{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/c3acf1c3-9cf0-4fc8-87cc-ae989d577c39/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/CA10604243/MONDO:0015152/187/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10604243/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": "2026/1/12", "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/CA10604243/MONDO:0015152/187/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA10604243/MONDO:0015152/187/ci/CA10604243/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 individual with this variant and a second presumed diagnostic CAPN3 variant displayed progressive limb girdle muscle weakness or had a clinical suspicion of LGMD (PMID: 9150160, 16100770, 16411092, 18854869, 25046369, 33304817, 37526466; PP4).", "contributionDate": { "date": "2026/1/12", "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": "CA10604243/MONDO:0015152/187/ci/CA10604243/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA10604243/MONDO:0015152/187/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA10604243/MONDO:0015152/187/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA10604243/MONDO:0015152/187/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10604243/MONDO:0015152/187/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10604243/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": "2026/1/12", "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/CA10604243/MONDO:0015152/187/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA10604243/MONDO:0015152/187/ci/CA10604243/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 Grpmax variant allele frequency in gnomAD v4.1.0 is 0.000002542 (3/1180032 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting).\n\n", "contributionDate": { "date": "2026/1/12", "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": "CA10604243/MONDO:0015152/187/ci/CA10604243/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA10604243/MONDO:0015152/187/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA10604243/MONDO:0015152/187/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA10604243/MONDO:0015152/187/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10604243/MONDO:0015152/187/el/0/1717", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10604243/MONDO:0015152/187/ei/1/1718", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/1/12", "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/CA10604243/MONDO:0015152/187/el/0/1717/1719", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA10604243/MONDO:0015152/187/ci/CA10604243/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 reported in at least seven unrelated individuals with features consistent with LGMD (PMID: 9150160, 16100770, 16411092, 18854869, 25046369, 33304817, 37526466), including in a homozygous state in the probands of two consanguineous families (0.25 pts x2; PMID: 9150160, 16411092) and confirmed in trans with a pathogenic variant in one patient (c.550del, p.(Thr184ArgfsTer36), 1.0 pt, PMID: 16100770) (PM3).\n\n\n550delA is pathogenic in VCEP = 1.0 pts (PMID: 16100770)\n\n2 separate homozygous occurrence = 0.5 pts (PMID: 16411092)\n\nCurated variant is absent from gnomAD v2 so co-occurrence cannot be evaluated", "contributionDate": { "date": "2026/1/12", "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": "CA10604243/MONDO:0015152/187/ci/CA10604243/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA10604243/MONDO:0015152/187/0/1717/1719", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA10604243/MONDO:0015152/187/1/1718", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA10604243/MONDO:0015152/187/0/1717", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10604243/MONDO:0015152/187/el/0/1630", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10604243/MONDO:0015152/187/ei/1/1631", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/1/12", "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/CA10604243/MONDO:0015152/187/el/0/1630/1632", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA10604243/MONDO:0015152/187/ci/CA10604243/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 also been reported to co-segregate with autosomal recessive LGMD in two affected family members from two families (PMID: 9150160, 16100770; PP1_Moderate)", "contributionDate": { "date": "2026/1/12", "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": "CA10604243/MONDO:0015152/187/ci/CA10604243/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA10604243/MONDO:0015152/187/0/1630/1632", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA10604243/MONDO:0015152/187/1/1631", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA10604243/MONDO:0015152/187/0/1630", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10604243/MONDO:0015152/187/el/0/1594", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10604243/MONDO:0015152/187/ei/1/1595", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/1/12", "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/CA10604243/MONDO:0015152/187/el/0/1594/1596", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA10604243/MONDO:0015152/187/ci/CA10604243/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 NM_000070.3: c.1611C>A variant in CAPN3 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 13/24, p.(Tyr537Ter), leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1).\n\nChecked SpliceAI - no predicted impact", "contributionDate": { "date": "2026/1/12", "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": "CA10604243/MONDO:0015152/187/ci/CA10604243/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA10604243/MONDO:0015152/187/0/1594/1596", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA10604243/MONDO:0015152/187/1/1595", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA10604243/MONDO:0015152/187/0/1594", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA10604243/MONDO:0015152/187", "metadata": { "created": "2026-01-12T15:25:54.037Z", "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": "Mon, 12 Jan 2026 15:25:53 -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": "c3acf1c3-9cf0-4fc8-87cc-ae989d577c39", "variant": { "@id": "https://reg.genome.network/allele/CA10604243", "id": "CAR:CA10604243", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000070.3:c.1611C>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000070.3(CAPN3):c.1611C>A (p.Tyr537Ter)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-31T17:26:38.913Z" } }, "status": { "code": 200, "name": "OK" } }