{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/02c8c70e-5a36-40bb-b81e-534e414b6839/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/CA346852/MONDO:0015152/187/el/0/1798", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA346852/MONDO:0015152/187/ei/1/1799", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/5/7", "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/CA346852/MONDO:0015152/187/el/0/1798/1800", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA346852/MONDO:0015152/187/ci/CA346852/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 upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.1 is 0.0001005 (4/91080 South Asian alleles), which is greater than the VCEP threshold of 0.0001 (PM2_Supporting not met).\n\nCriterion met with European (non-Finnish) and East Asian data but not with South Asian data but code not needed for P classification.", "contributionDate": { "date": "2026/5/7", "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": "CA346852/MONDO:0015152/187/ci/CA346852/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA346852/MONDO:0015152/187/0/1798/1800", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA346852/MONDO:0015152/187/1/1799", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA346852/MONDO:0015152/187/0/1798", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA346852/MONDO:0015152/187/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA346852/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": "2026/5/7", "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/CA346852/MONDO:0015152/187/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA346852/MONDO:0015152/187/ci/CA346852/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 0.734, which is above the VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3).\n\nNo predicted impact on Splicing", "contributionDate": { "date": "2026/5/7", "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": "CA346852/MONDO:0015152/187/ci/CA346852/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA346852/MONDO:0015152/187/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA346852/MONDO:0015152/187/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA346852/MONDO:0015152/187/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA346852/MONDO:0015152/187/el/0/1738", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA346852/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": "2026/5/7", "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/CA346852/MONDO:0015152/187/el/0/1738/1740", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA346852/MONDO:0015152/187/ci/CA346852/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 variant displayed progressive limb girdle muscle weakness as well as absent expression of calpain-3, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 35198268, 19556129).", "contributionDate": { "date": "2026/5/7", "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": "CA346852/MONDO:0015152/187/ci/CA346852/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA346852/MONDO:0015152/187/0/1738/1740", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA346852/MONDO:0015152/187/1/1739", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA346852/MONDO:0015152/187/0/1738", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA346852/MONDO:0015152/187/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA346852/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": "2026/5/7", "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/CA346852/MONDO:0015152/187/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA346852/MONDO:0015152/187/ci/CA346852/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.146G>A p.(Arg49His), has been classified as pathogenic by the ClinGen LGMD VCEP (PM5).\n\nboth variants have REVEL scores above PP3 threshold\nneither is predicted to affect splicing\n\nThe NM_000070.3: c.146G>A variant in CAPN3 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 49 (p.Arg49His). This variant has been detected in at least six unrelated individuals with limb girdle muscular dystrophy (PMID: 16650086, 17318636, 25135358; ClinVar SCV003459936.1 internal data communication, ClinVar SCV001164521.1 internal data communication), including in a homozygous state in one individual (ClinVar SCV001164521.1 internal data communication, 0.5 pts), confirmed in trans with a pathogenic variant (c.967G>T p.(Glu323Ter), 1.0 pt, PMID: 17318636), and confirmed in trans with two variants not yet curated by the VCEP and considered VUS (0.5 pts) (PM3_Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent expression of calpain-3, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 16650086). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.84, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PP3. ", "contributionDate": { "date": "2026/5/7", "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": "CA346852/MONDO:0015152/187/ci/CA346852/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA346852/MONDO:0015152/187/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA346852/MONDO:0015152/187/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA346852/MONDO:0015152/187/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA346852/MONDO:0015152/187/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA346852/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": "2026/5/7", "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/CA346852/MONDO:0015152/187/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA346852/MONDO:0015152/187/ci/CA346852/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 detected in at least six unrelated individuals with limb girdle muscular dystrophy (PMID: 35198268, 19285864, 19556129, 28403181, 31862442), including in a homozygous state in one individual with known consanguinity (PMID: 19285864, 0.25 pts), confirmed in trans with a pathogenic variant (c.2120A>G p.(Asp707Gly), 1.0 pt, PMID: 28403181), and in unknown phase with a second pathogenic variant in two individuals (c.2242C>T p.(Arg748Ter), 0.5 pt, PMID: 35198268; c.1468C>T p.(Arg490Trp), 0.5 pt, PMID: 19556129) (PM3_Strong).\n\npredicted on different haplotypes with c.1468C>T p.(Arg490Trp) and c.2242C>T p.(Arg748Ter)", "contributionDate": { "date": "2026/5/7", "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": "CA346852/MONDO:0015152/187/ci/CA346852/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA346852/MONDO:0015152/187/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA346852/MONDO:0015152/187/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA346852/MONDO:0015152/187/0/1651", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA346852/MONDO:0015152/187", "metadata": { "created": "2026-05-07T16:08:50.228Z", "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, 07 May 2026 16:08:50 -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": "02c8c70e-5a36-40bb-b81e-534e414b6839", "variant": { "@id": "https://reg.genome.network/allele/CA346852", "id": "CAR:CA346852", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000070.3:c.145C>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000070.3(CAPN3):c.145C>T (p.Arg49Cys)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-13T22:19:20.655Z" } }, "status": { "code": 200, "name": "OK" } }