{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/572c20a5-4352-4af4-86df-93d13df66327/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1812056141", "label": "ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CAPN3 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/CA7511324/MONDO:0015152/187/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511324/MONDO:0015152/187/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": "2026/2/17", "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/CA7511324/MONDO:0015152/187/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA7511324/MONDO:0015152/187/ci/CA7511324/MONDO:0015152/187.002", "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 0.846, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3).\n\nSpliceAI 0.06", "contributionDate": { "date": "2026/2/17", "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": "CA7511324/MONDO:0015152/187/ci/CA7511324/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA7511324/MONDO:0015152/187/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511324/MONDO:0015152/187/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA7511324/MONDO:0015152/187/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511324/MONDO:0015152/187/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511324/MONDO:0015152/187/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": "2026/2/17", "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/CA7511324/MONDO:0015152/187/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA7511324/MONDO:0015152/187/ci/CA7511324/MONDO:0015152/187.002", "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 frequency for this variant in gnomAD v4.1.0 is 0.00003412 (2/58616 Admixed American chromosomes), which is lower than the ClinGen LGMD VCEP threshold of <0.0001 for PM2_Supporting, meeting this criterion (PM2_Supporting). ", "contributionDate": { "date": "2026/2/17", "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": "CA7511324/MONDO:0015152/187/ci/CA7511324/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA7511324/MONDO:0015152/187/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511324/MONDO:0015152/187/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA7511324/MONDO:0015152/187/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511324/MONDO:0015152/187/el/0/1738", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511324/MONDO:0015152/187/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": "2026/2/17", "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/CA7511324/MONDO:0015152/187/el/0/1738/1740", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA7511324/MONDO:0015152/187/ci/CA7511324/MONDO:0015152/187.002", "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 homozygous for this variant had both progressive limb girdle muscle weakness and absent calpain-3 protein expression in skeletal muscle, which is highly specific for CAPN3-associated LGMD (PMID: 18854869, 15221789; PP4_Strong). ", "contributionDate": { "date": "2026/2/17", "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": "CA7511324/MONDO:0015152/187/ci/CA7511324/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA7511324/MONDO:0015152/187/0/1738/1740", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511324/MONDO:0015152/187/1/1739", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA7511324/MONDO:0015152/187/0/1738", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511324/MONDO:0015152/187/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511324/MONDO:0015152/187/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": "2026/2/17", "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/CA7511324/MONDO:0015152/187/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA7511324/MONDO:0015152/187/ci/CA7511324/MONDO:0015152/187.002", "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 codon, c.1343G>A p.(Arg448His), has been classified as pathogenic by the ClinGen LGMD VCEP (PM5). \n\ncurated variant: Revel 0.846, spliceAI 0.06\n\ncomparison variants:\nc.1343G>T p.(Arg448Leu): curation in progress\nc.1343G>A p.(Arg448His): provisionally P without use of PM5; REVEL 0.904, spliceAI 0.01\n\nGrantham \nArg-Cys: 0.644\nArg-His: 0.567\nArg-Leu: 0.415\ndifference score for variant being curated is greater than that for P comparison variant, p.(Arg448His). \n\ncode not needed for P classification but applies\n\n", "contributionDate": { "date": "2026/2/17", "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": "CA7511324/MONDO:0015152/187/ci/CA7511324/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA7511324/MONDO:0015152/187/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511324/MONDO:0015152/187/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA7511324/MONDO:0015152/187/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511324/MONDO:0015152/187/el/0/1828", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511324/MONDO:0015152/187/ei/1/1829", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/2/17", "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/CA7511324/MONDO:0015152/187/el/0/1828/1830", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA7511324/MONDO:0015152/187/ci/CA7511324/MONDO:0015152/187.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/2/17", "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": "CA7511324/MONDO:0015152/187/ci/CA7511324/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA7511324/MONDO:0015152/187/0/1828/1830", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511324/MONDO:0015152/187/1/1829", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA7511324/MONDO:0015152/187/0/1828", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511324/MONDO:0015152/187/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511324/MONDO:0015152/187/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": "2026/2/17", "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/CA7511324/MONDO:0015152/187/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA7511324/MONDO:0015152/187/ci/CA7511324/MONDO:0015152/187.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "This missense variant has been identified in at least nine individuals with clinical features consistent with limb-girdle muscular dystrophy (LGMD) (PMID: 37852290, 39733240, 16141003, 37526466, 17318636, 27447704, 18854869, 15221789, 17236769; GRASP-LGMD Consortium internal data communication), including in a homozygous state in at least four patients without reported familial consanguinity (1.0 pts; PMID: 16141003, 37526466, 17318636, 27447704, 18854869, 17236769). It has also been identified in unconfirmed phase with a pathogenic CAPN3 variant in at least two patients (c.550del p.(Thr184ArgfsTer36), 0.5 pts, PMID: 39733240; c.1115+5G>C, 0.5 pts, GRASP-LGMD Consortium internal data communication) (PM3_Strong).\n\nco-occurrence checked for all scored variants in unconfirmed phase\n\nunscored cases:\nc.2362_2363delinsTCA p.(Arg788SerfsTer13), which hasn't been curated yet but is on priority list for curation", "contributionDate": { "date": "2026/2/17", "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": "CA7511324/MONDO:0015152/187/ci/CA7511324/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA7511324/MONDO:0015152/187/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511324/MONDO:0015152/187/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA7511324/MONDO:0015152/187/0/1651", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511324/MONDO:0015152/187", "metadata": { "created": "2026-02-17T20:09:01.350Z", "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": "Tue, 17 Feb 2026 20:09:01 -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": "572c20a5-4352-4af4-86df-93d13df66327", "variant": { "@id": "https://reg.genome.network/allele/CA7511324", "id": "CAR:CA7511324", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000070.3:c.1342C>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000070.3(CAPN3):c.1342C>T (p.Arg448Cys)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-26T03:14:55.976Z" } }, "status": { "code": 200, "name": "OK" } }