{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/c8bd6484-ecbf-4b5a-bc87-a052f79f612e/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/CA347482/MONDO:0015152/187/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347482/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/CA347482/MONDO:0015152/187/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA347482/MONDO:0015152/187/ci/CA347482/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 c.1343G>A (p.Arg448His) variant has been reported in at least 19 unrelated patients with features consistent with limb-girdle muscular dystrophy (PMID: 18854869, 9150160, 32994280, 30564623, 30919934, 25135358, 27447704, 16141003; LOVD CAPN3_000096). It has been observed in the homozygous state in one patient without reported consanguinity (0.5 pts; PMID: 30919934; LOVD Individual #00313874) as well as in five Indian patients without known relatedness but possible consanguinity (0.5 pts; PMID: 35169782). It has also been identified in a heterozygous state in unconfirmed phase with a pathogenic or likely pathogenic CAPN3 variant in several patients, including c.550del (0.5 pts; PMID: 18854869), c.1319G>A p.(Arg440Gln) (0.25 pts; PMID: 18854869), c.2362_2363delinsTCATCT p.(Arg788SerfsTer14) (0.5 pts; PMID: 9150160), and c.2120A>G p.(Asp707Gly) (0.5 pts; PMID: 32994280) (PM3_Strong).\n\nco-occurrence for scored variants in unconfirmed phase:\nc.550del p.(Thr184ArgfsTer36): predicted on different haplotypes\nc.1319G>A (p.Arg440Gln): predicted on different haplotypes \nc.2362_2363delinsTCATCT (p.Arg788SerfsTer14): not in gnomAD v2 \nc.2120A>G (p.Asp707Gly): predicted on different haplotypes \n\nCo-occurrences with variants of uncertain or unestablished pathogenicity (c.1992+1G>T, c.2393C>A (p.Ala798Glu), c.2371G>A (p.Gly791Ser), c.1657G>A (p.Glu553Lys), c.2093G>A (p.Arg698His), c.1043del (p.Gly348fs), c.2442G>C (p.Trp814Cys)) were not scored.\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": "CA347482/MONDO:0015152/187/ci/CA347482/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA347482/MONDO:0015152/187/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA347482/MONDO:0015152/187/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA347482/MONDO:0015152/187/0/1651", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347482/MONDO:0015152/187/el/0/1738", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347482/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/CA347482/MONDO:0015152/187/el/0/1738/1740", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA347482/MONDO:0015152/187/ci/CA347482/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 with two presumed diagnostic CAPN3 alleles, including this variant, displayed progressive limb girdle muscle weakness and absent expression of calpain-3 protein in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 18854869; 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": "CA347482/MONDO:0015152/187/ci/CA347482/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA347482/MONDO:0015152/187/0/1738/1740", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA347482/MONDO:0015152/187/1/1739", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA347482/MONDO:0015152/187/0/1738", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347482/MONDO:0015152/187/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347482/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/CA347482/MONDO:0015152/187/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA347482/MONDO:0015152/187/ci/CA347482/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 0.904, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3).\n\nSpliceAI: 0.00", "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": "CA347482/MONDO:0015152/187/ci/CA347482/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA347482/MONDO:0015152/187/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA347482/MONDO:0015152/187/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA347482/MONDO:0015152/187/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347482/MONDO:0015152/187/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347482/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/CA347482/MONDO:0015152/187/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA347482/MONDO:0015152/187/ci/CA347482/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 population allele frequency of this variant is 0.000002630 in the Admixed American population of gnomAD v4.1.0 (1/58530 chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting).\n\nGrpmax Filtering AF:\nEuropean (non-Finnish) 95% confidence: 0.000011208, also meets 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": "CA347482/MONDO:0015152/187/ci/CA347482/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA347482/MONDO:0015152/187/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA347482/MONDO:0015152/187/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA347482/MONDO:0015152/187/0/1636", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA347482/MONDO:0015152/187", "metadata": { "created": "2026-02-17T18:26:40.660Z", "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 18:26:40 -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": "c8bd6484-ecbf-4b5a-bc87-a052f79f612e", "variant": { "@id": "https://reg.genome.network/allele/CA347482", "id": "CAR:CA347482", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000070.3:c.1343G>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000070.3(CAPN3):c.1343G>A (p.Arg448His)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-05T22:21:36.544Z" } }, "status": { "code": 200, "name": "OK" } }