "strengthDescriptor": "Strong", "text": "Not Applicable: The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\nCCDS VCEP notes for PS4:\nThis rule is typically used for autosomal dominant disorders, with PM3 used as a case-counting mechanism for autosomal recessive conditions." }, { "baseStrength": "Pathogenic", "id": "643243222", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243222", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Not Applicable: The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\nCCDS VCEP notes for PS4:\nThis rule is typically used for autosomal dominant disorders, with PM3 used as a case-counting mechanism for autosomal recessive conditions." }, { "baseStrength": "Pathogenic", "id": "643243222", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243222", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Not Applicable: The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\nCCDS VCEP notes for PS4:\nThis rule is typically used for autosomal dominant disorders, with PM3 used as a case-counting mechanism for autosomal recessive conditions." }, { "baseStrength": "Benign", "id": "643243244", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243244", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243244", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243244", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243244", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243244", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243244", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243244", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243243", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243243", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: An individual could be a carrier of a pathogenic variant in GAMT and have another disorder." }, { "baseStrength": "Benign", "id": "643243243", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243243", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable: An individual could be a carrier of a pathogenic variant in GAMT and have another disorder." }, { "baseStrength": "Benign", "id": "643243243", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243243", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: An individual could be a carrier of a pathogenic variant in GAMT and have another disorder." }, { "baseStrength": "Benign", "id": "643243243", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243243", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: An individual could be a carrier of a pathogenic variant in GAMT and have another disorder." }, { "baseStrength": "Pathogenic", "id": "643243229", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243229", "label": "PP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nCCDS VCEP notes for PP1: Sibships large enough to use meet this criterion are extremely rare. In addition, because GAMT is the only gene involved in GAMT-D, ALL patients are expected to be bi-allelic, regardless of whether the pathogenic variants can be, or have been, detected. A variant under assessment may not be the true pathogenic variant but instead in linkage disequilibrium with an unidentified pathogenic variant. For this reason, this criterion does not facilitate assessment of pathogenicity." }, { "baseStrength": "Pathogenic", "id": "643243229", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243229", "label": "PP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nCCDS VCEP notes for PP1: Sibships large enough to use meet this criterion are extremely rare. In addition, because GAMT is the only gene involved in GAMT-D, ALL patients are expected to be bi-allelic, regardless of whether the pathogenic variants can be, or have been, detected. A variant under assessment may not be the true pathogenic variant but instead in linkage disequilibrium with an unidentified pathogenic variant. For this reason, this criterion does not facilitate assessment of pathogenicity." }, { "baseStrength": "Pathogenic", "id": "643243229", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243229", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nCCDS VCEP notes for PP1: Sibships large enough to use meet this criterion are extremely rare. In addition, because GAMT is the only gene involved in GAMT-D, ALL patients are expected to be bi-allelic, regardless of whether the pathogenic variants can be, or have been, detected. A variant under assessment may not be the true pathogenic variant but instead in linkage disequilibrium with an unidentified pathogenic variant. For this reason, this criterion does not facilitate assessment of pathogenicity." }, { "baseStrength": "Pathogenic", "id": "643243229", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243229", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nCCDS VCEP notes for PP1: Sibships large enough to use meet this criterion are extremely rare. In addition, because GAMT is the only gene involved in GAMT-D, ALL patients are expected to be bi-allelic, regardless of whether the pathogenic variants can be, or have been, detected. A variant under assessment may not be the true pathogenic variant but instead in linkage disequilibrium with an unidentified pathogenic variant. For this reason, this criterion does not facilitate assessment of pathogenicity." }, { "baseStrength": "Benign", "id": "643243239", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243239", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Does not apply. All types of variants cause GAMT-D." }, { "baseStrength": "Benign", "id": "643243239", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243239", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Does not apply. All types of variants cause GAMT-D." }, { "baseStrength": "Benign", "id": "643243239", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243239", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Does not apply. All types of variants cause GAMT-D." }, { "baseStrength": "Benign", "id": "643243239", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243239", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Does not apply. All types of variants cause GAMT-D." }, { "baseStrength": "Benign", "id": "643243236", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243236", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in the homozygous state in a healthy adult." }, { "baseStrength": "Pathogenic", "id": "643243232", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243232", "label": "PP4", "strengthDescriptor": "Strong", "text": "4 points based on any combination of the following. Two or more data types are required to apply PP4\\_Strong: \n• Elevated urine guanidinoacetate with or without low or low normal creatine (1 point) \n• Elevated plasma guanidinoacetate with or without low or low normal creatine (2 points) \n• Significantly decreased creatine peak in brain magnetic resonance spectroscopy with or without visible guanidinoacetate peak (3 points) \n• GAMT enzyme activity \\<5% of normal (3 points)\n\n\\* Variant must meet PM2\\_Supporting for PP4 to apply at any strength. \n\\* For PP4 to be applied at strong, full GAMT gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading." }, { "baseStrength": "Pathogenic", "id": "643243232", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243232", "label": "PP4", "strengthDescriptor": "Moderate", "text": "3 points based on any combination of the following. Two or more data types are recommended to apply PP4\\_Moderate: \n• Elevated urine guanidinoacetate with or without low or low normal creatine (1 point) \n• Elevated plasma guanidinoacetate with or without low or low normal creatine (2 points) \n• Significantly decreased creatine peak in brain magnetic resonance spectroscopy with or without visible guanidinoacetate peak (3 points) \n• GAMT enzyme activity \\<5% of normal (3 points)\n\n\\* Variant must meet PM2\\_Supporting for PP4 to apply at any strength." }, { "baseStrength": "Pathogenic", "id": "643243232", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243232", "label": "PP4", "strengthDescriptor": "Supporting", "text": "1-2 points based on:  \n• Elevated urine guanidinoacetate with or without low or low normal creatine (1 point) \n• Elevated plasma guanidinoacetate with or without low or low normal creatine (2 points)\n\n\\* Variant must meet PM2\\_Supporting for PP4 to apply at any strength" }, { "baseStrength": "Pathogenic", "id": "643243231", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243231", "label": "PP3", "strengthDescriptor": "Moderate", "text": "Non-canonical splice site variant predicted to be more deleterious, by SpliceAI and varSEAK, than a previously observed pathogenic variant at the same nucleotide." }, { "baseStrength": "Pathogenic", "id": "643243231", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243231", "label": "PP3", "strengthDescriptor": "Supporting", "text": "* For missense changes, those with a REVEL score more than 0.75 will meet PP3.\n* For in frame insertions and deletions, use PROVEAN and Mutation Taster. Results must be consistent to count.\n* For non-canonical splice site variants (e.g., +3, -3), use SpliceAI ([https://spliceailookup.broadinstitute.org/](https://spliceailookup.broadinstitute.org/) ) and varSEAK ([https://varseak.bio/](https://varseak.bio/)). Results must be consistent to apply this criterion.\n* For SpliceAI, any donor loss or acceptor loss with a score >0.5. For varSEAK, any variant with splicing class 4 or 5. Evidence for creation of a cryptic splice site should also be assessed.\n* Do not apply this rule for canonical splice site changes meeting PVS1." }, { "baseStrength": "Pathogenic", "id": "643243230", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243230", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease.\nCCDS VCEP notes for PP2: Does not apply; there are benign and pathogenic missense variants in GAMT" }, { "baseStrength": "Pathogenic", "id": "643243230", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243230", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease.\nCCDS VCEP notes for PP2: Does not apply; there are benign and pathogenic missense variants in GAMT" }, { "baseStrength": "Pathogenic", "id": "643243230", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243230", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease.\nCCDS VCEP notes for PP2: Does not apply; there are benign and pathogenic missense variants in GAMT" }, { "baseStrength": "Pathogenic", "id": "643243230", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243230", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease.\nCCDS VCEP notes for PP2: Does not apply; there are benign and pathogenic missense variants in GAMT" }, { "baseStrength": "Pathogenic", "id": "643243221", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243221", "label": "PS3", "strengthDescriptor": "Strong", "text": "**RT-PCR evidence of mis-splicing for non-canonical +1, +2, -2, -1 intronic variants with no evidence of normal splice products.**  \n\nGAMT specifications: \nAny variant meeting the description for splicing assays below can meet PS3 or PS3\\_Supporting, and variants meeting the description for in vitro activity assays can meet PS3\\_Supporting. If a variant meets the description for both e.g., a splice site variant with evidence of abnormal splicing and deficient GAMT activity in vitro, PS3 must only be counted once.\n\n**Splicing assays** \nFor non-canonical splicing variants, use PS3 if there is RT-PCR and/or RNA sequencing evidence demonstrating only abnormal splice products, with no evidence of normal splicing. \n\\* Evidence of abnormal splicing includes transcripts of alternative length or with specific intron or exon inclusion/exclusion. These studies can be performed on mRNA extracted from patient-derived cells, or by inserting the mutant genomic DNA into plasmid vectors and introducing these into human or other mammalian host cells. \n\\* Note that in patients who are compound heterozygotes for a splicing variant and another variants type that does not disrupt splicing, such as a missense variant, evidence of normal splicing is expected. However, the presence of normal splice products could complicate the assessment of the impact of the splice variant. Therefore, if there is any evidence of normal splice products, either when using RNA from patient cells or in an in vitro expression system, use PS3\\_Supporting. \n\\* PP3 may also be used for non-canonical splice variants meeting PS3 or PS3\\_Supporting." }, { "baseStrength": "Pathogenic", "id": "643243221", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243221", "label": "PS3", "strengthDescriptor": "Supporting", "text": "**\\<15% control activity when variant is expressed in GAMT-deficient fibroblasts or HeLa cells.** \n**\\* RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.**  \n\nGAMT specifications: \nAny variant meeting the description for splicing assays below can meet PS3 or PS3\\_Supporting, and variants meeting the description for in vitro activity assays can meet PS3\\_Supporting. If a variant meets the description for both e.g., a splice site variant with evidence of abnormal splicing and deficient GAMT activity in vitro, PS3 must only be counted once.\n\n**In vitro expression** \nPS3\\_Supporting can be assigned if a variant is expressed in GAMT-deficient fibroblasts or HeLa cells and has \\<15% of the control value, for values published in Mercimek-Mahmutoglu et al, 2014, PMID 24415674; Mercimek-Mahmutoglu et al, 2016, PMID 26319512; or DesRoches et al, 2016, PMID 26003046. See [Appendix 2](https://docs.google.com/spreadsheets/d/1mjJRDMde-gPFVjnuP-Jbzr68GoaTr5pD/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) for further details on GAMT functional assays.  \n\n**Splicing assays** \nFor non-canonical splicing variants, use PS3 if there is RT-PCR and/or RNA sequencing evidence demonstrating only abnormal splice products, with no evidence of normal splicing. \n\\* Evidence of abnormal splicing includes transcripts of alternative length or with specific intron or exon inclusion/exclusion. These studies can be performed on mRNA extracted from patient-derived cells, or by inserting the mutant genomic DNA into plasmid vectors and introducing these into human or other mammalian host cells. \n\\* Note that in patients who are compound heterozygotes for a splicing variant and another variants type that does not disrupt splicing, such as a missense variant, evidence of normal splicing is expected. However, the presence of normal splice products could complicate the assessment of the impact of the splice variant. Therefore, if there is any evidence of normal splice products, either when using RNA from patient cells or in an in vitro expression system, use PS3\\_Supporting. \n\\* PP3 may also be used for non-canonical splice variants meeting PS3 or PS3\\_Supporting." }, { "baseStrength": "Pathogenic", "id": "643243218", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243218", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "**Nonsense-mediated decay predicted**\n\nCCDS VCEP notes: \nLoss of function (LOF) of GAMT is a known mechanism of disease for guanidinoacetate methyltransferase deficiency (GAMT-D). There are examples of various LOF variants, including nonsense and frameshift, in GAMT in individuals with GAMT-D (https://databases.lovd.nl/shared/variants/GAMT/unique). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).\n\n**Nonsense and frameshift variants** \n\\* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1\\_Strong or PVS1\\_Moderate will be applied, depending on whether >10% or \\<10% of the protein is lost.\n\n**Splice site variants (+1, +2, -1, -2)** \n\\* All canonical splice site pairs in GAMT are GT-AG. \n\\* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. \n\\* For the predicted in frame/out of frame consequences of exon skipping and assigned strength of PVS1, see [Appendix 1](https://docs.google.com/spreadsheets/d/14TbVpD0EkHQF6AqGfUqc9oaaF-LN8Zjn/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true). \n\\* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \n\\* To apply PVS1, splice site variants must have no detectable nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. Otherwise, the PVS1 strength should be reduced accordingly. \n\\* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.\n\n**Deletions (single or multi exon)** \n\\* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1\\_Strong if >10% of the protein is predicted to be removed, and use PVS1\\_Moderate if \\<10% of the protein is predicted to be removed. \n\\* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\\_Strong if more than 10% of the protein is removed and PVS1\\_Moderate if \\<10% of the protein is removed. \n\\* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \n\\* [Appendix 1](https://docs.google.com/spreadsheets/d/14TbVpD0EkHQF6AqGfUqc9oaaF-LN8Zjn/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) can be used to predict the consequences of single exon deletions.\n\n**Duplications** \n\\* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications." }, { "baseStrength": "Pathogenic", "id": "643243218", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243218", "label": "PVS1", "strengthDescriptor": "Strong", "text": "**In frame loss of >10% of the protein.**\n\nCCDS VCEP notes: \nLoss of function (LOF) of GAMT is a known mechanism of disease for guanidinoacetate methyltransferase deficiency (GAMT-D). There are examples of various LOF variants, including nonsense and frameshift, in GAMT in individuals with GAMT-D (https://databases.lovd.nl/shared/variants/GAMT/unique). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).\n\n**Nonsense and frameshift variants** \n\\* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1\\_Strong will be applied if >10% of the protein is lost.\n\n**Splice site variants (+1, +2, -1, -2)** \n\\* All canonical splice site pairs in GAMT are GT-AG. \n\\* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. \n\\* Use SpliceAI and varSEAK to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing.  \n\\* For considerations for strength at which PVS1 may be applied see [Appendix 1](https://docs.google.com/spreadsheets/d/14TbVpD0EkHQF6AqGfUqc9oaaF-LN8Zjn/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true). \n\\* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \n\\* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.\n\n**Deletions (single or multi exon)** \n\\* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1\\_Strong if >10% of the protein is predicted to be removed, and use PVS1\\_Moderate if \\<10% of the protein is predicted to be removed. \n\\* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\\_Strong if more than 10% of the protein is removed and PVS1\\_Moderate if \\<10% of the protein is removed. \n\\* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \n\\* [Appendix 1](https://docs.google.com/spreadsheets/d/14TbVpD0EkHQF6AqGfUqc9oaaF-LN8Zjn/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) can be used to predict the consequences of single exon deletions.\n\n**Duplications** \n\\* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications." }, { "baseStrength": "Pathogenic", "id": "643243218", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243218", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "**Single exon or larger deletion resulting in loss of \\<10% of the protein.**\n\n**Initiator codon variant.**  \n\nCCDS VCEP notes: \nLoss of function (LOF) of GAMT is a known mechanism of disease for guanidinoacetate methyltransferase deficiency (GAMT-D). There are examples of various LOF variants, including nonsense and frameshift, in GAMT in individuals with GAMT-D (https://databases.lovd.nl/shared/variants/GAMT/unique). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).\n\n**Nonsense and frameshift variants** \n\\* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1\\_Moderate will be applied if \\<10% of the protein is lost.\n\n**Splice site variants (+1, +2, -1, -2)** \n\\* All canonical splice site pairs in GAMT are GT-AG. \n\\* Use SpliceAI and varSEAK to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing.  \n\\* For any canonical splice site variant (+1, +2, -1, -2), if RT-PCR data predicts in-frame loss of \\<10% of the protein, apply PVS1\\_Moderate. \n\\* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \n\\* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.\n\n**Initiator codon variants** \n\\* To our knowledge, initiator codon variants have not been reported in GAMT (01/2019) but may occur. \n\\* All initiator codon variants will meet PVS1\\_Moderate. The next in-frame methionine is at amino acid position 42 (based on NP\\_000147.1).\n\n**Deletions (single or multi exon)** \n\\* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1\\_Strong if >10% of the protein is predicted to be removed, and use PVS1\\_Moderate if \\<10% of the protein is predicted to be removed. \n\\* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\\_Strong if more than 10% of the protein is removed and PVS1\\_Moderate if \\<10% of the protein is removed. \n\\* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \n\\* [Appendix 1](https://docs.google.com/spreadsheets/d/14TbVpD0EkHQF6AqGfUqc9oaaF-LN8Zjn/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) can be used to predict the consequences of single exon deletions.\n\n**Duplications** \n\\* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications." }, { "baseStrength": "Benign", "id": "643243242", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243242", "label": "BP4", "strengthDescriptor": "Supporting", "text": "* For missense changes, REVEL score \\<0.5.\n* For in frame insertions and deletions, use PROVEAN and Mutation Taster. Results must be consistent to count.\n* For non-canonical splice site variants, use SpliceAI ([https://spliceailookup.broadinstitute.org/](https://spliceailookup.broadinstitute.org/) ) and varSEAK ([https://varseak.bio/](https://varseak.bio/)) to assess the impact of variants that are not +/-1 or 2 canonical splice site variants. For SpliceAI, this criterion can be applied for scores \\<0.2, and for varSEAK class 1 and 2. If there is any evidence for possible creation of a cryptic splice site, this criterion should not be applied." }, { "baseStrength": "Benign", "id": "643243241", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243241", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: There are no known repetitive regions without known function in GAMT." }, { "baseStrength": "Benign", "id": "643243241", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243241", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: There are no known repetitive regions without known function in GAMT." }, { "baseStrength": "Benign", "id": "643243241", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243241", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: There are no known repetitive regions without known function in GAMT." }, { "baseStrength": "Benign", "id": "643243241", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243241", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: There are no known repetitive regions without known function in GAMT." }, { "baseStrength": "Pathogenic", "id": "643243227", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243227", "label": "PM5", "strengthDescriptor": "Moderate", "text": "If the pathogenicity of another missense change at the same amino acid residue is unknown, determine its pathogenicity using these specifications in order to determine if this criterion can be used. If the variant is pathogenic, use PM5. If the variant is likely pathogenic, use PM5\\_Supporting." }, { "baseStrength": "Pathogenic", "id": "643243227", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243227", "label": "PM5", "strengthDescriptor": "Supporting", "text": "If the pathogenicity of another missense change at the same amino acid residue is unknown, determine its pathogenicity using these specifications in order to determine if this criterion can be used. If the variant is pathogenic, use PM5. If the variant is likely pathogenic, use PM5\\_Supporting." }, { "baseStrength": "Pathogenic", "id": "643243220", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243220", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "643243220", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243220", "label": "PS2", "strengthDescriptor": "Strong", "text": "Not Applicable: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "643243220", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243220", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Not Applicable: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "643243220", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243220", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Not Applicable: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to non-maternity." }, { "baseStrength": "Benign", "id": "643243240", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243240", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Observed in cis with a pathogenic variant (to take AR inheritance into account)." }, { "baseStrength": "Benign", "id": "643243238", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243238", "label": "BS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Lack of segregation in a family. Caveat: The presence of phenocopies for common phenotypes." }, { "baseStrength": "Benign", "id": "643243238", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243238", "label": "BS4", "strengthDescriptor": "Strong", "text": "Not Applicable: Lack of segregation in a family. Caveat: The presence of phenocopies for common phenotypes." }, { "baseStrength": "Benign", "id": "643243238", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243238", "label": "BS4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Lack of segregation in a family. Caveat: The presence of phenocopies for common phenotypes." }, { "baseStrength": "Benign", "id": "643243238", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243238", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Lack of segregation in a family. Caveat: The presence of phenocopies for common phenotypes." }, { "baseStrength": "Pathogenic", "id": "643243228", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243228", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Assumed de novo but without confirmation of paternity and maternity.\nCCDS VCEP notes for PS2 and PM6: De novo variants have not been reported in patients with GAMT deficiency, to our knowledge. Furthermore, the observation that a variant in GAMT has arisen de novo does not support its causality because GAMT deficiency is an autosomal recessive disorder. The occurrence of de novo variants is more supportive in autosomal dominant and X-linked disorders. Any de novo variants in GAMT, should they be observed, will be assessed based on the variant type, functional evidence, and in trans data as described." }, { "baseStrength": "Pathogenic", "id": "643243228", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243228", "label": "PM6", "strengthDescriptor": "Strong", "text": "Not Applicable: Assumed de novo but without confirmation of paternity and maternity.\nCCDS VCEP notes for PS2 and PM6: De novo variants have not been reported in patients with GAMT deficiency, to our knowledge. Furthermore, the observation that a variant in GAMT has arisen de novo does not support its causality because GAMT deficiency is an autosomal recessive disorder. The occurrence of de novo variants is more supportive in autosomal dominant and X-linked disorders. Any de novo variants in GAMT, should they be observed, will be assessed based on the variant type, functional evidence, and in trans data as described." }, { "baseStrength": "Pathogenic", "id": "643243228", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243228", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Not Applicable: Assumed de novo but without confirmation of paternity and maternity.\nCCDS VCEP notes for PS2 and PM6: De novo variants have not been reported in patients with GAMT deficiency, to our knowledge. Furthermore, the observation that a variant in GAMT has arisen de novo does not support its causality because GAMT deficiency is an autosomal recessive disorder. The occurrence of de novo variants is more supportive in autosomal dominant and X-linked disorders. Any de novo variants in GAMT, should they be observed, will be assessed based on the variant type, functional evidence, and in trans data as described." }, { "baseStrength": "Pathogenic", "id": "643243228", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243228", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Not Applicable: Assumed de novo but without confirmation of paternity and maternity.\nCCDS VCEP notes for PS2 and PM6: De novo variants have not been reported in patients with GAMT deficiency, to our knowledge. Furthermore, the observation that a variant in GAMT has arisen de novo does not support its causality because GAMT deficiency is an autosomal recessive disorder. The occurrence of de novo variants is more supportive in autosomal dominant and X-linked disorders. Any de novo variants in GAMT, should they be observed, will be assessed based on the variant type, functional evidence, and in trans data as described." }, { "baseStrength": "Pathogenic", "id": "643243224", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243224", "label": "PM2", "strengthDescriptor": "Supporting", "text": "**Allele frequency \\<0.0004 (\\<0.04%) in all populations in gnomAD.