{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/02177028-5a64-4cb6-ad09-d2699a4ceab8/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1807907463", "label": "ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DYSF Version 2.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "2.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0015152", "id": "MONDO:0015152", "label": "autosomal recessive limb-girdle muscular dystrophy", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347227869/MONDO:0015152/180/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347227869/MONDO:0015152/180/ei/1/1652", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2025/11/11", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347227869/MONDO:0015152/180/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA347227869/MONDO:0015152/180/ci/CA347227869/MONDO:0015152/180.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "This variant has been reported in at least three patients with features consistent with LGMD or dysferlinopathy (PMID: 39350328, 37974208, 33560664, 17828519, 17129727; LOVD Individual #00313788); in two of these individuals, it was identified in a compound heterozygous state with a likely pathogenic or pathogenic variant (NM_003494.4: c.5350C>T p.(Gln1784Ter), 1.0 pt, PMID: 39350328, 37974208, 33560664; NM_003494.4: c.1813C>T p.(Gln605Ter), 1.0 pt, PMID: 17828519, 17129727) (PM3_Strong). \n\nScoring the third case would not upgrade the classification, no other patients identified. ", "contributionDate": { "date": "2025/11/11", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA347227869/MONDO:0015152/180/ci/CA347227869/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA347227869/MONDO:0015152/180/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA347227869/MONDO:0015152/180/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA347227869/MONDO:0015152/180/0/1651", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347227869/MONDO:0015152/180/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347227869/MONDO:0015152/180/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2025/11/11", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347227869/MONDO:0015152/180/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA347227869/MONDO:0015152/180/ci/CA347227869/MONDO:0015152/180.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "The highest population allele frequency for this variant 8.475e-7 in gnomAD v4.1.0 (1/1180004 European (non-Finnish) alleles), which is less than the VCEP threshold for PM2_Supporting, meeting this criterion (PM2_Supporting). ", "contributionDate": { "date": "2025/11/11", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA347227869/MONDO:0015152/180/ci/CA347227869/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA347227869/MONDO:0015152/180/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA347227869/MONDO:0015152/180/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA347227869/MONDO:0015152/180/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347227869/MONDO:0015152/180/el/0/1588", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347227869/MONDO:0015152/180/ei/1/1589", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2025/11/11", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347227869/MONDO:0015152/180/el/0/1588/1590", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA347227869/MONDO:0015152/180/ci/CA347227869/MONDO:0015152/180.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "The Met2073Val protein was classified as functional in both the 2-A and immunofluorescence assay of dysferlin membrane localization, indicating the variant does not impact this aspect of protein function (PMID: 35028538; BS3 not met).", "contributionDate": { "date": "2025/11/11", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA347227869/MONDO:0015152/180/ci/CA347227869/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA347227869/MONDO:0015152/180/0/1588/1590", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA347227869/MONDO:0015152/180/1/1589", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA347227869/MONDO:0015152/180/0/1588", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347227869/MONDO:0015152/180/el/0/1738", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347227869/MONDO:0015152/180/ei/1/1739", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2025/11/11", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347227869/MONDO:0015152/180/el/0/1738/1740", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA347227869/MONDO:0015152/180/ci/CA347227869/MONDO:0015152/180.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "At least one patient with this variant and a second presumed diagnostic DYSF variant exhibited muscle weakness with a clinical diagnosis of LGMD and had severely reduced or absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PMID: 37974208, 33560664; LOVD Individual #00455530; PP4_Strong). \n\nPat18/LOVD Individual #00455530: 19-y-o male. elevated CK level (102.4x), EMG myopathic. initial diagnosis of limb-girdle muscular dystrophy, polymyositis. dysferlin expression reduced by IHC. In Lin et al. (2023), which also reports on this same patient, protein expression is described as \"absent or a severe reduction\". Second variant is a stop-gained, c.5350C>T p.(Gln1784Ter).\n", "contributionDate": { "date": "2025/11/11", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA347227869/MONDO:0015152/180/ci/CA347227869/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA347227869/MONDO:0015152/180/0/1738/1740", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA347227869/MONDO:0015152/180/1/1739", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA347227869/MONDO:0015152/180/0/1738", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347227869/MONDO:0015152/180/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347227869/MONDO:0015152/180/ei/1/1781", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2025/11/11", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347227869/MONDO:0015152/180/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA347227869/MONDO:0015152/180/ci/CA347227869/MONDO:0015152/180.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "NM_003494.4:c.6218T>G p.(Met2073Arg) is LP in ClinVar by CeGaT Center for Human Genetics Tuebingen but no citations. This variant is not in LOVD or HGMD and doesn't seem to be reported in the literature. Not in gnomAD, REVEL 0.71. Does not seem likely to reach LP. ", "contributionDate": { "date": "2025/11/11", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA347227869/MONDO:0015152/180/ci/CA347227869/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA347227869/MONDO:0015152/180/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA347227869/MONDO:0015152/180/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA347227869/MONDO:0015152/180/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347227869/MONDO:0015152/180/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347227869/MONDO:0015152/180/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2025/11/11", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347227869/MONDO:0015152/180/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA347227869/MONDO:0015152/180/ci/CA347227869/MONDO:0015152/180.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "The computational predictor REVEL gives a score of 0.838, which is greater than the VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function. \n\nnot in a splice region, SpliceAI 0", "contributionDate": { "date": "2025/11/11", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA347227869/MONDO:0015152/180/ci/CA347227869/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA347227869/MONDO:0015152/180/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA347227869/MONDO:0015152/180/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA347227869/MONDO:0015152/180/0/1747", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA347227869/MONDO:0015152/180", "metadata": { "created": "2025-11-12T16:11:58.690Z", "note": "DISCLAIMER: While the data/content in this document is approved by ClinGen expert panel(s), the SEPIO schema presented here is an initial prototype and has not been reviewed nor finalized by the ClinGen Data Exchange Modeling Team. We expect it to differ significantly from the final schema.", "producedAtUTC": "Wed, 12 Nov 2025 16:11:58 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA6668-3", "id": "LN:LA6668-3", "label": "Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "02177028-5a64-4cb6-ad09-d2699a4ceab8", "variant": { "@id": "https://reg.genome.network/allele/CA347227869", "id": "CAR:CA347227869", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_001130987.2:c.6334A>G" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_001130987.2(DYSF):c.6334A>G (p.Met2112Val)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-02T00:38:10.817Z" } }, "status": { "code": 200, "name": "OK" } }