{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/83d2e780-32b3-4547-a009-947ee3e4acc8/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/CA49771569/MONDO:0015152/180/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA49771569/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": "2026/4/9", "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/CA49771569/MONDO:0015152/180/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA49771569/MONDO:0015152/180/ci/CA49771569/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 REVEL score for this variant is 0.488 (PP3 and BP4 not met).\n\nSpliceAI score 0.", "contributionDate": { "date": "2026/4/9", "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": "CA49771569/MONDO:0015152/180/ci/CA49771569/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA49771569/MONDO:0015152/180/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA49771569/MONDO:0015152/180/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA49771569/MONDO:0015152/180/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA49771569/MONDO:0015152/180/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA49771569/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": "2026/4/9", "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/CA49771569/MONDO:0015152/180/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA49771569/MONDO:0015152/180/ci/CA49771569/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 Grpmax variant allele frequency in gnomAD v4.1.0 is 0.00004465 (2/44788 East Asian chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). ", "contributionDate": { "date": "2026/4/9", "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": "CA49771569/MONDO:0015152/180/ci/CA49771569/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA49771569/MONDO:0015152/180/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA49771569/MONDO:0015152/180/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA49771569/MONDO:0015152/180/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA49771569/MONDO:0015152/180/el/0/1738", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA49771569/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": "2026/4/9", "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/CA49771569/MONDO:0015152/180/el/0/1738/1740", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA49771569/MONDO:0015152/180/ci/CA49771569/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 individual with this variant and a second presumed diagnostic DYSF variant exhibited progressive proximal muscle weakness and severely reduced dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PMID: 27647186; LOVD Individual #00305668) (PP4_Strong).", "contributionDate": { "date": "2026/4/9", "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": "CA49771569/MONDO:0015152/180/ci/CA49771569/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA49771569/MONDO:0015152/180/0/1738/1740", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA49771569/MONDO:0015152/180/1/1739", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA49771569/MONDO:0015152/180/0/1738", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA49771569/MONDO:0015152/180/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA49771569/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": "2026/4/9", "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/CA49771569/MONDO:0015152/180/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA49771569/MONDO:0015152/180/ci/CA49771569/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": "Another missense variant at the same position, p.(Glu389Gln), has been reported as pathogenic (PMID:15515206) (ClinVar Variation ID: 6674). However, the REVEL score for the missense variant under curation should be >0.7 to apply PM5, and the REVEL score for this variant is only 0.488. Both have SpliceAI scores <0.1.\n\nThe Grantham difference for the curated variant (Glu - Lys: 56) is higher than that for the comparison variant (Glu - Gln: 29). The REVEL for the comparison variant, 0.57, also doesn't meet the threshold for PP3. \n", "contributionDate": { "date": "2026/4/9", "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": "CA49771569/MONDO:0015152/180/ci/CA49771569/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA49771569/MONDO:0015152/180/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA49771569/MONDO:0015152/180/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA49771569/MONDO:0015152/180/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA49771569/MONDO:0015152/180/el/0/1609", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA49771569/MONDO:0015152/180/ei/1/1610", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/4/9", "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/CA49771569/MONDO:0015152/180/el/0/1609/1611", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA49771569/MONDO:0015152/180/ci/CA49771569/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 identified in at least two individuals with clinical features consistent with limb-girdle muscular dystrophy (PMID: 27647186, 33613410, 34559919; DYSF_001156), including in unconfirmed phase with a pathogenic variant in one patient (c.4003G>A p.(Glu1335Lys) 0.5 pts, PMID: 33613410) (PM3_Supporting). \n\nThis variant is not present in gnomAD v2, and so co-occurrence cannot be assessed.\n\nUnscored cases:\nPMID: 27647186: c.2997G>T p.(Trp999Cys), unconfirmed phase: 0.5 pts if curated as P\nDysferlin Registry: homozygous, no known consanguinity: 0.5 pts if phenotype confirmed\nDysferlin Registry: c.3119_3123del p.(Arg1040fs), unconfirmed phase: 0.5 pts if curated as P and phenotype confirmed\n\nAdditional cases possible from ClinVar submitters, but with PP3 and PM5 excluded, PM3_Very Strong will be required to upgrade classification from LP to P (3.5 more PM3 pts). Getting this many points seems unlikely, and so queries not pursued at this time. ", "contributionDate": { "date": "2026/4/9", "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": "CA49771569/MONDO:0015152/180/ci/CA49771569/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA49771569/MONDO:0015152/180/0/1609/1611", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA49771569/MONDO:0015152/180/1/1610", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA49771569/MONDO:0015152/180/0/1609", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA49771569/MONDO:0015152/180", "metadata": { "created": "2026-04-09T22:56:39.058Z", "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": "Thu, 09 Apr 2026 22:56:38 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA26332-9", "id": "LN:LA26332-9", "label": "Likely Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "83d2e780-32b3-4547-a009-947ee3e4acc8", "variant": { "@id": "https://reg.genome.network/allele/CA49771569", "id": "CAR:CA49771569", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_001130987.2:c.1261G>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_001130987.2(DYSF):c.1261G>A (p.Glu421Lys)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-14T05:17:22.159Z" } }, "status": { "code": 200, "name": "OK" } }