**\n\nCCDS VCEP notes: It is acceptable for a GAMT variant to be present in controls, if heterozygous, because GAMT-D is a recessive disorder. Homozygotes should not be seen in a population database, such as gnomAD, because the penetrance of this condition in individuals with biallelic pathogenic variants is expected to be 100%.\n\nGAMT specifications:\n\n* All subpopulations in gnomAD must have a maximum allele frequency less than 0.0004 (the highest population minor allele frequency of the most common pathogenic GAMT variant, c.327G>A, in gnomAD). Any variant with a frequency below this cutoff will meet PM2\\_Supporting (See Appendix 3). Note – PM2 will NOT be used at moderate strength; PM2 will only be applied as a Supporting criterion.\n* If homozygotes are observed, the variant will meet BS2 (assuming 100% penetrance for an individual with 2 pathogenic variants in trans)." }, { "baseStrength": "Pathogenic", "id": "643243219", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243219", "label": "PS1", "strengthDescriptor": "Strong", "text": "This criterion is applicable as described.\n\nIf the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing." } ], "diseases": [ { "id": "MONDO:0012999", "iri": "https://genboree.org/cspec/Disease/id/467873663", "label": "guanidinoacetate methyltransferase deficiency" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467827323", "label": "GAMT" } ], "ruleSet": { "id": "643243103", "iri": "https://genboree.org/cspec/RuleSet/id/643243103" }, "svi": { "id": "GN026", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243096", "label": "ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GAMT Version 1.1.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "643243272", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243272", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243272", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243272", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243272", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243272", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243272", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243272", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "643243263", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243263", "label": "BS1", "strengthDescriptor": "Strong", "text": "Allele frequency > 0.0002 (0.02%) OR ≥ 5 hemizygotes in gnomAD" }, { "baseStrength": "Pathogenic", "id": "643243257", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243257", "label": "PP1", "strengthDescriptor": "Strong", "text": "* 3 affected segregations + 0 unaffected segregations OR\n* 2 affected segregations + 3 unaffected segregations" }, { "baseStrength": "Pathogenic", "id": "643243257", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243257", "label": "PP1", "strengthDescriptor": "Moderate", "text": "* 2 affected segregations + 0 unaffected segregations." }, { "baseStrength": "Pathogenic", "id": "643243257", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243257", "label": "PP1", "strengthDescriptor": "Supporting", "text": "* 1 affected family member + 3 unaffected segregations." }, { "baseStrength": "Pathogenic", "id": "643243255", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243255", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." }, { "baseStrength": "Pathogenic", "id": "643243255", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243255", "label": "PM5", "strengthDescriptor": "Supporting", "text": "Missense change at an amino acid residue where a different missense change determined to be likely pathogenic has been seen before." }, { "baseStrength": "Pathogenic", "id": "643243249", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243249", "label": "PS3", "strengthDescriptor": "Strong", "text": "**RT-PCR evidence of mis-splicing for non-canonical intronic variants.**\n\nFor non-canonical splicing variants, RT-PCR evidence demonstrating transcripts of alternative length or specific intron or exon inclusion/exclusion. These studies can be performed in patient derived cells, by placing the mutant genomic DNA into plasmid vectors, or by over-expressing mutant transcript. Assays should demonstrate defective splicing with RT-PCR analysis or RNA sequencing to confirm alternative transcripts." }, { "baseStrength": "Pathogenic", "id": "643243249", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243249", "label": "PS3", "strengthDescriptor": "Supporting", "text": "* Creatine transport activity <10% wild type with less than or equal to 125uM creatine used in SLC6A8 deficient fibroblasts\n* RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.\nFor non-canonical splicing variants, RT-PCR evidence demonstrating transcripts of alternative length or specific intron or exon inclusion/exclusion. These studies can be performed in patient derived cells, by placing the mutant genomic DNA into plasmid vectors, or by over-expressing mutant transcript. Assays should demonstrate defective splicing with RT-PCR analysis or RNA sequencing to confirm alternative transcripts." }, { "baseStrength": "Benign", "id": "643243270", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243270", "label": "BP4", "strengthDescriptor": "Supporting", "text": "* REVEL score <0.2 for missense variants\n* In frame deletion or insertion predicted benign by PROVEAN, MutPred indel, and MutationTaster.\n* No predicted impact on splicing by SpliceAI and varSEAK." }, { "baseStrength": "Pathogenic", "id": "643243260", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243260", "label": "PP4", "strengthDescriptor": "Strong", "text": "4 or more points based on combinations of the following. \n\n* Elevated urine creatine/creatinine ratio on one occasion (1 point)\n* Elevated urine creatine/creatinine ratio on more than one occasion (2 points)\n* Significantly decreased creatine peak, with absent guanidinoacetate peak, if reported (3 points)\n* Deficient creatine uptake in cultured fibroblasts (\\<10% of normal with \\<125uM creatine) (3 points)\n\nAdditional specifications:\n\n* Two or more data types are required for PP4\\_Strong.\n* An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.\n* Variant must meet PM2\\_Supporting for PP4 to apply at any strength.\n* For PP4 to be applied at strong, full SLC6A8 gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading." }, { "baseStrength": "Pathogenic", "id": "643243260", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243260", "label": "PP4", "strengthDescriptor": "Moderate", "text": "3 or more points based on: \n\n* Elevated urine creatine/creatinine ratio on one occasion (1 point)\n* Elevated urine creatine/creatinine ratio on more than one occasion (2 points)\n* Significantly decreased creatine peak, with absent guanidinoacetate peak, if reported (3 points)\n* Deficient creatine uptake in cultured fibroblasts (\\<10% of normal with \\<125uM creatine) (3 points)\n\nAdditional specifications:\n\n* Two or more data types are recommended for PP4\\_Moderate.\n* An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.\n* Variant must meet PM2\\_Supporting for PP4 to apply at any strength." }, { "baseStrength": "Pathogenic", "id": "643243260", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243260", "label": "PP4", "strengthDescriptor": "Supporting", "text": "1-2 or more points based on: \n\n* Elevated urine creatine/creatinine ratio on one occasion (1 point)\n* Elevated urine creatine/creatinine ratio on more than one occasion (2 points)\n\nAdditional specifications:\n\n* An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.\n* Variant must meet PM2\\_Supporting for PP4 to apply at any strength." }, { "baseStrength": "Pathogenic", "id": "643243259", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243259", "label": "PP3", "strengthDescriptor": "Supporting", "text": "* REVEL score >0.75 for missense variants\n* In frame deletion or insertion predicted deleterious by PROVEAN, MutPred indel, and MutationTaster.\n* Predicted impact on splicing by SpliceAI and varSEAK." }, { "baseStrength": "Pathogenic", "id": "643243254", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243254", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." }, { "baseStrength": "Pathogenic", "id": "643243247", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243247", "label": "PS1", "strengthDescriptor": "Strong", "text": "PS1 is applicable as described." }, { "baseStrength": "Benign", "id": "643243266", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243266", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected members of a family." }, { "baseStrength": "Benign", "id": "643243273", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243273", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved." }, { "baseStrength": "Benign", "id": "643243271", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243271", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease.\nBP5 applicable as described; the case must have specific features of creatine transporter deficiency, such as low creatine on brain magnetic resonance spectroscopy, or elevated urine creatine in order to apply this criterion. Presence of developmental delay and seizures is not sufficient." }, { "baseStrength": "Benign", "id": "643243269", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243269", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243269", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243269", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243269", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243269", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243269", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243269", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243267", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243267", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243267", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243267", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243267", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243267", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243267", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243267", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243265", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243265", "label": "BS3", "strengthDescriptor": "Supporting", "text": "* Creatine transport assay demonstrating ≥50% normal transport activity using physiological creatine concentrations (≤125μM creatine).\n* RT-PCR evidence demonstrating no observable effect of splicing.\n* Expression assay demonstrating wild type transcript levels" }, { "baseStrength": "Pathogenic", "id": "643243261", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243261", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243261", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243261", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243261", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243261", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243261", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243261", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "643243253", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243253", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: SLC6A8 is an X-linked gene, therefore PM3 is not applicable" }, { "baseStrength": "Pathogenic", "id": "643243253", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243253", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: SLC6A8 is an X-linked gene, therefore PM3 is not applicable" }, { "baseStrength": "Pathogenic", "id": "643243253", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243253", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: SLC6A8 is an X-linked gene, therefore PM3 is not applicable" }, { "baseStrength": "Pathogenic", "id": "643243253", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243253", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: SLC6A8 is an X-linked gene, therefore PM3 is not applicable" }, { "baseStrength": "Pathogenic", "id": "643243250", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243250", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "* 4 independent male probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4.\n* Variant must meet PM2_Supporting criterion for PS4 to apply." }, { "baseStrength": "Pathogenic", "id": "643243250", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243250", "label": "PS4", "strengthDescriptor": "Strong", "text": "* 3 independent male probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4.\n* Variant must meet PM2_Supporting criterion for PS4 to apply." }, { "baseStrength": "Pathogenic", "id": "643243250", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243250", "label": "PS4", "strengthDescriptor": "Moderate", "text": "* 2 independent male probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4.\n* Variant must meet PM2_Supporting criterion for PS4 to apply." }, { "baseStrength": "Pathogenic", "id": "643243250", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243250", "label": "PS4", "strengthDescriptor": "Supporting", "text": "* One independent male proband in addition to any proband used for PP4.\n* Variant must meet PM2\\_Supporting criterion for PS4 to apply." }, { "baseStrength": "Pathogenic", "id": "643243248", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243248", "label": "PS2", "strengthDescriptor": "Strong", "text": "Note: Confirmation of paternity in females only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.\n\nX-linked disorder. Only maternity needs to be confirmed." }, { "baseStrength": "Pathogenic", "id": "643243248", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243248", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Newly hemizygous male with the variant identified de novo in the mother with no family history of other affected males." }, { "baseStrength": "Benign", "id": "643243268", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243268", "label": "BP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243268", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243268", "label": "BP2", "strengthDescriptor": "Strong", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243268", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243268", "label": "BP2", "strengthDescriptor": "Moderate", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243268", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243268", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Not Applicable" }, { "baseStrength": "Benign", "id": "643243264", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243264", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in the homozygous state in a healthy adult" }, { "baseStrength": "Benign", "id": "643243262", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243262", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Allele frequency >0.0020 (0.2%) OR ≥10 hemizygotes in gnomAD" }, { "baseStrength": "Pathogenic", "id": "643243258", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243258", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable, gnomAD (01/2019) expected missense 243.5, observed missense 117, for Z=2.94 (o/e =0.48). No constraint against missense variation." }, { "baseStrength": "Pathogenic", "id": "643243258", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243258", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable, gnomAD (01/2019) expected missense 243.5, observed missense 117, for Z=2.94 (o/e =0.48). No constraint against missense variation." }, { "baseStrength": "Pathogenic", "id": "643243258", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243258", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable, gnomAD (01/2019) expected missense 243.5, observed missense 117, for Z=2.94 (o/e =0.48). No constraint against missense variation." }, { "baseStrength": "Pathogenic", "id": "643243258", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243258", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable, gnomAD (01/2019) expected missense 243.5, observed missense 117, for Z=2.94 (o/e =0.48). No constraint against missense variation." }, { "baseStrength": "Pathogenic", "id": "643243256", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243256", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Variant identified as de novo in an affected male with the mother negative for the variant but maternity not confirmed." }, { "baseStrength": "Pathogenic", "id": "643243252", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243252", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Absent/rare from controls in an ethnically-matched cohort population sample. Threshold: \\<0.00002 (0.002%) AND 0 hemizygotes in gnomAD." }, { "baseStrength": "Pathogenic", "id": "643243251", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243251", "label": "PM1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Pathogenic", "id": "643243251", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243251", "label": "PM1", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Pathogenic", "id": "643243251", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243251", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Pathogenic", "id": "643243251", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243251", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable" }, { "baseStrength": "Pathogenic", "id": "643243246", "iri": "https://genboree.org/cspec/CriteriaCode/id/643243246", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "* Loss of function is a known mechanism of disease for Creatine Transporter Deficiency.\n* Specifications are based on the decision tree as outlined in Tayoun etal, 2018 (Hum Mutat. 2018 Nov;39(11):1517-1524; PMID: 30192042) SLC6A8: PVS1, at appropriate strength, is applicable as described in Abou Tayoun et al, 2018 (PMID: 30192042)" } ], "diseases": [ { "id": "MONDO:0010305", "iri": "https://genboree.org/cspec/Disease/id/467873958", "label": "creatine transporter deficiency" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467856291", "label": "SLC6A8" } ], "ruleSet": { "id": "643243104", "iri": "https://genboree.org/cspec/RuleSet/id/643243104" }, "svi": { "id": "GN027", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243097", "label": "ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC6A8 Version 1.1.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1572176862", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176862", "label": "BP5", "strengthDescriptor": "Strong", "text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease." }, { "baseStrength": "Benign", "id": "1572176862", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176862", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease." }, { "baseStrength": "Pathogenic", "id": "1572176855", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176855", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." }, { "baseStrength": "Benign", "id": "1572176850", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176850", "label": "BS1", "strengthDescriptor": "Strong", "text": "Allele frequency greater than expected for disease.\n\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and \\<0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles." }, { "baseStrength": "Pathogenic", "id": "1572176846", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176846", "label": "PS4", "strengthDescriptor": "Strong", "text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations." }, { "baseStrength": "Pathogenic", "id": "1572176846", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176846", "label": "PS4", "strengthDescriptor": "Moderate", "text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations." }, { "baseStrength": "Pathogenic", "id": "1572176846", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176846", "label": "PS4", "strengthDescriptor": "Supporting", "text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence." }, { "baseStrength": "Benign", "id": "1572176840", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176840", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 2 unaffected (related or unrelated) heterozygotes" }, { "baseStrength": "Benign", "id": "1572176840", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176840", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 1 unaffected (related or unrelated) heterozygote" }, { "baseStrength": "Pathogenic", "id": "1572176861", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176861", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable up to p.E643 which corresponds to the distal most de novo truncating variant in an affected patient reported to date.[1](#PMID_29695756)\n* PVS1 can be applied for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-of-frame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 15)." }, { "baseStrength": "Pathogenic", "id": "1572176861", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176861", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Moderate is applicable for any truncating variant distal of p.E643 and for single exon deletions that involve just non-coding exon 20." }, { "baseStrength": "Pathogenic", "id": "1572176861", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176861", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Supporting is applicable for initiation codon variants in _TCF4._" }, { "baseStrength": "Benign", "id": "1572176848", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176848", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Allele frequency above 0.05%.\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles." }, { "baseStrength": "Pathogenic", "id": "1572176845", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176845", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.\n\n* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site)." }, { "baseStrength": "Pathogenic", "id": "1572176844", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176844", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for TCF4." }, { "baseStrength": "Pathogenic", "id": "1572176844", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176844", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for TCF4." }, { "baseStrength": "Pathogenic", "id": "1572176844", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176844", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for TCF4." }, { "baseStrength": "Pathogenic", "id": "1572176844", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176844", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for TCF4." }, { "baseStrength": "Pathogenic", "id": "1572176842", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176842", "label": "PM5", "strengthDescriptor": "Strong", "text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations." }, { "baseStrength": "Pathogenic", "id": "1572176842", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176842", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant." }, { "baseStrength": "Pathogenic", "id": "1572176864", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176864", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1572176864", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176864", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1572176864", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176864", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1572176864", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176864", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1572176859", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176859", "label": "BP4", "strengthDescriptor": "Supporting", "text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site)." }, { "baseStrength": "Pathogenic", "id": "1572176847", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176847", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.\n* Evidence from literature must be fully evaluated to support independent events." }, { "baseStrength": "Pathogenic", "id": "1572176847", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176847", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history." }, { "baseStrength": "Pathogenic", "id": "1572176839", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176839", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines." }, { "baseStrength": "Pathogenic", "id": "1572176838", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176838", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases." }, { "baseStrength": "Benign", "id": "1572176865", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176865", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species." }, { "baseStrength": "Benign", "id": "1572176863", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176863", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1572176863", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176863", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1572176863", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176863", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1572176863", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176863", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1572176854", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176854", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* ≥4 independent occurrences of PM6." }, { "baseStrength": "Pathogenic", "id": "1572176854", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176854", "label": "PM6", "strengthDescriptor": "Strong", "text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* ≥2 independent occurrences of PM6." }, { "baseStrength": "Pathogenic", "id": "1572176854", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176854", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Confirmed de novo without confirmation of paternity and maternity." }, { "baseStrength": "Benign", "id": "1572176852", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176852", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for TCF4." }, { "baseStrength": "Benign", "id": "1572176852", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176852", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for TCF4." }, { "baseStrength": "Benign", "id": "1572176852", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176852", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for TCF4." }, { "baseStrength": "Benign", "id": "1572176852", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176852", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for TCF4." }, { "baseStrength": "Pathogenic", "id": "1572176860", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176860", "label": "PP1", "strengthDescriptor": "Strong", "text": "Co-segregation with disease in multiple affected family members.\n\n* ≥5 informative meiosis" }, { "baseStrength": "Pathogenic", "id": "1572176860", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176860", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Co-segregation with disease in multiple affected family members.\n\n* 3-4 informative meiosis" }, { "baseStrength": "Pathogenic", "id": "1572176860", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176860", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Co-segregation with disease in multiple affected family members.\n\n* 2 informative meiosis" }, { "baseStrength": "Pathogenic", "id": "1572176858", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176858", "label": "PS3", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an out-offrame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used." }, { "baseStrength": "Pathogenic", "id": "1572176858", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176858", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See included table for acceptable functional studies." }, { "baseStrength": "Benign", "id": "1572176857", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176857", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for TCF4." }, { "baseStrength": "Benign", "id": "1572176857", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176857", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for TCF4." }, { "baseStrength": "Benign", "id": "1572176857", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176857", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for TCF4." }, { "baseStrength": "Benign", "id": "1572176857", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176857", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for TCF4." }, { "baseStrength": "Benign", "id": "1572176856", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176856", "label": "BP2", "strengthDescriptor": "Supporting", "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* Applicable for _TCF4_ for _in trans_ state" }, { "baseStrength": "Benign", "id": "1572176853", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176853", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member, when seen in two or more families\n* Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum." }, { "baseStrength": "Benign", "id": "1572176853", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176853", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member" }, { "baseStrength": "Pathogenic", "id": "1572176851", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176851", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." }, { "baseStrength": "Pathogenic", "id": "1572176851", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176851", "label": "PM4", "strengthDescriptor": "Supporting", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene)." }, { "baseStrength": "Pathogenic", "id": "1572176849", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176849", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for TCF4." }, { "baseStrength": "Pathogenic", "id": "1572176849", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176849", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for TCF4." }, { "baseStrength": "Pathogenic", "id": "1572176849", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176849", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for TCF4." }, { "baseStrength": "Pathogenic", "id": "1572176849", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176849", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for TCF4." }, { "baseStrength": "Pathogenic", "id": "1572176843", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176843", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n\n* Basic Helix-Loop-Helix domain (bHLH): aa 564-617[3](#PMID_17436254),[2](#PMID_22045651)" }, { "baseStrength": "Benign", "id": "1572176841", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572176841", "label": "BS3", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies)." } ], "diseases": [ { "id": "MONDO:0012589", "iri": "https://genboree.org/cspec/Disease/id/135642214", "label": "Pitt-Hopkins syndrome" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641942", "label": "TCF4" } ], "ruleSet": { "id": "643243109", "iri": "https://genboree.org/cspec/RuleSet/id/643243109" }, "svi": { "id": "GN032", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243102", "label": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TCF4 Version 3.0.