{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/b708dc64-c8c3-4823-a58b-ad4406c82733/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/CA391999624/MONDO:0015152/187/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA391999624/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": "2026/4/9", "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/CA391999624/MONDO:0015152/187/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA391999624/MONDO:0015152/187/ci/CA391999624/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 0.872, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function.", "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": "CA391999624/MONDO:0015152/187/ci/CA391999624/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA391999624/MONDO:0015152/187/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA391999624/MONDO:0015152/187/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA391999624/MONDO:0015152/187/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA391999624/MONDO:0015152/187/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA391999624/MONDO:0015152/187/ei/1/1634", "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/CA391999624/MONDO:0015152/187/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA391999624/MONDO:0015152/187/ci/CA391999624/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 this variant and a second presumed diagnostic CAPN3 allele displayed progressive limb girdle muscle weakness and reduced (<50%) or absent expression of calpain-3 protein in skeletal muscle, though the exact level was not specified (PMID: 22926650; PP4).", "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": "CA391999624/MONDO:0015152/187/ci/CA391999624/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA391999624/MONDO:0015152/187/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA391999624/MONDO:0015152/187/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA391999624/MONDO:0015152/187/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA391999624/MONDO:0015152/187/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA391999624/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": "2026/4/9", "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/CA391999624/MONDO:0015152/187/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA391999624/MONDO:0015152/187/ci/CA391999624/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 variant has been identified in at least six unrelated individuals with features consistent with LGMD (PMID: 25987458, 29797799, 22926650, 33250842, 32994280, 28403181), including in a homozygous state in one patient without reported consanguinity (0.5 pts, PMID: 32994280), confirmed in trans with a pathogenic variant in one patient (c.734dup p.(Ser246Ter), 1.0 pt, PMID: 28403181), and in unconfirmed phase with a pathogenic variant in one patient (c.2120A>G p.(Asp707Gly), 0.5 pts, PMID: 3299428). In two other patients, it was reported in unconfirmed phase with a variant classified as likely pathogenic by the VCEP (c.1319G>A p.(Arg440Gln), 0.25 pts, PMID: 33250842; c.2306G>C p.(Arg769Pro), 0.25 pts, PMID: 25987458) (PM3_Strong).\n\nco-occurrence predictions for variants in unconfirmed phase\nc.2120A>G (p.Asp707Gly): predicted on different haplotype in gnomAD v2\nc.1319G>A (p.Arg440Gln): predicted on different haplotype in gnomAD v2\nc.2306G>C p.(Arg769Pro): no prediction\n\nunscored cases:\nunknown phase with c.2243G>A (p.Arg748Gln) (not in VCI, Pathogenic in ClinVar)\n\ncurrently insufficient evidence to upgrade to PM3_Very Strong\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": "CA391999624/MONDO:0015152/187/ci/CA391999624/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA391999624/MONDO:0015152/187/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA391999624/MONDO:0015152/187/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA391999624/MONDO:0015152/187/0/1651", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA391999624/MONDO:0015152/187/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA391999624/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": "2026/4/9", "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/CA391999624/MONDO:0015152/187/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA391999624/MONDO:0015152/187/ci/CA391999624/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 for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5).\n\nc.1343G>A (p.Arg448His) is provisionally pathogenic without use of PM5\nSpliceAI <0.5, no splice effect\nThe Revel score for curated variant is >0.7\nNot located near an exon-intron boundary.", "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": "CA391999624/MONDO:0015152/187/ci/CA391999624/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA391999624/MONDO:0015152/187/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA391999624/MONDO:0015152/187/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA391999624/MONDO:0015152/187/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA391999624/MONDO:0015152/187/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA391999624/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": "2026/4/9", "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/CA391999624/MONDO:0015152/187/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA391999624/MONDO:0015152/187/ci/CA391999624/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 variant is absent from gnomAD v.4.1.0, meeting the criteria for 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": "CA391999624/MONDO:0015152/187/ci/CA391999624/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA391999624/MONDO:0015152/187/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA391999624/MONDO:0015152/187/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA391999624/MONDO:0015152/187/0/1636", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA391999624/MONDO:0015152/187", "metadata": { "created": "2026-04-09T23:53:28.764Z", "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 23:53:28 -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": "b708dc64-c8c3-4823-a58b-ad4406c82733", "variant": { "@id": "https://reg.genome.network/allele/CA391999624", "id": "CAR:CA391999624", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000070.3:c.1343G>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000070.3(CAPN3):c.1343G>T (p.Arg448Leu)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-05T02:07:30.264Z" } }, "status": { "code": 200, "name": "OK" } }