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1572178244", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178244", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species." }, { "baseStrength": "Benign", "id": "1572178235", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178235", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n\n* BP2 is not applicable for SLC9A6 for _in trans_ state." }, { "baseStrength": "Pathogenic", "id": "1572178234", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178234", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." }, { "baseStrength": "Benign", "id": "1572178231", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178231", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for SLC9A6." }, { "baseStrength": "Benign", "id": "1572178231", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178231", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for SLC9A6." }, { "baseStrength": "Benign", "id": "1572178231", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178231", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for SLC9A6." }, { "baseStrength": "Benign", "id": "1572178231", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178231", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for SLC9A6." }, { "baseStrength": "Pathogenic", "id": "1572178239", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178239", "label": "PP1", "strengthDescriptor": "Strong", "text": "Co-segregation with disease in multiple affected family members.\n\n* ≥5 informative meiosis" }, { "baseStrength": "Pathogenic", "id": "1572178239", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178239", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Co-segregation with disease in multiple affected family members.\n\n* 3-4 informative meiosis" }, { "baseStrength": "Pathogenic", "id": "1572178239", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178239", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Co-segregation with disease in multiple affected family members.\n\n* 2 informative meiosis" }, { "baseStrength": "Benign", "id": "1572178238", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178238", "label": "BP4", "strengthDescriptor": "Supporting", "text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site)." }, { "baseStrength": "Benign", "id": "1572178236", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178236", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for SLC9A6." }, { "baseStrength": "Benign", "id": "1572178236", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178236", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for SLC9A6." }, { "baseStrength": "Benign", "id": "1572178236", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178236", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for SLC9A6." }, { "baseStrength": "Benign", "id": "1572178236", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178236", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for SLC9A6." }, { "baseStrength": "Benign", "id": "1572178232", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178232", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member, when seen in two or more families" }, { "baseStrength": "Benign", "id": "1572178232", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178232", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member" }, { "baseStrength": "Pathogenic", "id": "1572178228", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178228", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for SLC9A6." }, { "baseStrength": "Pathogenic", "id": "1572178228", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178228", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for SLC9A6." }, { "baseStrength": "Pathogenic", "id": "1572178228", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178228", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for SLC9A6." }, { "baseStrength": "Pathogenic", "id": "1572178228", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178228", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for SLC9A6." }, { "baseStrength": "Pathogenic", "id": "1572178225", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178225", "label": "PS4", "strengthDescriptor": "Strong", "text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations." }, { "baseStrength": "Pathogenic", "id": "1572178225", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178225", "label": "PS4", "strengthDescriptor": "Moderate", "text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations." }, { "baseStrength": "Pathogenic", "id": "1572178225", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178225", "label": "PS4", "strengthDescriptor": "Supporting", "text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence." }, { "baseStrength": "Pathogenic", "id": "1572178222", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178222", "label": "PM1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for SLC9A6." }, { "baseStrength": "Pathogenic", "id": "1572178222", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178222", "label": "PM1", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for SLC9A6." }, { "baseStrength": "Pathogenic", "id": "1572178222", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178222", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for SLC9A6." }, { "baseStrength": "Pathogenic", "id": "1572178222", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178222", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for SLC9A6." }, { "baseStrength": "Pathogenic", "id": "1572178233", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178233", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events." }, { "baseStrength": "Pathogenic", "id": "1572178233", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178233", "label": "PM6", "strengthDescriptor": "Strong", "text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events." }, { "baseStrength": "Pathogenic", "id": "1572178233", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178233", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* 1 occurrence of PM6" }, { "baseStrength": "Pathogenic", "id": "1572178230", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178230", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." }, { "baseStrength": "Pathogenic", "id": "1572178230", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178230", "label": "PM4", "strengthDescriptor": "Supporting", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n\n* Smaller in-frame events (\\< 3 amino acid residues)." }, { "baseStrength": "Benign", "id": "1572178229", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178229", "label": "BS1", "strengthDescriptor": "Strong", "text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and \\<0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles." }, { "baseStrength": "Benign", "id": "1572178227", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178227", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles." }, { "baseStrength": "Pathogenic", "id": "1572178221", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178221", "label": "PM5", "strengthDescriptor": "Strong", "text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations." }, { "baseStrength": "Pathogenic", "id": "1572178221", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178221", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant." }, { "baseStrength": "Pathogenic", "id": "1572178217", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178217", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases." }, { "baseStrength": "Benign", "id": "1572178242", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178242", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1572178242", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178242", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1572178242", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178242", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1572178242", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178242", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1572178240", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178240", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable up to p.A563, for canonical splice site variants predicted to result in an out-of-frame product, for canonical splice site variants or single exon in-frame deletion predicted to preserve the reading frame (exon 10), and multiple in-frame exon deletions that include exon 10." }, { "baseStrength": "Pathogenic", "id": "1572178240", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178240", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Strong is applicable for any truncating variant from p.C564 to p.T601 and for canonical splice site variants that flank exon 3 (in-frame exon).[2](#PMID_27256868),[3](#PMID_19377476),[1](#PMID_18342287)" }, { "baseStrength": "Pathogenic", "id": "1572178240", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178240", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Moderate is applicable for any truncating variant between p.Y602 to p.A669 and any frameshift variant that results in a read-through of the stop codon." }, { "baseStrength": "Pathogenic", "id": "1572178240", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178240", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Supporting is applicable for initiation codon variants in _SLC9A6_" }, { "baseStrength": "Pathogenic", "id": "1572178223", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178223", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for SLC9A6." }, { "baseStrength": "Pathogenic", "id": "1572178223", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178223", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for SLC9A6." }, { "baseStrength": "Pathogenic", "id": "1572178223", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178223", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for SLC9A6." }, { "baseStrength": "Pathogenic", "id": "1572178223", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178223", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for SLC9A6." }, { "baseStrength": "Benign", "id": "1572178220", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178220", "label": "BS3", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies)." }, { "baseStrength": "Pathogenic", "id": "1572178243", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178243", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1572178243", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178243", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1572178243", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178243", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1572178243", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178243", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1572178241", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178241", "label": "BP5", "strengthDescriptor": "Strong", "text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease." }, { "baseStrength": "Benign", "id": "1572178241", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178241", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease.\n\n* 1-2 cases with alternate molecular basis for disease" }, { "baseStrength": "Pathogenic", "id": "1572178237", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178237", "label": "PS3", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an out-of-frame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used." }, { "baseStrength": "Pathogenic", "id": "1572178237", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178237", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section)." }, { "baseStrength": "Pathogenic", "id": "1572178226", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178226", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.\n* Evidence from literature must be fully evaluated to support independent events." }, { "baseStrength": "Pathogenic", "id": "1572178226", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178226", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* 1 occurrence of PS2" }, { "baseStrength": "Pathogenic", "id": "1572178224", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178224", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.\n\n* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site)." }, { "baseStrength": "Benign", "id": "1572178219", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178219", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 2 unaffected (related or unrelated) hemizygotes" }, { "baseStrength": "Benign", "id": "1572178219", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178219", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 1 unaffected (related or unrelated) hemizygote" }, { "baseStrength": "Pathogenic", "id": "1572178218", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572178218", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines." } ], "diseases": [ { "id": "MONDO:0010278", "iri": "https://genboree.org/cspec/Disease/id/135642212", "label": "Christianson syndrome" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641940", "label": "SLC9A6" } ], "ruleSet": { "id": "643243110", "iri": "https://genboree.org/cspec/RuleSet/id/643243110" }, "svi": { "id": "GN033", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243103", "label": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC9A6 Version 3.0.0" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "1572179065", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179065", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1572179065", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179065", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1572179065", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179065", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1572179065", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179065", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1572179060", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179060", "label": "BP4", "strengthDescriptor": "Supporting", "text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site)." }, { "baseStrength": "Benign", "id": "1572179057", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179057", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n\n* BP2 is not applicable for _in trans_ state." }, { "baseStrength": "Pathogenic", "id": "1572179052", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179052", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n\n* Do not use for in-frame deletions/insertions in CDKL5 C-terminus (exons 19-21, or after p.904) (when using the NM\\_003159.2 transcript)." }, { "baseStrength": "Pathogenic", "id": "1572179052", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179052", "label": "PM4", "strengthDescriptor": "Supporting", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene)." }, { "baseStrength": "Benign", "id": "1572179051", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179051", "label": "BS1", "strengthDescriptor": "Strong", "text": "Allele frequency greater than expected for disease (0.025%).\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles." }, { "baseStrength": "Benign", "id": "1572179042", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179042", "label": "BS3", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies)." }, { "baseStrength": "Benign", "id": "1572179063", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179063", "label": "BP5", "strengthDescriptor": "Strong", "text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease." }, { "baseStrength": "Benign", "id": "1572179063", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179063", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease." }, { "baseStrength": "Pathogenic", "id": "1572179062", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179062", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable up to p.R948 **when using the major brain isoform which has an alternative C-terminus (NM\\_001323289.2)**, for canonical splice site variants predicted to result in an out-of-frame product, for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exons 7, 10, 13), and for the non-coding CDKL5 exon (exon 1)." }, { "baseStrength": "Pathogenic", "id": "1572179062", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179062", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Moderate is applicable for any truncating variant distal of p.R948.(**when using the major brain isoform, NM\\_001323289.2**) and for canonical splice site variants that flank exon 17 (in-frame exon)." }, { "baseStrength": "Pathogenic", "id": "1572179062", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179062", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Supporting is applicable for initiation codon variants in _CDKL5._" }, { "baseStrength": "Pathogenic", "id": "1572179059", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179059", "label": "PS3", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an out-offrame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used." }, { "baseStrength": "Pathogenic", "id": "1572179059", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179059", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See included table for acceptable functional studies." }, { "baseStrength": "Pathogenic", "id": "1572179055", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179055", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events." }, { "baseStrength": "Pathogenic", "id": "1572179055", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179055", "label": "PM6", "strengthDescriptor": "Strong", "text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events." }, { "baseStrength": "Pathogenic", "id": "1572179055", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179055", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* 1 occurrence of PM6." }, { "baseStrength": "Pathogenic", "id": "1572179050", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179050", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for CDKL5." }, { "baseStrength": "Pathogenic", "id": "1572179050", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179050", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for CDKL5." }, { "baseStrength": "Pathogenic", "id": "1572179050", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179050", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for CDKL5." }, { "baseStrength": "Pathogenic", "id": "1572179050", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179050", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for CDKL5." }, { "baseStrength": "Pathogenic", "id": "1572179048", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179048", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2." }, { "baseStrength": "Pathogenic", "id": "1572179048", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179048", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\\\\\n\n* 1 occurrence of PS2." }, { "baseStrength": "Pathogenic", "id": "1572179046", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179046", "label": "PP3", "strengthDescriptor": "Supporting", "text": "* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site)." }, { "baseStrength": "Pathogenic", "id": "1572179061", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179061", "label": "PP1", "strengthDescriptor": "Strong", "text": "Co-segregation with disease in multiple affected family members.\n\n* ≥5 informative meiosis" }, { "baseStrength": "Pathogenic", "id": "1572179061", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179061", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Co-segregation with disease in multiple affected family members.\n\n* 3-4 informative meiosis" }, { "baseStrength": "Pathogenic", "id": "1572179061", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179061", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Co-segregation with disease in multiple affected family members.\n\n* 2 informative meiosis" }, { "baseStrength": "Benign", "id": "1572179054", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179054", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member, when seen in two or more families" }, { "baseStrength": "Benign", "id": "1572179054", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179054", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member" }, { "baseStrength": "Pathogenic", "id": "1572179047", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179047", "label": "PS4", "strengthDescriptor": "Strong", "text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations." }, { "baseStrength": "Pathogenic", "id": "1572179047", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179047", "label": "PS4", "strengthDescriptor": "Moderate", "text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations." }, { "baseStrength": "Pathogenic", "id": "1572179047", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179047", "label": "PS4", "strengthDescriptor": "Supporting", "text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence." }, { "baseStrength": "Pathogenic", "id": "1572179045", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179045", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for CDKL5." }, { "baseStrength": "Pathogenic", "id": "1572179045", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179045", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for CDKL5." }, { "baseStrength": "Pathogenic", "id": "1572179045", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179045", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for CDKL5." }, { "baseStrength": "Pathogenic", "id": "1572179045", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179045", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for CDKL5." }, { "baseStrength": "Pathogenic", "id": "1572179044", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179044", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n\n* ATP binding region: aa 19-43; TEY phosphorylation site: aa 169-171[1](#PMID_28544139),[4](#PMID_17993579),[2](#PMID_23064044),[3](#PMID_29264392)" }, { "baseStrength": "Benign", "id": "1572179064", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179064", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1572179064", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179064", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1572179064", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179064", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1572179064", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179064", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1572179058", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179058", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for CDKL5." }, { "baseStrength": "Benign", "id": "1572179058", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179058", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for CDKL5." }, { "baseStrength": "Benign", "id": "1572179058", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179058", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for CDKL5." }, { "baseStrength": "Benign", "id": "1572179058", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179058", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for CDKL5." }, { "baseStrength": "Pathogenic", "id": "1572179056", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179056", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." }, { "baseStrength": "Benign", "id": "1572179053", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179053", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for CDKL5." }, { "baseStrength": "Benign", "id": "1572179053", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179053", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for CDKL5." }, { "baseStrength": "Benign", "id": "1572179053", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179053", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for CDKL5." }, { "baseStrength": "Benign", "id": "1572179053", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179053", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for CDKL5." }, { "baseStrength": "Pathogenic", "id": "1572179043", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179043", "label": "PM5", "strengthDescriptor": "Strong", "text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations." }, { "baseStrength": "Pathogenic", "id": "1572179043", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179043", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* Applicable to all genes as written.\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant." }, { "baseStrength": "Pathogenic", "id": "1572179040", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179040", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines." }, { "baseStrength": "Benign", "id": "1572179066", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179066", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species." }, { "baseStrength": "Benign", "id": "1572179049", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179049", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Allele frequency above 0.05%.\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles." }, { "baseStrength": "Benign", "id": "1572179041", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179041", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 2 unaffected (related or unrelated) heterozygotes or hemizygotes" }, { "baseStrength": "Benign", "id": "1572179041", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179041", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 1 unaffected (related or unrelated) heterozygote or hemizygote" }, { "baseStrength": "Pathogenic", "id": "1572179039", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179039", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases." } ], "diseases": [ { "id": "MONDO:0100039", "iri": "https://genboree.org/cspec/Disease/id/135642215", "label": "CDKL5 disorder" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641943", "label": "CDKL5" } ], "ruleSet": { "id": "643243111", "iri": "https://genboree.org/cspec/RuleSet/id/643243111" }, "svi": { "id": "GN034", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243104", "label": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDKL5 Version 3.0.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1572179857", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179857", "label": "BP5", "strengthDescriptor": "Strong", "text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease." }, { "baseStrength": "Benign", "id": "1572179857", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179857", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease.\n\n* 1-2 cases with alternate molecular basis for disease." }, { "baseStrength": "Pathogenic", "id": "1572179856", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179856", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable up to p.S468[1](#PMID_30525188)" }, { "baseStrength": "Pathogenic", "id": "1572179856", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179856", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Strong is applicable for any truncating variant from p.G469 to p.Q480[6](#PMID_29655203)." }, { "baseStrength": "Pathogenic", "id": "1572179856", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179856", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Moderate is applicable for any truncating variant distal of p.Q480." }, { "baseStrength": "Pathogenic", "id": "1572179856", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179856", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Supporting is applicable for initiation codon variants in _FOXG1._" }, { "baseStrength": "Benign", "id": "1572179854", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179854", "label": "BP4", "strengthDescriptor": "Supporting", "text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site)." }, { "baseStrength": "Benign", "id": "1572179848", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179848", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member, when seen in two or more families" }, { "baseStrength": "Benign", "id": "1572179848", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179848", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member" }, { "baseStrength": "Pathogenic", "id": "1572179841", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179841", "label": "PS4", "strengthDescriptor": "Strong", "text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations." }, { "baseStrength": "Pathogenic", "id": "1572179841", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179841", "label": "PS4", "strengthDescriptor": "Moderate", "text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations." }, { "baseStrength": "Pathogenic", "id": "1572179841", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179841", "label": "PS4", "strengthDescriptor": "Supporting", "text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence." }, { "baseStrength": "Pathogenic", "id": "1572179837", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179837", "label": "PM5", "strengthDescriptor": "Strong", "text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations." }, { "baseStrength": "Pathogenic", "id": "1572179837", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179837", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant." }, { "baseStrength": "Benign", "id": "1572179836", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179836", "label": "BS3", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies)." }, { "baseStrength": "Pathogenic", "id": "1572179849", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179849", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events." }, { "baseStrength": "Pathogenic", "id": "1572179849", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179849", "label": "PM6", "strengthDescriptor": "Strong", "text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events." }, { "baseStrength": "Pathogenic", "id": "1572179849", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179849", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* 1 occurrence of PM6." }, { "baseStrength": "Benign", "id": "1572179847", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179847", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for FOXG1." }, { "baseStrength": "Benign", "id": "1572179847", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179847", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for FOXG1." }, { "baseStrength": "Benign", "id": "1572179847", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179847", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for FOXG1." }, { "baseStrength": "Benign", "id": "1572179847", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179847", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for FOXG1." }, { "baseStrength": "Benign", "id": "1572179845", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179845", "label": "BS1", "strengthDescriptor": "Strong", "text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and \\<0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles." }, { "baseStrength": "Benign", "id": "1572179843", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179843", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles." }, { "baseStrength": "Pathogenic", "id": "1572179840", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179840", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.\n\n* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site)." }, { "baseStrength": "Pathogenic", "id": "1572179838", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179838", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n\n* Forkhead: aa 181-275[7](#PMID_18571142),[8](#PMID_28661489)" }, { "baseStrength": "Benign", "id": "1572179851", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179851", "label": "BP2", "strengthDescriptor": "Supporting", "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* Applicable for _in trans_ state" }, { "baseStrength": "Pathogenic", "id": "1572179833", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179833", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases." }, { "baseStrength": "Benign", "id": "1572179858", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179858", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1572179858", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179858", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1572179858", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179858", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1572179858", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179858", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1572179855", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179855", "label": "PP1", "strengthDescriptor": "Strong", "text": "Co-segregation with disease in multiple affected family members.\n\n* ≥5 informative meiosis" }, { "baseStrength": "Pathogenic", "id": "1572179855", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179855", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Co-segregation with disease in multiple affected family members.\n\n* 3-4 informative meiosis" }, { "baseStrength": "Pathogenic", "id": "1572179855", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179855", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Co-segregation with disease in multiple affected family members.\n\n* 2 informative meiosis" }, { "baseStrength": "Pathogenic", "id": "1572179853", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179853", "label": "PS3", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an out-of-frame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used." }, { "baseStrength": "Pathogenic", "id": "1572179853", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179853", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See included table for acceptable functional studies." }, { "baseStrength": "Benign", "id": "1572179852", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179852", "label": "BP3", "strengthDescriptor": "Supporting", "text": "In-frame deletions/insertions in a repetitive region without a known function\n\n* Inframe expansions or deletions in _FOXG1_ repetitive regions: poly His (p.His47-p.His57), poly Gln (p.Gln70-p.Gln73) and poly Pro (p.Pro58-p.Pro61; p.Pro65-p.Pro69; p.Pro74-p.Pro80)" }, { "baseStrength": "Pathogenic", "id": "1572179842", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179842", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.\n* Evidence from literature must be fully evaluated to support independent events." }, { "baseStrength": "Pathogenic", "id": "1572179842", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179842", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* 1 occurrence of PS2." }, { "baseStrength": "Benign", "id": "1572179860", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179860", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species." }, { "baseStrength": "Pathogenic", "id": "1572179859", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179859", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1572179859", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179859", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1572179859", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179859", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1572179859", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179859", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1572179850", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179850", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." }, { "baseStrength": "Pathogenic", "id": "1572179846", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179846", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n\n* Do not use PM4 for in-frame deletions/insertions in the Histidine-rich region (p.37-p.57), Proline- and Glutamine-rich region (p.58-p.86) and Proline-rich region (p.105-p.112)." }, { "baseStrength": "Pathogenic", "id": "1572179846", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179846", "label": "PM4", "strengthDescriptor": "Supporting", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene)." }, { "baseStrength": "Pathogenic", "id": "1572179844", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179844", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for FOXG1." }, { "baseStrength": "Pathogenic", "id": "1572179844", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179844", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for FOXG1." }, { "baseStrength": "Pathogenic", "id": "1572179844", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179844", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for FOXG1." }, { "baseStrength": "Pathogenic", "id": "1572179844", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179844", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for FOXG1." }, { "baseStrength": "Pathogenic", "id": "1572179839", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179839", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for FOXG1." }, { "baseStrength": "Pathogenic", "id": "1572179839", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179839", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for FOXG1." }, { "baseStrength": "Pathogenic", "id": "1572179839", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179839", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for FOXG1." }, { "baseStrength": "Pathogenic", "id": "1572179839", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179839", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for FOXG1." }, { "baseStrength": "Benign", "id": "1572179835", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179835", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 2 unaffected (related or unrelated) heterozygotes." }, { "baseStrength": "Benign", "id": "1572179835", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179835", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 1 unaffected (related or unrelated) heterozygote" }, { "baseStrength": "Pathogenic", "id": "1572179834", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572179834", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines." } ], "diseases": [ { "id": "MONDO:0100040", "iri": "https://genboree.org/cspec/Disease/id/135642211", "label": "FOXG1 disorder" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641939", "label": "FOXG1" } ], "ruleSet": { "id": "643243112", "iri": "https://genboree.org/cspec/RuleSet/id/643243112" }, "svi": { "id": "GN035", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243105", "label": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for FOXG1 Version 3.0.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1572180617", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180617", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species." }, { "baseStrength": "Benign", "id": "1572180614", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180614", "label": "BP5", "strengthDescriptor": "Strong", "text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease." }, { "baseStrength": "Benign", "id": "1572180614", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180614", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease." }, { "baseStrength": "Benign", "id": "1572180602", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180602", "label": "BS1", "strengthDescriptor": "Strong", "text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and \\<0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles." }, { "baseStrength": "Benign", "id": "1572180600", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180600", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles." }, { "baseStrength": "Benign", "id": "1572180593", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180593", "label": "BS3", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies)." }, { "baseStrength": "Pathogenic", "id": "1572180612", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180612", "label": "PP1", "strengthDescriptor": "Strong", "text": "Co-segregation with disease in multiple affected family members.\n\n* ≥5 informative meiosis" }, { "baseStrength": "Pathogenic", "id": "1572180612", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180612", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Co-segregation with disease in multiple affected family members.\n\n* 3-4 informative meiosis" }, { "baseStrength": "Pathogenic", "id": "1572180612", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180612", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Co-segregation with disease in multiple affected family members.\n\n* 2 informative meiosis" }, { "baseStrength": "Pathogenic", "id": "1572180610", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180610", "label": "PS3", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an out-offrame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used." }, { "baseStrength": "Pathogenic", "id": "1572180610", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180610", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See included table for approved functional studies." }, { "baseStrength": "Benign", "id": "1572180604", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180604", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for MECP2." }, { "baseStrength": "Benign", "id": "1572180604", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180604", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for MECP2." }, { "baseStrength": "Benign", "id": "1572180604", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180604", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for MECP2." }, { "baseStrength": "Benign", "id": "1572180604", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180604", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for MECP2." }, { "baseStrength": "Pathogenic", "id": "1572180599", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180599", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2." }, { "baseStrength": "Pathogenic", "id": "1572180599", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180599", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* 1 occurrence of PS2." }, { "baseStrength": "Pathogenic", "id": "1572180598", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180598", "label": "PS4", "strengthDescriptor": "Strong", "text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations." }, { "baseStrength": "Pathogenic", "id": "1572180598", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180598", "label": "PS4", "strengthDescriptor": "Moderate", "text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations." }, { "baseStrength": "Pathogenic", "id": "1572180598", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180598", "label": "PS4", "strengthDescriptor": "Supporting", "text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence." }, { "baseStrength": "Pathogenic", "id": "1572180594", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180594", "label": "PM5", "strengthDescriptor": "Strong", "text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations." }, { "baseStrength": "Pathogenic", "id": "1572180594", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180594", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant." }, { "baseStrength": "Pathogenic", "id": "1572180590", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180590", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases." }, { "baseStrength": "Benign", "id": "1572180611", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180611", "label": "BP4", "strengthDescriptor": "Supporting", "text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site)." }, { "baseStrength": "Benign", "id": "1572180608", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180608", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder." }, { "baseStrength": "Pathogenic", "id": "1572180603", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180603", "label": "PM4", "strengthDescriptor": "Strong", "text": "Protein length changes due to stop-loss variants.\n\n* PM4\\_Strong is applicable to stop-loss variants in _MECP2_, as several stop loss variants in this gene has been described in affected individuals.[2](#PMID_11469283)" }, { "baseStrength": "Pathogenic", "id": "1572180603", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180603", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n\n* Do not use PM4 for in-frame deletions/insertions in the Proline-rich region of gene (p.381-p.405)" }, { "baseStrength": "Pathogenic", "id": "1572180603", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180603", "label": "PM4", "strengthDescriptor": "Supporting", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene)." }, { "baseStrength": "Pathogenic", "id": "1572180595", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180595", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n\n* Methyl-DNA binding (MBD): aa 90-162\n* Transcirptional repression domain (TRD): aa 302-306" }, { "baseStrength": "Benign", "id": "1572180609", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180609", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for MECP2." }, { "baseStrength": "Benign", "id": "1572180609", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180609", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for MECP2." }, { "baseStrength": "Benign", "id": "1572180609", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180609", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for MECP2." }, { "baseStrength": "Benign", "id": "1572180609", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180609", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for MECP2." }, { "baseStrength": "Pathogenic", "id": "1572180607", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180607", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." }, { "baseStrength": "Benign", "id": "1572180605", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180605", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member, when seen in two or more families" }, { "baseStrength": "Benign", "id": "1572180605", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180605", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member" }, { "baseStrength": "Benign", "id": "1572180592", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180592", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 2 unaffected (related or unrelated) heterozygotes or hemizygotes." }, { "baseStrength": "Benign", "id": "1572180592", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180592", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 1 unaffected (related or unrelated) heterozygote or hemizygote" }, { "baseStrength": "Pathogenic", "id": "1572180591", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180591", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines." }, { "baseStrength": "Pathogenic", "id": "1572180616", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180616", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1572180616", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180616", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1572180616", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180616", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1572180616", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180616", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1572180615", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180615", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1572180615", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180615", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1572180615", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180615", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1572180615", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180615", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1572180613", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180613", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable up to p.E472, for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-offrame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 3). PVS1 is not applicable for initiation codons" }, { "baseStrength": "Pathogenic", "id": "1572180613", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180613", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Moderate is applicable for any truncating variant distal of p.E472." }, { "baseStrength": "Pathogenic", "id": "1572180606", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180606", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* ≥4 independent occurrences of PM6. \n* Evidence from literature must be fully evaluated to support independent events." }, { "baseStrength": "Pathogenic", "id": "1572180606", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180606", "label": "PM6", "strengthDescriptor": "Strong", "text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events." }, { "baseStrength": "Pathogenic", "id": "1572180606", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180606", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* 1 occurrence of PM6." }, { "baseStrength": "Pathogenic", "id": "1572180601", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180601", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for MECP2." }, { "baseStrength": "Pathogenic", "id": "1572180601", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180601", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for MECP2." }, { "baseStrength": "Pathogenic", "id": "1572180601", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180601", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for MECP2." }, { "baseStrength": "Pathogenic", "id": "1572180601", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180601", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for MECP2." }, { "baseStrength": "Pathogenic", "id": "1572180597", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180597", "label": "PP3", "strengthDescriptor": "Supporting", "text": "* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site)." }, { "baseStrength": "Pathogenic", "id": "1572180596", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180596", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for MECP2." }, { "baseStrength": "Pathogenic", "id": "1572180596", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180596", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for MECP2." }, { "baseStrength": "Pathogenic", "id": "1572180596", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180596", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for MECP2." }, { "baseStrength": "Pathogenic", "id": "1572180596", "iri": "https://genboree.org/cspec/CriteriaCode/id/1572180596", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for MECP2." } ], "diseases": [ { "id": "MONDO:0010726", "iri": "https://genboree.org/cspec/Disease/id/135642210", "label": "Rett syndrome" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641938", "label": "MECP2" } ], "ruleSet": { "id": "643243113", "iri": "https://genboree.org/cspec/RuleSet/id/643243113" }, "svi": { "id": "GN036", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243106", "label": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MECP2 Version 3.0.0" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "1533266902", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266902", "label": "PS3", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an out-of-frame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used." }, { "baseStrength": "Pathogenic", "id": "1533266902", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266902", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See included table for acceptable functional studies." }, { "baseStrength": "Benign", "id": "1533266900", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266900", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n\n* BP2 is not applicable for UBE3A _in trans_ state." }, { "baseStrength": "Pathogenic", "id": "1533266898", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266898", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Assumed de novo without confirmation of paternity and maternity.\n\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events." }, { "baseStrength": "Pathogenic", "id": "1533266898", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266898", "label": "PM6", "strengthDescriptor": "Strong", "text": "Assumed de novo without confirmation of paternity and maternity.\n\n* ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events." }, { "baseStrength": "Pathogenic", "id": "1533266898", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266898", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Assumed de novo without confirmation of paternity and maternity.\n\n* 1 occurrence of PM6." }, { "baseStrength": "Pathogenic", "id": "1533266893", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266893", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for UBE3A." }, { "baseStrength": "Pathogenic", "id": "1533266893", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266893", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for UBE3A." }, { "baseStrength": "Pathogenic", "id": "1533266893", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266893", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for UBE3A." }, { "baseStrength": "Pathogenic", "id": "1533266893", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266893", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for UBE3A." }, { "baseStrength": "Pathogenic", "id": "1533266888", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266888", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for UBE3A." }, { "baseStrength": "Pathogenic", "id": "1533266888", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266888", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for UBE3A." }, { "baseStrength": "Pathogenic", "id": "1533266888", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266888", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for UBE3A." }, { "baseStrength": "Pathogenic", "id": "1533266888", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266888", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for UBE3A." }, { "baseStrength": "Pathogenic", "id": "1533266887", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266887", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n\n* 3’ cysteine binding site: aa 820[5](#PMID_9887341)" }, { "baseStrength": "Pathogenic", "id": "1533266886", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266886", "label": "PM5", "strengthDescriptor": "Strong", "text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations." }, { "baseStrength": "Pathogenic", "id": "1533266886", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266886", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant." }, { "baseStrength": "Benign", "id": "1533266909", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266909", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species." }, { "baseStrength": "Benign", "id": "1533266907", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266907", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1533266907", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266907", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1533266907", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266907", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1533266907", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266907", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1533266906", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266906", "label": "BP5", "strengthDescriptor": "Strong", "text": "Variant found in a case with an alternate molecular basis for disease.\n\n* ≥3 cases with alternate molecular basis for disease." }, { "baseStrength": "Benign", "id": "1533266906", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266906", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease.\n\n* 1-2 cases with alternate molecular basis for disease." }, { "baseStrength": "Benign", "id": "1533266901", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266901", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for UBE3A." }, { "baseStrength": "Benign", "id": "1533266901", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266901", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for UBE3A." }, { "baseStrength": "Benign", "id": "1533266901", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266901", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for UBE3A." }, { "baseStrength": "Benign", "id": "1533266901", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266901", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for UBE3A." }, { "baseStrength": "Pathogenic", "id": "1533266899", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266899", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." }, { "baseStrength": "Pathogenic", "id": "1533266891", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266891", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.\n* Evidence from literature must be fully evaluated to support independent events." }, { "baseStrength": "Pathogenic", "id": "1533266891", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266891", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* 1 occurrence of PS2." }, { "baseStrength": "Benign", "id": "1533266885", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266885", "label": "BS3", "strengthDescriptor": "Strong", "text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for other functional studies (see tables for other accepted functional studies)." }, { "baseStrength": "Benign", "id": "1533266884", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266884", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 4 unaffected (related and maternally inherited or unrelated) heterozygotes" }, { "baseStrength": "Benign", "id": "1533266884", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266884", "label": "BS2", "strengthDescriptor": "Supporting", "text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 2 unaffected (related and maternally inherited or unrelated) heterozygotes" }, { "baseStrength": "Benign", "id": "1533266903", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266903", "label": "BP4", "strengthDescriptor": "Supporting", "text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site)." }, { "baseStrength": "Benign", "id": "1533266892", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266892", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles." }, { "baseStrength": "Pathogenic", "id": "1533266883", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266883", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines." }, { "baseStrength": "Pathogenic", "id": "1533266905", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266905", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable for any truncating variant up to p.K841[5](#PMID_9887341), for any frameshift variant that results in a read-through of the stop codon, for initiation codon variants, for canonical splice site variants predicted to result in an out-of-frame product, and for intragenic deletions/duplications predicted to result in an out-of-frame product." }, { "baseStrength": "Pathogenic", "id": "1533266905", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266905", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Strong is applicable for any truncating variant from p.K842 to p.G850 and for canonical splice site variants that flank exons 7, 8 (in-frame exons)." }, { "baseStrength": "Pathogenic", "id": "1533266905", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266905", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Moderate is applicable for any truncating variant distal of p.G850." }, { "baseStrength": "Benign", "id": "1533266896", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266896", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for UBE3A." }, { "baseStrength": "Benign", "id": "1533266896", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266896", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for UBE3A." }, { "baseStrength": "Benign", "id": "1533266896", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266896", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for UBE3A." }, { "baseStrength": "Benign", "id": "1533266896", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266896", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for UBE3A." }, { "baseStrength": "Benign", "id": "1533266894", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266894", "label": "BS1", "strengthDescriptor": "Strong", "text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and \\<0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles." }, { "baseStrength": "Pathogenic", "id": "1533266889", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266889", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.\n\n* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site)." }, { "baseStrength": "Pathogenic", "id": "1533266908", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266908", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1533266908", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266908", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1533266908", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266908", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1533266908", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266908", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1533266904", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266904", "label": "PP1", "strengthDescriptor": "Strong", "text": "Co-segregation with disease in multiple affected family members.\n\n* ≥5 informative meiosis." }, { "baseStrength": "Pathogenic", "id": "1533266904", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266904", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Co-segregation with disease in multiple affected family members.\n\n* 3-4 informative meiosis." }, { "baseStrength": "Pathogenic", "id": "1533266904", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266904", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Co-segregation with disease in multiple affected family members.\n\n* 2 informative meiosis." }, { "baseStrength": "Benign", "id": "1533266897", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266897", "label": "BS4", "strengthDescriptor": "Strong", "text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member, when seen in two or more families." }, { "baseStrength": "Benign", "id": "1533266897", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266897", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member." }, { "baseStrength": "Pathogenic", "id": "1533266895", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266895", "label": "PM4", "strengthDescriptor": "Strong", "text": "Protein length changes due to stop-loss variants.\n\n* PM4\\_Strong is applicable to stop-loss variants in UBE3A, as several stop loss variants in this gene has been described in affected individuals.[9](#PMID_25212744)" }, { "baseStrength": "Pathogenic", "id": "1533266895", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266895", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region." }, { "baseStrength": "Pathogenic", "id": "1533266895", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266895", "label": "PM4", "strengthDescriptor": "Supporting", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n\n* Smaller in-frame events (\\< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domain for this gene)." }, { "baseStrength": "Pathogenic", "id": "1533266890", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266890", "label": "PS4", "strengthDescriptor": "Strong", "text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations." }, { "baseStrength": "Pathogenic", "id": "1533266890", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266890", "label": "PS4", "strengthDescriptor": "Moderate", "text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations." }, { "baseStrength": "Pathogenic", "id": "1533266890", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266890", "label": "PS4", "strengthDescriptor": "Supporting", "text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence." }, { "baseStrength": "Pathogenic", "id": "1533266882", "iri": "https://genboree.org/cspec/CriteriaCode/id/1533266882", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases." } ], "diseases": [ { "id": "MONDO:0007113", "iri": "https://genboree.org/cspec/Disease/id/135642213", "label": "Angelman syndrome" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/135641941", "label": "UBE3A" } ], "ruleSet": { "id": "643243114", "iri": "https://genboree.org/cspec/RuleSet/id/643243114" }, "svi": { "id": "GN037", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243107", "label": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for UBE3A Version 4.0.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1746110681", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110681", "label": "BP3", "strengthDescriptor": "Supporting", "text": "In frame-deletions/insertions in a repetitive region without a known function." }, { "baseStrength": "Pathogenic", "id": "1746110677", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110677", "label": "PS3", "strengthDescriptor": "Strong", "text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 72.7% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 135% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.2 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 4.1 mV (absolute value).\n* Mouse knock-in model displays spontaneous seizures." }, { "baseStrength": "Pathogenic", "id": "1746110677", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110677", "label": "PS3", "strengthDescriptor": "Moderate", "text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 80.6% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 125% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.1 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 3.0 mV (absolute value).\n* Mouse knock-in model displays induced seizures\n* Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies" }, { "baseStrength": "Pathogenic", "id": "1746110677", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110677", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies" }, { "baseStrength": "Benign", "id": "1746110668", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110668", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in a healthy adult individual." }, { "baseStrength": "Benign", "id": "1746110664", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110664", "label": "BS3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n" }, { "baseStrength": "Benign", "id": "1746110664", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110664", "label": "BS3", "strengthDescriptor": "Strong", "text": "Not Applicable: Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n" }, { "baseStrength": "Benign", "id": "1746110664", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110664", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n" }, { "baseStrength": "Benign", "id": "1746110664", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110664", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n" }, { "baseStrength": "Pathogenic", "id": "1746110663", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110663", "label": "PM5", "strengthDescriptor": "Strong", "text": "Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene)." }, { "baseStrength": "Pathogenic", "id": "1746110663", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110663", "label": "PM5", "strengthDescriptor": "Moderate", "text": "Novel missense change at an amino acid residue in the same gene where a different missense variant was determined to be Pathogenic." }, { "baseStrength": "Pathogenic", "id": "1746110663", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110663", "label": "PM5", "strengthDescriptor": "Supporting", "text": "* Novel missense change at an amino acid residue where a different missense change determined to be **Likely Pathogenic** has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. \n* \\>1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be **Pathogenic** or **Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level." }, { "baseStrength": "Pathogenic", "id": "1746110684", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110684", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n* **\\>1** Identical amino acid change in paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). \n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\")." }, { "baseStrength": "Pathogenic", "id": "1746110684", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110684", "label": "PS1", "strengthDescriptor": "Moderate", "text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Likely Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\")." }, { "baseStrength": "Pathogenic", "id": "1746110684", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110684", "label": "PS1", "strengthDescriptor": "Supporting", "text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* A single identical amino acid change in a paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\")." }, { "baseStrength": "Benign", "id": "1746110679", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110679", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease." }, { "baseStrength": "Pathogenic", "id": "1746110672", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110672", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1601. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3." }, { "baseStrength": "Pathogenic", "id": "1746110672", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110672", "label": "PVS1", "strengthDescriptor": "Strong", "text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1601. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3." }, { "baseStrength": "Pathogenic", "id": "1746110672", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110672", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1601. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3." }, { "baseStrength": "Pathogenic", "id": "1746110672", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110672", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1601. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3." }, { "baseStrength": "Pathogenic", "id": "1746110661", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110661", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **16+ points** will arrive at **Very Strong**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points" }, { "baseStrength": "Pathogenic", "id": "1746110661", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110661", "label": "PS4", "strengthDescriptor": "Strong", "text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4-15.5 points** will arrive at **Strong**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points" }, { "baseStrength": "Pathogenic", "id": "1746110661", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110661", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2-3.5 points** will arrive at **Moderate**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points" }, { "baseStrength": "Pathogenic", "id": "1746110661", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110661", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1-1.5 points** will arrive at **Supporting**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points" }, { "baseStrength": "Benign", "id": "1746110685", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110685", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1746110685", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110685", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1746110685", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110685", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1746110685", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110685", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1746110682", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110682", "label": "PP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Phenotypic specificity incorporated into PS2, PM6, PS4" }, { "baseStrength": "Pathogenic", "id": "1746110682", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110682", "label": "PP4", "strengthDescriptor": "Strong", "text": "Not Applicable: Phenotypic specificity incorporated into PS2, PM6, PS4" }, { "baseStrength": "Pathogenic", "id": "1746110682", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110682", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Phenotypic specificity incorporated into PS2, PM6, PS4" }, { "baseStrength": "Pathogenic", "id": "1746110682", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110682", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Phenotypic specificity incorporated into PS2, PM6, PS4" }, { "baseStrength": "Benign", "id": "1746110675", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110675", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved." }, { "baseStrength": "Pathogenic", "id": "1746110669", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110669", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1746110669", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110669", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1746110669", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110669", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1746110669", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110669", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1746110686", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110686", "label": "BP4", "strengthDescriptor": "Moderate", "text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)) using REVEL as the computational tool." }, { "baseStrength": "Benign", "id": "1746110686", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110686", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)) using REVEL as the computational tool." }, { "baseStrength": "Pathogenic", "id": "1746110683", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110683", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 points** will arrive at **Very Strong**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "1746110683", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110683", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "1746110683", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110683", "label": "PS2", "strengthDescriptor": "Moderate", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "1746110683", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110683", "label": "PS2", "strengthDescriptor": "Supporting", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "1746110680", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110680", "label": "PP1", "strengthDescriptor": "Strong", "text": "Co-segregation with disease in multiple affected family members.\n\n\\>=7 independent meioses" }, { "baseStrength": "Pathogenic", "id": "1746110680", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110680", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Co-segregation with disease in multiple affected family members.\n\n5-6 independent meioses" }, { "baseStrength": "Pathogenic", "id": "1746110680", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110680", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Co-segregation with disease in multiple affected family members.\n\n3-4 independent meioses" }, { "baseStrength": "Benign", "id": "1746110678", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110678", "label": "BS1", "strengthDescriptor": "Strong", "text": "Allele frequency is above 0.0004% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed." }, { "baseStrength": "Pathogenic", "id": "1746110674", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110674", "label": "PM6", "strengthDescriptor": "Strong", "text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. Total of **4 points** will arrive at **Very Strong**. \n\nDravet\\*: 1 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 0.5 points\n\nDevelopmental and Epileptic Encephalopathy: 0.5 points\n\nHemiplegic migraine: 0.25 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points" }, { "baseStrength": "Pathogenic", "id": "1746110674", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110674", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\nDravet\\*: 1 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 0.5 points\n\nDevelopmental and Epileptic Encephalopathy: 0.5 points\n\nHemiplegic migraine: 0.25 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points" }, { "baseStrength": "Pathogenic", "id": "1746110674", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110674", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\nDravet\\*: 1 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 0.5 points\n\nDevelopmental and Epileptic Encephalopathy: 0.5 points\n\nHemiplegic migraine: 0.25 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points" }, { "baseStrength": "Benign", "id": "1746110666", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110666", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Missense variants are common cause of disease. " }, { "baseStrength": "Benign", "id": "1746110666", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110666", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Missense variants are common cause of disease. " }, { "baseStrength": "Benign", "id": "1746110666", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110666", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Missense variants are common cause of disease. " }, { "baseStrength": "Benign", "id": "1746110666", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110666", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Missense variants are common cause of disease. " }, { "baseStrength": "Benign", "id": "1746110665", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110665", "label": "BS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Reduced penetrance, variable expressivity and phenocopies" }, { "baseStrength": "Benign", "id": "1746110665", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110665", "label": "BS4", "strengthDescriptor": "Strong", "text": "Not Applicable: Reduced penetrance, variable expressivity and phenocopies" }, { "baseStrength": "Benign", "id": "1746110665", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110665", "label": "BS4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Reduced penetrance, variable expressivity and phenocopies" }, { "baseStrength": "Benign", "id": "1746110665", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110665", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Reduced penetrance, variable expressivity and phenocopies" }, { "baseStrength": "Benign", "id": "1746110662", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110662", "label": "BP2", "strengthDescriptor": "Supporting", "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." }, { "baseStrength": "Pathogenic", "id": "1746110676", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110676", "label": "PP3", "strengthDescriptor": "Moderate", "text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)) using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong" }, { "baseStrength": "Pathogenic", "id": "1746110676", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110676", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)) using REVEL as the computational tool, with the following stipulations: with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong" }, { "baseStrength": "Benign", "id": "1746110673", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110673", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Allele frequency is above 0.02% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed." }, { "baseStrength": "Pathogenic", "id": "1746110671", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110671", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table\"." }, { "baseStrength": "Pathogenic", "id": "1746110670", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110670", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: SCN1A is associated with autosomal dominant inheritance. " }, { "baseStrength": "Pathogenic", "id": "1746110670", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110670", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: SCN1A is associated with autosomal dominant inheritance. " }, { "baseStrength": "Pathogenic", "id": "1746110670", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110670", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: SCN1A is associated with autosomal dominant inheritance. " }, { "baseStrength": "Pathogenic", "id": "1746110670", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110670", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: SCN1A is associated with autosomal dominant inheritance. " }, { "baseStrength": "Pathogenic", "id": "1746110667", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110667", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Benign missense variants are common. " }, { "baseStrength": "Pathogenic", "id": "1746110667", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110667", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Benign missense variants are common. " }, { "baseStrength": "Pathogenic", "id": "1746110667", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110667", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Benign missense variants are common. " }, { "baseStrength": "Pathogenic", "id": "1746110667", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110667", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Benign missense variants are common. " }, { "baseStrength": "Pathogenic", "id": "1746110660", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110660", "label": "PM2", "strengthDescriptor": "Supporting", "text": "One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing." }, { "baseStrength": "Pathogenic", "id": "1746110659", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746110659", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." } ], "diseases": [ { "id": "MONDO:0100135", "iri": "https://genboree.org/cspec/Disease/id/467880999", "label": "Dravet syndrome" }, { "id": "MONDO:0018214", "iri": "https://genboree.org/cspec/Disease/id/467877022", "label": "generalized epilepsy with febrile seizures plus" }, { "id": "MONDO:0100062", "iri": "https://genboree.org/cspec/Disease/id/467881472", "label": "genetic developmental and epileptic encephalopathy" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467855388", "label": "SCN1A" } ], "ruleSet": { "id": "643243144", "iri": "https://genboree.org/cspec/RuleSet/id/643243144" }, "svi": { "id": "GN067", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243137", "label": "ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN1A Version 1.0.0" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "1746111566", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111566", "label": "PP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Phenotypic specificity incorporated into PS2, PM6, PS4" }, { "baseStrength": "Pathogenic", "id": "1746111566", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111566", "label": "PP4", "strengthDescriptor": "Strong", "text": "Not Applicable: Phenotypic specificity incorporated into PS2, PM6, PS4" }, { "baseStrength": "Pathogenic", "id": "1746111566", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111566", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Phenotypic specificity incorporated into PS2, PM6, PS4" }, { "baseStrength": "Pathogenic", "id": "1746111566", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111566", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Phenotypic specificity incorporated into PS2, PM6, PS4" }, { "baseStrength": "Benign", "id": "1746111563", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111563", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease." }, { "baseStrength": "Pathogenic", "id": "1746111560", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111560", "label": "PP3", "strengthDescriptor": "Moderate", "text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong" }, { "baseStrength": "Pathogenic", "id": "1746111560", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111560", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong" }, { "baseStrength": "Benign", "id": "1746111552", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111552", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in a healthy adult individual with full penetrance expected at an early age." }, { "baseStrength": "Pathogenic", "id": "1746111545", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111545", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **16+ points** will arrive at **Very Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746111545", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111545", "label": "PS4", "strengthDescriptor": "Strong", "text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 - 15.5 points** will arrive at **Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746111545", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111545", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 - 3.5 points** will arrive at **Moderate**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746111545", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111545", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 - 1.5 points** will arrive at **Supporting**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Benign", "id": "1746111570", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111570", "label": "BP4", "strengthDescriptor": "Moderate", "text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)) using REVEL as the computational tool." }, { "baseStrength": "Benign", "id": "1746111570", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111570", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)) using REVEL as the computational tool." }, { "baseStrength": "Pathogenic", "id": "1746111567", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111567", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 points** will arrive at **Very Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "1746111567", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111567", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "1746111567", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111567", "label": "PS2", "strengthDescriptor": "Moderate", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "1746111567", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111567", "label": "PS2", "strengthDescriptor": "Supporting", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "1746111558", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111558", "label": "PM6", "strengthDescriptor": "Strong", "text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. Total of **4 points** will arrive at **Very Strong**. \n\n* Complex Neurodevelopmental Disorder: 0.5 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746111558", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111558", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\n* Complex Neurodevelopmental Disorder: 0.5 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746111558", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111558", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\n* Complex Neurodevelopmental Disorder: 0.5 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746111555", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111555", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table\"." }, { "baseStrength": "Benign", "id": "1746111548", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111548", "label": "BS3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic ID/ASD, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n" }, { "baseStrength": "Benign", "id": "1746111548", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111548", "label": "BS3", "strengthDescriptor": "Strong", "text": "Not Applicable: Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic ID/ASD, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n" }, { "baseStrength": "Benign", "id": "1746111548", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111548", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic ID/ASD, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n" }, { "baseStrength": "Benign", "id": "1746111548", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111548", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic ID/ASD, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n" }, { "baseStrength": "Benign", "id": "1746111546", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111546", "label": "BP2", "strengthDescriptor": "Supporting", "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." }, { "baseStrength": "Pathogenic", "id": "1746111544", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111544", "label": "PM2", "strengthDescriptor": "Supporting", "text": "One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing." }, { "baseStrength": "Pathogenic", "id": "1746111568", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111568", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n* **\\>1** Identical amino acid change in paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). \n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\")." }, { "baseStrength": "Pathogenic", "id": "1746111568", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111568", "label": "PS1", "strengthDescriptor": "Moderate", "text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Likely Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\")." }, { "baseStrength": "Pathogenic", "id": "1746111568", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111568", "label": "PS1", "strengthDescriptor": "Supporting", "text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* A single identical amino acid change in a paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\")." }, { "baseStrength": "Pathogenic", "id": "1746111553", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111553", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1746111553", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111553", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1746111553", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111553", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1746111553", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111553", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1746111543", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111543", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." }, { "baseStrength": "Benign", "id": "1746111562", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111562", "label": "BS1", "strengthDescriptor": "Strong", "text": "Allele frequency is above 0.0002% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed." }, { "baseStrength": "Pathogenic", "id": "1746111561", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111561", "label": "PS3", "strengthDescriptor": "Strong", "text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 72.7% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 135% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.2 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 4.1 mV (absolute value).\n* Mouse knock-in model displays spontaneous seizures." }, { "baseStrength": "Pathogenic", "id": "1746111561", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111561", "label": "PS3", "strengthDescriptor": "Moderate", "text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 80.6% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 125% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.1 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 3.0 mV (absolute value).\n* Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies" }, { "baseStrength": "Pathogenic", "id": "1746111561", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111561", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies" }, { "baseStrength": "Benign", "id": "1746111557", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111557", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Allele frequency is above **0.01%** is gnomAD or other large population databases, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed." }, { "baseStrength": "Benign", "id": "1746111549", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111549", "label": "BS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Reduced penetrance and phenocopies" }, { "baseStrength": "Benign", "id": "1746111549", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111549", "label": "BS4", "strengthDescriptor": "Strong", "text": "Not Applicable: Reduced penetrance and phenocopies" }, { "baseStrength": "Benign", "id": "1746111549", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111549", "label": "BS4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Reduced penetrance and phenocopies" }, { "baseStrength": "Benign", "id": "1746111549", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111549", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Reduced penetrance and phenocopies" }, { "baseStrength": "Benign", "id": "1746111569", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111569", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1746111569", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111569", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1746111569", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111569", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1746111569", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111569", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1746111565", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111565", "label": "BP3", "strengthDescriptor": "Supporting", "text": "In frame-deletions/insertions in a repetitive region without a known function." }, { "baseStrength": "Pathogenic", "id": "1746111564", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111564", "label": "PP1", "strengthDescriptor": "Strong", "text": "\\>=7 independent meioses" }, { "baseStrength": "Pathogenic", "id": "1746111564", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111564", "label": "PP1", "strengthDescriptor": "Moderate", "text": "5-6 independent meioses" }, { "baseStrength": "Pathogenic", "id": "1746111564", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111564", "label": "PP1", "strengthDescriptor": "Supporting", "text": "3-4 independent meioses" }, { "baseStrength": "Benign", "id": "1746111559", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111559", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved." }, { "baseStrength": "Pathogenic", "id": "1746111556", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111556", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3." }, { "baseStrength": "Pathogenic", "id": "1746111556", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111556", "label": "PVS1", "strengthDescriptor": "Strong", "text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591.\n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3." }, { "baseStrength": "Pathogenic", "id": "1746111556", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111556", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3." }, { "baseStrength": "Pathogenic", "id": "1746111556", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111556", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3." }, { "baseStrength": "Pathogenic", "id": "1746111554", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111554", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: SCN2A is associated with autosomal dominant inheritance. " }, { "baseStrength": "Pathogenic", "id": "1746111554", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111554", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: SCN2A is associated with autosomal dominant inheritance. " }, { "baseStrength": "Pathogenic", "id": "1746111554", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111554", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: SCN2A is associated with autosomal dominant inheritance. " }, { "baseStrength": "Pathogenic", "id": "1746111554", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111554", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: SCN2A is associated with autosomal dominant inheritance. " }, { "baseStrength": "Pathogenic", "id": "1746111551", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111551", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Benign missense variants are common. " }, { "baseStrength": "Pathogenic", "id": "1746111551", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111551", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Benign missense variants are common. " }, { "baseStrength": "Pathogenic", "id": "1746111551", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111551", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Benign missense variants are common. " }, { "baseStrength": "Pathogenic", "id": "1746111551", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111551", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Benign missense variants are common. " }, { "baseStrength": "Benign", "id": "1746111550", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111550", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Missense variants are common cause of disease. " }, { "baseStrength": "Benign", "id": "1746111550", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111550", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Missense variants are common cause of disease. " }, { "baseStrength": "Benign", "id": "1746111550", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111550", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Missense variants are common cause of disease. " }, { "baseStrength": "Benign", "id": "1746111550", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111550", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Missense variants are common cause of disease. " }, { "baseStrength": "Pathogenic", "id": "1746111547", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111547", "label": "PM5", "strengthDescriptor": "Strong", "text": "Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene).\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level." }, { "baseStrength": "Pathogenic", "id": "1746111547", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111547", "label": "PM5", "strengthDescriptor": "Moderate", "text": "* Novel missense change at an amino acid residue where a different missense change determined to be Pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level." }, { "baseStrength": "Pathogenic", "id": "1746111547", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746111547", "label": "PM5", "strengthDescriptor": "Supporting", "text": "* Novel missense change at an amino acid residue where a different missense change determined to be **Likely Pathogenic** has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. \n* \\>1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be **Pathogenic**or **Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level." } ], "diseases": [ { "id": "MONDO:0100038", "iri": "https://genboree.org/cspec/Disease/id/467881646", "label": "complex neurodevelopmental disorder" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467855391", "label": "SCN2A" } ], "ruleSet": { "id": "643243145", "iri": "https://genboree.org/cspec/RuleSet/id/643243145" }, "svi": { "id": "GN068", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243138", "label": "ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN2A Version 1.0.0" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "1746112475", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112475", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 points** will arrive at **Very Strong**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "1746112475", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112475", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "1746112475", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112475", "label": "PS2", "strengthDescriptor": "Moderate", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "1746112475", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112475", "label": "PS2", "strengthDescriptor": "Supporting", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Benign", "id": "1746112471", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112471", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease." }, { "baseStrength": "Benign", "id": "1746112465", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112465", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Allele frequency is above **0.01%** is gnomAD or other large population databases, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed." }, { "baseStrength": "Pathogenic", "id": "1746112463", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112463", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table\"." }, { "baseStrength": "Pathogenic", "id": "1746112462", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112462", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: SCN3A is associated with autosomal dominant inheritance. " }, { "baseStrength": "Pathogenic", "id": "1746112462", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112462", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: SCN3A is associated with autosomal dominant inheritance. " }, { "baseStrength": "Pathogenic", "id": "1746112462", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112462", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: SCN3A is associated with autosomal dominant inheritance. " }, { "baseStrength": "Pathogenic", "id": "1746112462", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112462", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: SCN3A is associated with autosomal dominant inheritance. " }, { "baseStrength": "Pathogenic", "id": "1746112461", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112461", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1746112461", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112461", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1746112461", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112461", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1746112461", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112461", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1746112459", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112459", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Benign missense variants are common. " }, { "baseStrength": "Pathogenic", "id": "1746112459", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112459", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Benign missense variants are common. " }, { "baseStrength": "Pathogenic", "id": "1746112459", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112459", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Benign missense variants are common. " }, { "baseStrength": "Pathogenic", "id": "1746112459", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112459", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Benign missense variants are common. " }, { "baseStrength": "Benign", "id": "1746112457", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112457", "label": "BS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Reduced penetrance and phenocopies" }, { "baseStrength": "Benign", "id": "1746112457", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112457", "label": "BS4", "strengthDescriptor": "Strong", "text": "Not Applicable: Reduced penetrance and phenocopies" }, { "baseStrength": "Benign", "id": "1746112457", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112457", "label": "BS4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Reduced penetrance and phenocopies" }, { "baseStrength": "Benign", "id": "1746112457", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112457", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Reduced penetrance and phenocopies" }, { "baseStrength": "Benign", "id": "1746112456", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112456", "label": "BS3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n" }, { "baseStrength": "Benign", "id": "1746112456", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112456", "label": "BS3", "strengthDescriptor": "Strong", "text": "Not Applicable: Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n" }, { "baseStrength": "Benign", "id": "1746112456", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112456", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n" }, { "baseStrength": "Benign", "id": "1746112456", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112456", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n" }, { "baseStrength": "Pathogenic", "id": "1746112453", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112453", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **16+ points** will arrive at **Very Strong**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746112453", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112453", "label": "PS4", "strengthDescriptor": "Strong", "text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4-15.5 points** will arrive at **Strong**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746112453", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112453", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2-3.5 points** will arrive at **Moderate**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746112453", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112453", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1-1.5 points** will arrive at **Supporting**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746112452", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112452", "label": "PM2", "strengthDescriptor": "Supporting", "text": "One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing." }, { "baseStrength": "Benign", "id": "1746112478", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112478", "label": "BP4", "strengthDescriptor": "Moderate", "text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool." }, { "baseStrength": "Benign", "id": "1746112478", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112478", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool." }, { "baseStrength": "Benign", "id": "1746112477", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112477", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1746112477", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112477", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1746112477", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112477", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1746112477", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112477", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1746112476", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112476", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n* **\\>1** Identical amino acid change in paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\")." }, { "baseStrength": "Pathogenic", "id": "1746112476", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112476", "label": "PS1", "strengthDescriptor": "Moderate", "text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Likely Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\")." }, { "baseStrength": "Pathogenic", "id": "1746112476", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112476", "label": "PS1", "strengthDescriptor": "Supporting", "text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* A single identical amino acid change in a paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A).\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\")." }, { "baseStrength": "Benign", "id": "1746112454", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112454", "label": "BP2", "strengthDescriptor": "Supporting", "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." }, { "baseStrength": "Pathogenic", "id": "1746112466", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112466", "label": "PM6", "strengthDescriptor": "Strong", "text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. Total of **4 points** will arrive at **Very Strong**. \n\nDevelopmental and Epileptic Encephalopathy: 0.5 points\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746112466", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112466", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\nDevelopmental and Epileptic Encephalopathy: 0.5 points\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746112466", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112466", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\nDevelopmental and Epileptic Encephalopathy: 0.5 points\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Benign", "id": "1746112460", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112460", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in a healthy adult individual." }, { "baseStrength": "Benign", "id": "1746112458", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112458", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Missense variants are common cause of disease. " }, { "baseStrength": "Benign", "id": "1746112458", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112458", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Missense variants are common cause of disease. " }, { "baseStrength": "Benign", "id": "1746112458", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112458", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Missense variants are common cause of disease. " }, { "baseStrength": "Benign", "id": "1746112458", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112458", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Missense variants are common cause of disease. " }, { "baseStrength": "Pathogenic", "id": "1746112474", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112474", "label": "PP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Phenotypic specificity incorporated into PS2, PM6, PS4" }, { "baseStrength": "Pathogenic", "id": "1746112474", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112474", "label": "PP4", "strengthDescriptor": "Strong", "text": "Not Applicable: Phenotypic specificity incorporated into PS2, PM6, PS4" }, { "baseStrength": "Pathogenic", "id": "1746112474", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112474", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Phenotypic specificity incorporated into PS2, PM6, PS4" }, { "baseStrength": "Pathogenic", "id": "1746112474", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112474", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Phenotypic specificity incorporated into PS2, PM6, PS4" }, { "baseStrength": "Pathogenic", "id": "1746112472", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112472", "label": "PP1", "strengthDescriptor": "Strong", "text": "\\>=7 independent meioses" }, { "baseStrength": "Pathogenic", "id": "1746112472", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112472", "label": "PP1", "strengthDescriptor": "Moderate", "text": "5-6 independent meioses" }, { "baseStrength": "Pathogenic", "id": "1746112472", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112472", "label": "PP1", "strengthDescriptor": "Supporting", "text": "3-4 independent meioses" }, { "baseStrength": "Pathogenic", "id": "1746112464", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112464", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN3A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1586. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3." }, { "baseStrength": "Pathogenic", "id": "1746112464", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112464", "label": "PVS1", "strengthDescriptor": "Strong", "text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN3A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1586. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3." }, { "baseStrength": "Pathogenic", "id": "1746112464", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112464", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN3A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1586. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3." }, { "baseStrength": "Pathogenic", "id": "1746112464", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112464", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN3A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1586. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3." }, { "baseStrength": "Pathogenic", "id": "1746112455", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112455", "label": "PM5", "strengthDescriptor": "Strong", "text": "Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene).\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level." }, { "baseStrength": "Pathogenic", "id": "1746112455", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112455", "label": "PM5", "strengthDescriptor": "Moderate", "text": "* Novel missense change at an amino acid residue where a different missense change determined to be Pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level." }, { "baseStrength": "Pathogenic", "id": "1746112455", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112455", "label": "PM5", "strengthDescriptor": "Supporting", "text": "* Novel missense change at an amino acid residue where a different missense change determined to be **Likely Pathogenic** has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. \n* \\>1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be **Pathogenic**or **Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level." }, { "baseStrength": "Benign", "id": "1746112473", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112473", "label": "BP3", "strengthDescriptor": "Supporting", "text": "In frame-deletions/insertions in a repetitive region without a known function." }, { "baseStrength": "Benign", "id": "1746112470", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112470", "label": "BS1", "strengthDescriptor": "Strong", "text": "Allele frequency is above 0.0002% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed." }, { "baseStrength": "Pathogenic", "id": "1746112469", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112469", "label": "PS3", "strengthDescriptor": "Strong", "text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 72.7% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 135% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.2 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 4.1 mV (absolute value).\n* Mouse knock-in model displays spontaneous seizures." }, { "baseStrength": "Pathogenic", "id": "1746112469", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112469", "label": "PS3", "strengthDescriptor": "Moderate", "text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 80.6% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 125% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.1 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 3.0 mV (absolute value).\n* Mouse knock-in model displays induced seizures\n* Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies" }, { "baseStrength": "Pathogenic", "id": "1746112469", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112469", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies" }, { "baseStrength": "Pathogenic", "id": "1746112468", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112468", "label": "PP3", "strengthDescriptor": "Moderate", "text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong" }, { "baseStrength": "Pathogenic", "id": "1746112468", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112468", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong" }, { "baseStrength": "Benign", "id": "1746112467", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112467", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved." }, { "baseStrength": "Pathogenic", "id": "1746112451", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746112451", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." } ], "diseases": [ { "id": "MONDO:0100062", "iri": "https://genboree.org/cspec/Disease/id/467881472", "label": "genetic developmental and epileptic encephalopathy" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467855393", "label": "SCN3A" } ], "ruleSet": { "id": "643243146", "iri": "https://genboree.org/cspec/RuleSet/id/643243146" }, "svi": { "id": "GN069", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243139", "label": "ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN3A Version 1.0.0" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "1746113413", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113413", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n* **\\>1** Identical amino acid change in paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\")." }, { "baseStrength": "Pathogenic", "id": "1746113413", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113413", "label": "PS1", "strengthDescriptor": "Moderate", "text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Likely Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\")." }, { "baseStrength": "Pathogenic", "id": "1746113413", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113413", "label": "PS1", "strengthDescriptor": "Supporting", "text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* A single identical amino acid change in a paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A).\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\")." }, { "baseStrength": "Pathogenic", "id": "1746113399", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113399", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: SCN8A is associated with autosomal dominant inheritance. " }, { "baseStrength": "Pathogenic", "id": "1746113399", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113399", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: SCN8A is associated with autosomal dominant inheritance. " }, { "baseStrength": "Pathogenic", "id": "1746113399", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113399", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: SCN8A is associated with autosomal dominant inheritance. " }, { "baseStrength": "Pathogenic", "id": "1746113399", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113399", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: SCN8A is associated with autosomal dominant inheritance. " }, { "baseStrength": "Benign", "id": "1746113394", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113394", "label": "BS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Reduced penetrance and phenocopies" }, { "baseStrength": "Benign", "id": "1746113394", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113394", "label": "BS4", "strengthDescriptor": "Strong", "text": "Not Applicable: Reduced penetrance and phenocopies" }, { "baseStrength": "Benign", "id": "1746113394", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113394", "label": "BS4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Reduced penetrance and phenocopies" }, { "baseStrength": "Benign", "id": "1746113394", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113394", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Reduced penetrance and phenocopies" }, { "baseStrength": "Benign", "id": "1746113393", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113393", "label": "BS3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n" }, { "baseStrength": "Benign", "id": "1746113393", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113393", "label": "BS3", "strengthDescriptor": "Strong", "text": "Not Applicable: Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n" }, { "baseStrength": "Benign", "id": "1746113393", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113393", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n" }, { "baseStrength": "Benign", "id": "1746113393", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113393", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n" }, { "baseStrength": "Pathogenic", "id": "1746113406", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113406", "label": "PS3", "strengthDescriptor": "Strong", "text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 72.7% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 135% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.2 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 4.1 mV (absolute value).\n* Mouse knock-in model displays spontaneous seizures." }, { "baseStrength": "Pathogenic", "id": "1746113406", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113406", "label": "PS3", "strengthDescriptor": "Moderate", "text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 80.6% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 125% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.1 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 3.0 mV (absolute value).\n* Mouse knock-in model displays induced seizures\n* Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies" }, { "baseStrength": "Pathogenic", "id": "1746113406", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113406", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies" }, { "baseStrength": "Benign", "id": "1746113404", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113404", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved." }, { "baseStrength": "Pathogenic", "id": "1746113398", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113398", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1746113398", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113398", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1746113398", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113398", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1746113398", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113398", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1746113395", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113395", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Missense variants are common cause of disease. " }, { "baseStrength": "Benign", "id": "1746113395", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113395", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Missense variants are common cause of disease. " }, { "baseStrength": "Benign", "id": "1746113395", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113395", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Missense variants are common cause of disease. " }, { "baseStrength": "Benign", "id": "1746113395", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113395", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Missense variants are common cause of disease. " }, { "baseStrength": "Pathogenic", "id": "1746113392", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113392", "label": "PM5", "strengthDescriptor": "Strong", "text": "Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene).\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level." }, { "baseStrength": "Pathogenic", "id": "1746113392", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113392", "label": "PM5", "strengthDescriptor": "Moderate", "text": "* Novel missense change at an amino acid residue where a different missense change determined to be Pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level." }, { "baseStrength": "Pathogenic", "id": "1746113392", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113392", "label": "PM5", "strengthDescriptor": "Supporting", "text": "* Novel missense change at an amino acid residue where a different missense change determined to be **Likely Pathogenic** has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. \n* \\>1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be **Pathogenic**or **Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level." }, { "baseStrength": "Pathogenic", "id": "1746113389", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113389", "label": "PM2", "strengthDescriptor": "Supporting", "text": "One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing." }, { "baseStrength": "Pathogenic", "id": "1746113412", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113412", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 points** will arrive at **Very Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "1746113412", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113412", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "1746113412", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113412", "label": "PS2", "strengthDescriptor": "Moderate", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "1746113412", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113412", "label": "PS2", "strengthDescriptor": "Supporting", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Benign", "id": "1746113410", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113410", "label": "BP3", "strengthDescriptor": "Supporting", "text": "In frame-deletions/insertions in a repetitive region without a known function." }, { "baseStrength": "Pathogenic", "id": "1746113409", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113409", "label": "PP1", "strengthDescriptor": "Strong", "text": "\\>=7 independent meioses" }, { "baseStrength": "Pathogenic", "id": "1746113409", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113409", "label": "PP1", "strengthDescriptor": "Moderate", "text": "5-6 independent meioses" }, { "baseStrength": "Pathogenic", "id": "1746113409", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113409", "label": "PP1", "strengthDescriptor": "Supporting", "text": "3-4 independent meioses" }, { "baseStrength": "Benign", "id": "1746113408", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113408", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease." }, { "baseStrength": "Pathogenic", "id": "1746113400", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113400", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table\"." }, { "baseStrength": "Pathogenic", "id": "1746113390", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113390", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **16+ points** will arrive at **Very Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746113390", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113390", "label": "PS4", "strengthDescriptor": "Strong", "text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 - 15.5 points** will arrive at **Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746113390", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113390", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 - 3.5 points** will arrive at **Moderate**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746113390", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113390", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 - 1.5 points** will arrive at **Supporting**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746113388", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113388", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." }, { "baseStrength": "Benign", "id": "1746113415", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113415", "label": "BP4", "strengthDescriptor": "Moderate", "text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool." }, { "baseStrength": "Benign", "id": "1746113415", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113415", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool." }, { "baseStrength": "Pathogenic", "id": "1746113411", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113411", "label": "PP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Phenotypic specificity incorporated into PS2, PM6, PS4" }, { "baseStrength": "Pathogenic", "id": "1746113411", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113411", "label": "PP4", "strengthDescriptor": "Strong", "text": "Not Applicable: Phenotypic specificity incorporated into PS2, PM6, PS4" }, { "baseStrength": "Pathogenic", "id": "1746113411", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113411", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Phenotypic specificity incorporated into PS2, PM6, PS4" }, { "baseStrength": "Pathogenic", "id": "1746113411", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113411", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Phenotypic specificity incorporated into PS2, PM6, PS4" }, { "baseStrength": "Pathogenic", "id": "1746113403", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113403", "label": "PM6", "strengthDescriptor": "Strong", "text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. Total of **4 points** will arrive at **Very Strong**. \n\n* Complex Neurodevelopmental Disorder: 0.5 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746113403", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113403", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\n* Complex Neurodevelopmental Disorder: 0.5 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746113403", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113403", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\n* Complex Neurodevelopmental Disorder: 0.5 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points" }, { "baseStrength": "Benign", "id": "1746113402", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113402", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Allele frequency is above **0.01%** is gnomAD or other large population databases, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed." }, { "baseStrength": "Pathogenic", "id": "1746113401", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113401", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN8A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1582. \n\nIn-frame exons: 1, 7, 8, 12, 17, 19, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18, 20-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3." }, { "baseStrength": "Pathogenic", "id": "1746113401", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113401", "label": "PVS1", "strengthDescriptor": "Strong", "text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN8A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1582. \n\nIn-frame exons: 1, 7, 8, 12, 17, 19, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18, 20-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3." }, { "baseStrength": "Pathogenic", "id": "1746113401", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113401", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN8A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1582. \n\nIn-frame exons: 1, 7, 8, 12, 17, 19, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18, 20-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3." }, { "baseStrength": "Pathogenic", "id": "1746113401", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113401", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN8A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1582. \n\nIn-frame exons: 1, 7, 8, 12, 17, 19, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18, 20-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3." }, { "baseStrength": "Pathogenic", "id": "1746113396", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113396", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Benign missense variants are common. " }, { "baseStrength": "Pathogenic", "id": "1746113396", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113396", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Benign missense variants are common. " }, { "baseStrength": "Pathogenic", "id": "1746113396", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113396", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Benign missense variants are common. " }, { "baseStrength": "Pathogenic", "id": "1746113396", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113396", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Benign missense variants are common. " }, { "baseStrength": "Benign", "id": "1746113414", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113414", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1746113414", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113414", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1746113414", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113414", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1746113414", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113414", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1746113407", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113407", "label": "BS1", "strengthDescriptor": "Strong", "text": "Allele frequency is above 0.0002% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed." }, { "baseStrength": "Pathogenic", "id": "1746113405", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113405", "label": "PP3", "strengthDescriptor": "Moderate", "text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong" }, { "baseStrength": "Pathogenic", "id": "1746113405", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113405", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong" }, { "baseStrength": "Benign", "id": "1746113397", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113397", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in a healthy adult individual with full penetrance expected at an early age." }, { "baseStrength": "Benign", "id": "1746113391", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746113391", "label": "BP2", "strengthDescriptor": "Supporting", "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." } ], "diseases": [ { "id": "MONDO:0100038", "iri": "https://genboree.org/cspec/Disease/id/467881646", "label": "complex neurodevelopmental disorder" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467855399", "label": "SCN8A" } ], "ruleSet": { "id": "643243147", "iri": "https://genboree.org/cspec/RuleSet/id/643243147" }, "svi": { "id": "GN070", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243140", "label": "ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN8A Version 1.0.0" } }, { "codes": [ { "baseStrength": "Pathogenic", "id": "1620362902", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362902", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Code can be applied for variants where the REVEL score is greater than or equal to 0.6 or a SpliceAI score of greater than or equal to 0.5." }, { "baseStrength": "Benign", "id": "1620362895", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362895", "label": "BP4", "strengthDescriptor": "Supporting", "text": "This code can be applied for variants reaching a REVEL score of 0.3 or below AND a Splice AI score of less than or equal to 0.05." }, { "baseStrength": "Benign", "id": "1620362888", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362888", "label": "BS4", "strengthDescriptor": "Strong", "text": "This evidence code can be used when a _F8_ variant is observed in a male with a family history of hemophilia A and has a normal factor VIII activity level." }, { "baseStrength": "Benign", "id": "1620362883", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362883", "label": "BS2", "strengthDescriptor": "Strong", "text": "This evidence code can be used when a _F8_ variant is observed in a male with a normal factor VIII activity level (\\<40% IU) using a one stage and/or a chromogenic assay." }, { "baseStrength": "Pathogenic", "id": "1620362908", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362908", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620362908", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362908", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620362908", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362908", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620362908", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362908", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620362906", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362906", "label": "PM2", "strengthDescriptor": "Supporting", "text": "Variant must be absent in males in population databases, such as gnomAD." }, { "baseStrength": "Pathogenic", "id": "1620362905", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362905", "label": "PM1", "strengthDescriptor": "Strong", "text": "This code can be applied at the strong level for variants involving the following residues: R391-S392, R759-S760, E1701-Q1705, R1708-S1709, Y1683, Y1689, Y737, Y742." }, { "baseStrength": "Pathogenic", "id": "1620362905", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362905", "label": "PM1", "strengthDescriptor": "Moderate", "text": "This code can be applied at the moderate level for variants involving the following residues: \n\nResidues affecting secretion: Arg1667, Arg1332\n\nFXa-binding residues: Gly2267-Gly2304 (with the exception of Ser2283)" }, { "baseStrength": "Benign", "id": "1620362903", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362903", "label": "BP7", "strengthDescriptor": "Supporting", "text": "Splice AI should be used to suggest no splicing impact. Splicing prediction score of less than or equal to 0.05 is required. Conservation should be assess using PhyloP (cutoff less than 0.1) and PhastCons (cutoff less than 0.5)." }, { "baseStrength": "Benign", "id": "1620362891", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362891", "label": "BP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not being used at this time. There are reports of males with hemophilia having two suspicious pathogenic variants." }, { "baseStrength": "Benign", "id": "1620362891", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362891", "label": "BP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Not being used at this time. There are reports of males with hemophilia having two suspicious pathogenic variants." }, { "baseStrength": "Benign", "id": "1620362891", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362891", "label": "BP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not being used at this time. There are reports of males with hemophilia having two suspicious pathogenic variants." }, { "baseStrength": "Benign", "id": "1620362891", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362891", "label": "BP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not being used at this time. There are reports of males with hemophilia having two suspicious pathogenic variants." }, { "baseStrength": "Benign", "id": "1620362885", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362885", "label": "BS3", "strengthDescriptor": "Strong", "text": "This code can be used for _F8_ gene variants studied in a cell line or mouse model setting that confer a normal factor VIII activity level AND normal factor VIII antigen level OR normal Western Blot." }, { "baseStrength": "Benign", "id": "1620362885", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362885", "label": "BS3", "strengthDescriptor": "Supporting", "text": "This code can be used for _F8_ gene variants studied in a cell line or mouse model setting that confer the following results:                    \n\n* Normal factor VIII activity level, OR\n* Abnormal factor VIII activity level with abnormal 2N binding assay suggesting a diagnosis of VWD Normandy (VWD 2N) instead of hemophilia A." }, { "baseStrength": "Pathogenic", "id": "1620362882", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362882", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for the F8 gene." }, { "baseStrength": "Pathogenic", "id": "1620362882", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362882", "label": "PM3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for the F8 gene." }, { "baseStrength": "Pathogenic", "id": "1620362882", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362882", "label": "PM3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for the F8 gene." }, { "baseStrength": "Pathogenic", "id": "1620362882", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362882", "label": "PM3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for the F8 gene." }, { "baseStrength": "Benign", "id": "1620362900", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362900", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "MAF cutoff of greater or equal to 0.0333% (or 0.000333)." }, { "baseStrength": "Pathogenic", "id": "1620362898", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362898", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree." }, { "baseStrength": "Pathogenic", "id": "1620362898", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362898", "label": "PVS1", "strengthDescriptor": "Strong", "text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree." }, { "baseStrength": "Pathogenic", "id": "1620362898", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362898", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree." }, { "baseStrength": "Pathogenic", "id": "1620362897", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362897", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "≥8 probands meet criteria described below" }, { "baseStrength": "Pathogenic", "id": "1620362897", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362897", "label": "PS4", "strengthDescriptor": "Strong", "text": "4-7 probands meet criteria described below" }, { "baseStrength": "Pathogenic", "id": "1620362897", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362897", "label": "PS4", "strengthDescriptor": "Moderate", "text": "2-3 probands meet criteria described below" }, { "baseStrength": "Pathogenic", "id": "1620362897", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362897", "label": "PS4", "strengthDescriptor": "Supporting", "text": "1 proband meets criteria described below" }, { "baseStrength": "Pathogenic", "id": "1620362896", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362896", "label": "PP1", "strengthDescriptor": "Strong", "text": "The code is application when there are ≥4 meioses across ≥2 families." }, { "baseStrength": "Pathogenic", "id": "1620362896", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362896", "label": "PP1", "strengthDescriptor": "Moderate", "text": "The code is application when there are at least 3 meioses across one or more families." }, { "baseStrength": "Pathogenic", "id": "1620362896", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362896", "label": "PP1", "strengthDescriptor": "Supporting", "text": "The code is application when there are 2 meioses in one family **OR** 1 meiosis between 2 affected siblings." }, { "baseStrength": "Pathogenic", "id": "1620362894", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362894", "label": "PS3", "strengthDescriptor": "Strong", "text": "Abnormal factor VIII activity (\\<40 IU/dL or 40%) via one-stage or two-stage chromogenic assay in a cell line and/or mouse model." }, { "baseStrength": "Pathogenic", "id": "1620362894", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362894", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Absent or significantly reduced factor VIII antigen levels compared to wildtype in a cell line by quantitative assay." }, { "baseStrength": "Benign", "id": "1620362893", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362893", "label": "BP3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for F8 gene." }, { "baseStrength": "Benign", "id": "1620362893", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362893", "label": "BP3", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for F8 gene." }, { "baseStrength": "Benign", "id": "1620362893", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362893", "label": "BP3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for F8 gene." }, { "baseStrength": "Benign", "id": "1620362893", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362893", "label": "BP3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for F8 gene." }, { "baseStrength": "Benign", "id": "1620362887", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362887", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for F8 gene." }, { "baseStrength": "Benign", "id": "1620362887", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362887", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for F8 gene." }, { "baseStrength": "Benign", "id": "1620362887", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362887", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for F8 gene." }, { "baseStrength": "Benign", "id": "1620362887", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362887", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for F8 gene." }, { "baseStrength": "Pathogenic", "id": "1620362886", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362886", "label": "PM5", "strengthDescriptor": "Moderate", "text": "This evidence code can be applied when there is 1 pathogenic variant or 2 likely pathogenic variants at the same residue based on the _F8_ rule specifications from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect." }, { "baseStrength": "Pathogenic", "id": "1620362886", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362886", "label": "PM5", "strengthDescriptor": "Supporting", "text": "This evidence code can be applied when there is 1 likely pathogenic variant at the same residue based on the _F8_ rule specifications from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect." }, { "baseStrength": "Pathogenic", "id": "1620362884", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362884", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Use code with no specification." }, { "baseStrength": "Pathogenic", "id": "1620362890", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362890", "label": "PS1", "strengthDescriptor": "Strong", "text": "This evidence code can be applied when there is 1 pathogenic variant or 2 likely pathogenic variants at the same residue based on _F8_ gene rule specifications from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect." }, { "baseStrength": "Pathogenic", "id": "1620362890", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362890", "label": "PS1", "strengthDescriptor": "Moderate", "text": "This evidence code can be applied when there is 1 likely pathogenic variants at the same residue based on _F8_ gene rule specifications from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggesting a splicing defect." }, { "baseStrength": "Pathogenic", "id": "1620362889", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362889", "label": "PM6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This rule code is combined with PS2. Please combined assumed de novo cases with confirmed de novo cases and apply PS2 at the appropriate weight." }, { "baseStrength": "Pathogenic", "id": "1620362889", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362889", "label": "PM6", "strengthDescriptor": "Strong", "text": "Not Applicable: This rule code is combined with PS2. Please combined assumed de novo cases with confirmed de novo cases and apply PS2 at the appropriate weight." }, { "baseStrength": "Pathogenic", "id": "1620362889", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362889", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This rule code is combined with PS2. Please combined assumed de novo cases with confirmed de novo cases and apply PS2 at the appropriate weight." }, { "baseStrength": "Pathogenic", "id": "1620362889", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362889", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This rule code is combined with PS2. Please combined assumed de novo cases with confirmed de novo cases and apply PS2 at the appropriate weight." }, { "baseStrength": "Benign", "id": "1620362907", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362907", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620362907", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362907", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620362907", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362907", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1620362907", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362907", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1620362904", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362904", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Proband must meet hemophilia A phenotype criteria AND have full gene sequencing and deletion/duplication analysis." }, { "baseStrength": "Pathogenic", "id": "1620362901", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362901", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Not applicable for F8." }, { "baseStrength": "Pathogenic", "id": "1620362901", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362901", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Not applicable for F8." }, { "baseStrength": "Pathogenic", "id": "1620362901", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362901", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Not applicable for F8." }, { "baseStrength": "Pathogenic", "id": "1620362901", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362901", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Not applicable for F8." }, { "baseStrength": "Benign", "id": "1620362899", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362899", "label": "BP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: While unlikely, it is possible for males with hemophilia to also have a diagnosis of von Willebrand Normandy (or VWD 2N)." }, { "baseStrength": "Benign", "id": "1620362899", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362899", "label": "BP5", "strengthDescriptor": "Strong", "text": "Not Applicable: While unlikely, it is possible for males with hemophilia to also have a diagnosis of von Willebrand Normandy (or VWD 2N)." }, { "baseStrength": "Benign", "id": "1620362899", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362899", "label": "BP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: While unlikely, it is possible for males with hemophilia to also have a diagnosis of von Willebrand Normandy (or VWD 2N)." }, { "baseStrength": "Benign", "id": "1620362899", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362899", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: While unlikely, it is possible for males with hemophilia to also have a diagnosis of von Willebrand Normandy (or VWD 2N)." }, { "baseStrength": "Pathogenic", "id": "1620362892", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362892", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "Use the SVI recommendations for de novo cases; 4 points. Use de novo guidance below to determine point value." }, { "baseStrength": "Pathogenic", "id": "1620362892", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362892", "label": "PS2", "strengthDescriptor": "Strong", "text": "Use the SVI recommendations for de novo cases; 2 points. Use de novo guidance below to determine point value." }, { "baseStrength": "Pathogenic", "id": "1620362892", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362892", "label": "PS2", "strengthDescriptor": "Moderate", "text": "Use the SVI recommendations for de novo cases; 1 point. Use de novo guidance below to determine point value." }, { "baseStrength": "Pathogenic", "id": "1620362892", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362892", "label": "PS2", "strengthDescriptor": "Supporting", "text": "Use the SVI recommendations for de novo cases; 0.5 point. Use de novo guidance below to determine point value." }, { "baseStrength": "Benign", "id": "1620362881", "iri": "https://genboree.org/cspec/CriteriaCode/id/1620362881", "label": "BS1", "strengthDescriptor": "Strong", "text": "MAF cutoff of greater than or equal to 0.00333% (or 0.0000333)." } ], "diseases": [ { "id": "MONDO:0010602", "iri": "https://genboree.org/cspec/Disease/id/467893775", "label": "hemophilia A" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467825573", "label": "F8" } ], "ruleSet": { "id": "643243148", "iri": "https://genboree.org/cspec/RuleSet/id/643243148" }, "svi": { "id": "GN071", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243141", "label": "ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0" } }, { "codes": [ { "baseStrength": "Benign", "id": "1746109683", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109683", "label": "BP3", "strengthDescriptor": "Supporting", "text": "In frame-deletions/insertions in a repetitive region without a known function." }, { "baseStrength": "Benign", "id": "1746109681", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109681", "label": "BP5", "strengthDescriptor": "Supporting", "text": "Variant found in a case with an alternate molecular basis for disease." }, { "baseStrength": "Pathogenic", "id": "1746109674", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109674", "label": "PVS1", "strengthDescriptor": "Very Strong", "text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1B-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr204. \n\nIn-frame exons: 3-5\n\nOut-of-frame exons: 1-2\n\nFor splice region variants, this criterion should not be applied with PP3." }, { "baseStrength": "Pathogenic", "id": "1746109674", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109674", "label": "PVS1", "strengthDescriptor": "Strong", "text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1B-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr204. \n\nIn-frame exons: 3-5\n\nOut-of-frame exons: 1-2\n\nFor splice region variants, this criterion should not be applied with PP3." }, { "baseStrength": "Pathogenic", "id": "1746109674", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109674", "label": "PVS1", "strengthDescriptor": "Moderate", "text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1B-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr204. \n\nIn-frame exons: 3-5\n\nOut-of-frame exons: 1-2\n\nFor splice region variants, this criterion should not be applied with PP3." }, { "baseStrength": "Pathogenic", "id": "1746109674", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109674", "label": "PVS1", "strengthDescriptor": "Supporting", "text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1B-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr204. \n\nIn-frame exons: 3-5\n\nOut-of-frame exons: 1-2\n\nFor splice region variants, this criterion should not be applied with PP3." }, { "baseStrength": "Benign", "id": "1746109667", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109667", "label": "BS4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Reduced penetrance, variable expressivity and phenocopies" }, { "baseStrength": "Benign", "id": "1746109667", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109667", "label": "BS4", "strengthDescriptor": "Strong", "text": "Not Applicable: Reduced penetrance, variable expressivity and phenocopies" }, { "baseStrength": "Benign", "id": "1746109667", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109667", "label": "BS4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Reduced penetrance, variable expressivity and phenocopies" }, { "baseStrength": "Benign", "id": "1746109667", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109667", "label": "BS4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Reduced penetrance, variable expressivity and phenocopies" }, { "baseStrength": "Benign", "id": "1746109666", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109666", "label": "BS3", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n" }, { "baseStrength": "Benign", "id": "1746109666", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109666", "label": "BS3", "strengthDescriptor": "Strong", "text": "Not Applicable: Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n" }, { "baseStrength": "Benign", "id": "1746109666", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109666", "label": "BS3", "strengthDescriptor": "Moderate", "text": "Not Applicable: Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n" }, { "baseStrength": "Benign", "id": "1746109666", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109666", "label": "BS3", "strengthDescriptor": "Supporting", "text": "Not Applicable: Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n" }, { "baseStrength": "Pathogenic", "id": "1746109665", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109665", "label": "PM5", "strengthDescriptor": "Strong", "text": "This should say greater than or equal to 2 known pathogenic variants at same site as novel change." }, { "baseStrength": "Pathogenic", "id": "1746109665", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109665", "label": "PM5", "strengthDescriptor": "Moderate", "text": "* Novel missense change at an amino acid residue where a different missense change determined to be **Pathogenic** has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level." }, { "baseStrength": "Pathogenic", "id": "1746109665", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109665", "label": "PM5", "strengthDescriptor": "Supporting", "text": "* Novel missense change at an amino acid residue where a different missense change determined to be **Likely Pathogenic** has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys." }, { "baseStrength": "Benign", "id": "1746109688", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109688", "label": "BP4", "strengthDescriptor": "Moderate", "text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool." }, { "baseStrength": "Benign", "id": "1746109688", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109688", "label": "BP4", "strengthDescriptor": "Supporting", "text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool." }, { "baseStrength": "Benign", "id": "1746109680", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109680", "label": "BS1", "strengthDescriptor": "Strong", "text": "Allele frequency is above **0.01%** in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed." }, { "baseStrength": "Pathogenic", "id": "1746109678", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109678", "label": "PP3", "strengthDescriptor": "Moderate", "text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong" }, { "baseStrength": "Pathogenic", "id": "1746109678", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109678", "label": "PP3", "strengthDescriptor": "Supporting", "text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong" }, { "baseStrength": "Pathogenic", "id": "1746109671", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109671", "label": "PP5", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1746109671", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109671", "label": "PP5", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1746109671", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109671", "label": "PP5", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1746109671", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109671", "label": "PP5", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1746109670", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109670", "label": "BS2", "strengthDescriptor": "Strong", "text": "Observed in a healthy adult individual." }, { "baseStrength": "Pathogenic", "id": "1746109669", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109669", "label": "PP2", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Benign missense variants are common. " }, { "baseStrength": "Pathogenic", "id": "1746109669", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109669", "label": "PP2", "strengthDescriptor": "Strong", "text": "Not Applicable: Benign missense variants are common. " }, { "baseStrength": "Pathogenic", "id": "1746109669", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109669", "label": "PP2", "strengthDescriptor": "Moderate", "text": "Not Applicable: Benign missense variants are common. " }, { "baseStrength": "Pathogenic", "id": "1746109669", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109669", "label": "PP2", "strengthDescriptor": "Supporting", "text": "Not Applicable: Benign missense variants are common. " }, { "baseStrength": "Benign", "id": "1746109668", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109668", "label": "BP1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Missense variants are common cause of disease. " }, { "baseStrength": "Benign", "id": "1746109668", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109668", "label": "BP1", "strengthDescriptor": "Strong", "text": "Not Applicable: Missense variants are common cause of disease. " }, { "baseStrength": "Benign", "id": "1746109668", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109668", "label": "BP1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Missense variants are common cause of disease. " }, { "baseStrength": "Benign", "id": "1746109668", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109668", "label": "BP1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Missense variants are common cause of disease. " }, { "baseStrength": "Benign", "id": "1746109664", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109664", "label": "BP2", "strengthDescriptor": "Supporting", "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." }, { "baseStrength": "Pathogenic", "id": "1746109662", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109662", "label": "PM2", "strengthDescriptor": "Supporting", "text": "One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing." }, { "baseStrength": "Pathogenic", "id": "1746109679", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109679", "label": "PS3", "strengthDescriptor": "Strong", "text": "Mouse knock-in model displays spontaneous seizures." }, { "baseStrength": "Pathogenic", "id": "1746109679", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109679", "label": "PS3", "strengthDescriptor": "Moderate", "text": "* Heterologous expression with voltage clamping shows statistically significant difference over wildtype in at least one parameter (https://bioportal.bioontology.org/ontologies/FENICS)\n* Mouse knock-in model displays induced seizures\n* Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies" }, { "baseStrength": "Pathogenic", "id": "1746109679", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109679", "label": "PS3", "strengthDescriptor": "Supporting", "text": "Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies" }, { "baseStrength": "Pathogenic", "id": "1746109673", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109673", "label": "PM1", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Currently, insufficient numbers of pathogenic variants have been reported in SCN1B to calculate “mutational hotspots”. SCN1B does not belong to a gene family to utilize PERs." }, { "baseStrength": "Pathogenic", "id": "1746109673", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109673", "label": "PM1", "strengthDescriptor": "Strong", "text": "Not Applicable: Currently, insufficient numbers of pathogenic variants have been reported in SCN1B to calculate “mutational hotspots”. SCN1B does not belong to a gene family to utilize PERs." }, { "baseStrength": "Pathogenic", "id": "1746109673", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109673", "label": "PM1", "strengthDescriptor": "Moderate", "text": "Not Applicable: Currently, insufficient numbers of pathogenic variants have been reported in SCN1B to calculate “mutational hotspots”. SCN1B does not belong to a gene family to utilize PERs." }, { "baseStrength": "Pathogenic", "id": "1746109673", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109673", "label": "PM1", "strengthDescriptor": "Supporting", "text": "Not Applicable: Currently, insufficient numbers of pathogenic variants have been reported in SCN1B to calculate “mutational hotspots”. SCN1B does not belong to a gene family to utilize PERs." }, { "baseStrength": "Pathogenic", "id": "1746109672", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109672", "label": "PM3", "strengthDescriptor": "Very Strong", "text": "For recessive disorders, points-based system based on confirmation of phase and classification of other variant. Total of **4.0 points** will arrive at **Very Strong**. \n\n* Classification of other variant is Pathogenic/Likely Pathogenic\n * Confirmed in trans: 1 point\n * Phase unknown: 0.5 (P) or 0.25 (LP) points\n* Homozygous occurrence (max point 1.0)\n * Confirmed in trans: 0.5 points\n* Classification of other variant is Uncertain Significance \n * Confirmed in trans: 0.25 points\n * Phase unknown: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746109672", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109672", "label": "PM3", "strengthDescriptor": "Strong", "text": "For recessive disorders, points-based system based on confirmation of phase and classification of other variant. Total of **2.0 points** will arrive at **Strong**. \n\n* Classification of other variant is Pathogenic/Likely Pathogenic\n * Confirmed in trans: 1 point\n * Phase unknown: 0.5 (P) or 0.25 (LP) points\n* Homozygous occurrence (max point 1.0)\n * Confirmed in trans: 0.5 points\n* Classification of other variant is Uncertain Significance \n * Confirmed in trans: 0.25 points\n * Phase unknown: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746109672", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109672", "label": "PM3", "strengthDescriptor": "Moderate", "text": "For recessive disorders, points-based system based on confirmation of phase and classification of other variant. Total of **1.0 point** will arrive at **Moderate**. \n\n* Classification of other variant is Pathogenic/Likely Pathogenic\n * Confirmed in trans: 1 point\n * Phase unknown: 0.5 (P) or 0.25 (LP) points\n* Homozygous occurrence (max point 1.0)\n * Confirmed in trans: 0.5 points\n* Classification of other variant is Uncertain Significance \n * Confirmed in trans: 0.25 points\n * Phase unknown: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746109672", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109672", "label": "PM3", "strengthDescriptor": "Supporting", "text": "For recessive disorders, points-based system based on confirmation of phase and classification of other variant. Total of **0.5 points** will arrive at **Supporting**. \n\n* Classification of other variant is Pathogenic/Likely Pathogenic\n * Confirmed in trans: 1 point\n * Phase unknown: 0.5 (P) or 0.25 (LP) points\n* Homozygous occurrence (max point 1.0)\n * Confirmed in trans: 0.5 points\n* Classification of other variant is Uncertain Significance \n * Confirmed in trans: 0.25 points\n * Phase unknown: 0 points" }, { "baseStrength": "Pathogenic", "id": "1746109686", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109686", "label": "PS1", "strengthDescriptor": "Strong", "text": "Same amino acid change as a previously established **Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\")." }, { "baseStrength": "Pathogenic", "id": "1746109686", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109686", "label": "PS1", "strengthDescriptor": "Moderate", "text": "Same amino acid change as a previously established **Likely Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\")." }, { "baseStrength": "Pathogenic", "id": "1746109686", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109686", "label": "PS1", "strengthDescriptor": "Supporting", "text": "Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\")." }, { "baseStrength": "Pathogenic", "id": "1746109685", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109685", "label": "PS2", "strengthDescriptor": "Very Strong", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 points** will arrive at **Very Strong**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "1746109685", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109685", "label": "PS2", "strengthDescriptor": "Strong", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "1746109685", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109685", "label": "PS2", "strengthDescriptor": "Moderate", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "1746109685", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109685", "label": "PS2", "strengthDescriptor": "Supporting", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity." }, { "baseStrength": "Pathogenic", "id": "1746109684", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109684", "label": "PP4", "strengthDescriptor": "Very Strong", "text": "Not Applicable: Phenotypic specificity incorporated into PS2, PM6, PS4" }, { "baseStrength": "Pathogenic", "id": "1746109684", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109684", "label": "PP4", "strengthDescriptor": "Strong", "text": "Not Applicable: Phenotypic specificity incorporated into PS2, PM6, PS4" }, { "baseStrength": "Pathogenic", "id": "1746109684", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109684", "label": "PP4", "strengthDescriptor": "Moderate", "text": "Not Applicable: Phenotypic specificity incorporated into PS2, PM6, PS4" }, { "baseStrength": "Pathogenic", "id": "1746109684", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109684", "label": "PP4", "strengthDescriptor": "Supporting", "text": "Not Applicable: Phenotypic specificity incorporated into PS2, PM6, PS4" }, { "baseStrength": "Pathogenic", "id": "1746109682", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109682", "label": "PP1", "strengthDescriptor": "Strong", "text": "Co-segregation with disease in multiple affected family members\n\nAD: ≥7 independent meioses\n\nAR: ≥3 affected segregations" }, { "baseStrength": "Pathogenic", "id": "1746109682", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109682", "label": "PP1", "strengthDescriptor": "Moderate", "text": "Co-segregation with disease in multiple affected family members\n\nAD: 5-6 independent meioses\n\nAR: 2 affected segregations" }, { "baseStrength": "Pathogenic", "id": "1746109682", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109682", "label": "PP1", "strengthDescriptor": "Supporting", "text": "Co-segregation with disease in multiple affected family members\n\nAD: 3-4 independent meioses\n\nAR: 1 affected segregation" }, { "baseStrength": "Benign", "id": "1746109677", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109677", "label": "BP7", "strengthDescriptor": "Supporting", "text": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved." }, { "baseStrength": "Benign", "id": "1746109675", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109675", "label": "BA1", "strengthDescriptor": "Stand Alone", "text": "Allele frequency is above **0.3%** in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed." }, { "baseStrength": "Benign", "id": "1746109687", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109687", "label": "BP6", "strengthDescriptor": "Very Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1746109687", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109687", "label": "BP6", "strengthDescriptor": "Strong", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1746109687", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109687", "label": "BP6", "strengthDescriptor": "Supporting", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Benign", "id": "1746109687", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109687", "label": "BP6", "strengthDescriptor": "Moderate", "text": "Not Applicable: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee." }, { "baseStrength": "Pathogenic", "id": "1746109676", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109676", "label": "PM6", "strengthDescriptor": "Strong", "text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. Total of **4 points** will arrive at **Very Strong**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points" }, { "baseStrength": "Pathogenic", "id": "1746109676", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109676", "label": "PM6", "strengthDescriptor": "Moderate", "text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points" }, { "baseStrength": "Pathogenic", "id": "1746109676", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109676", "label": "PM6", "strengthDescriptor": "Supporting", "text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points" }, { "baseStrength": "Pathogenic", "id": "1746109663", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109663", "label": "PS4", "strengthDescriptor": "Very Strong", "text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **16+ points** will arrive at **Very Strong**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points" }, { "baseStrength": "Pathogenic", "id": "1746109663", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109663", "label": "PS4", "strengthDescriptor": "Strong", "text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4-15.5 points** will arrive at **Strong**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points" }, { "baseStrength": "Pathogenic", "id": "1746109663", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109663", "label": "PS4", "strengthDescriptor": "Moderate", "text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2-3.5 points** will arrive at **Moderate**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points" }, { "baseStrength": "Pathogenic", "id": "1746109663", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109663", "label": "PS4", "strengthDescriptor": "Supporting", "text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1-1.5 points** will arrive at **Supporting**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points" }, { "baseStrength": "Pathogenic", "id": "1746109661", "iri": "https://genboree.org/cspec/CriteriaCode/id/1746109661", "label": "PM4", "strengthDescriptor": "Moderate", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." } ], "diseases": [ { "id": "MONDO:0018214", "iri": "https://genboree.org/cspec/Disease/id/467877022", "label": "generalized epilepsy with febrile seizures plus" }, { "id": "MONDO:0100062", "iri": "https://genboree.org/cspec/Disease/id/467881472", "label": "genetic developmental and epileptic encephalopathy" } ], "geneType": "nuclear", "genes": [ { "iri": "https://genboree.org/cspec/Gene/id/467855390", "label": "SCN1B" } ], "ruleSet": { "id": "643243153", "iri": "https://genboree.org/cspec/RuleSet/id/643243153" }, "svi": { "id": "GN076", "iri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243146", "label": "ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN1B Version 1.0.0" } } ], "metadata": { "rendered": { "by": "https://genboree.org/cspec/srvc", "when": "2026-04-12T10:05:44.009Z" } }, "status": { "code": 200, "name": "OK" } }