{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/f77e66d1-d86f-4674-8e90-d2b2c50e7803/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/CA7511375/MONDO:0015152/187/el/0/1798", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511375/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/CA7511375/MONDO:0015152/187/el/0/1798/1800", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA7511375/MONDO:0015152/187/ci/CA7511375/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 filtering allele frequency of this variant is 0.0005825 (the upper threshold of the 95% CI of 644/1179854 European (non-Finnish) chromosomes) in gnomAD v4.1.1, which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met).", "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": "CA7511375/MONDO:0015152/187/ci/CA7511375/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA7511375/MONDO:0015152/187/0/1798/1800", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511375/MONDO:0015152/187/1/1799", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA7511375/MONDO:0015152/187/0/1798", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511375/MONDO:0015152/187/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511375/MONDO:0015152/187/ei/1/1832", "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/CA7511375/MONDO:0015152/187/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA7511375/MONDO:0015152/187/ci/CA7511375/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 CAPN3 variant displayed progressive limb girdle muscle weakness and significantly reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PMID: 26810512; PP4_Moderate).\n\n PMID: 26810512 Lahoria et al. (2016) patient 5: 48 year old male, exercise triggered 1 episode of rhabdomyolysis at 48 y with no preceding symptoms, elevated CK. at 23 y, clinical findings include proximal weakness with proximal myopathy with fibrillation potentials on EMG. Calpain-3 was reduced to less than 10% by Western blot of muscle biopsy, which also showed signs of myopathy. c.1327T>C p.Ser443Pro in unknown phase (LP without the data from this observation)\n", "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": "CA7511375/MONDO:0015152/187/ci/CA7511375/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA7511375/MONDO:0015152/187/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511375/MONDO:0015152/187/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA7511375/MONDO:0015152/187/0/1831", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511375/MONDO:0015152/187/el/0/1630", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511375/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": "2026/5/7", "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/CA7511375/MONDO:0015152/187/el/0/1630/1632", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA7511375/MONDO:0015152/187/ci/CA7511375/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 co-segregated with autosomal recessive disease in two affected family members from one family (PMID: 30919934, 17562833).", "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": "CA7511375/MONDO:0015152/187/ci/CA7511375/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA7511375/MONDO:0015152/187/0/1630/1632", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511375/MONDO:0015152/187/1/1631", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA7511375/MONDO:0015152/187/0/1630", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511375/MONDO:0015152/187/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511375/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/CA7511375/MONDO:0015152/187/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA7511375/MONDO:0015152/187/ci/CA7511375/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 0.963, 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": "2026/5/7", "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": "CA7511375/MONDO:0015152/187/ci/CA7511375/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA7511375/MONDO:0015152/187/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511375/MONDO:0015152/187/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA7511375/MONDO:0015152/187/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511375/MONDO:0015152/187/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511375/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/CA7511375/MONDO:0015152/187/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA7511375/MONDO:0015152/187/ci/CA7511375/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 in CAPN3 affecting the same codon, c.1505T>G p.(Ile502Ser), is currently classified as VUS (PM5 not met). ", "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": "CA7511375/MONDO:0015152/187/ci/CA7511375/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA7511375/MONDO:0015152/187/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511375/MONDO:0015152/187/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA7511375/MONDO:0015152/187/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511375/MONDO:0015152/187/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511375/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/CA7511375/MONDO:0015152/187/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA7511375/MONDO:0015152/187/ci/CA7511375/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 16 individuals with features of LGMD, including in trans with a pathogenic variant in one patient (c.1333G>A p.(Gly445Arg), 1.0 pt, PMID: 30919934, 10330340, LOVD Individual #00214106) and in unconfirmed phase with six unique pathogenic variants in 8 patients (c.146G>A, p.(Arg49His), 0.5 pts, ClinVar SCV000766735.7 internal data communication; c.550del p.(Thr184ArgfsTer36), 0.5 pts, PMID: 30564623, LOVD Individual #00220543; c.598_612del p.(Phe200_Leu204del), 0.5 pts x2, PMID: 3056462, ClinVar SCV000612634.3 internal data communication; c.759_761del p.(Lys254del), 0.5 pts, ClinVar SCV000612634.3 internal data communication; c.643_663del p.(Ser215_Gly221del), 0.5 pts x2, ClinVar SCV000491158.7 internal data communication; c.145C>T (p.Arg49Cys), 0.5 pts, SCV000612634.3 internal data communication (PM3_Very Strong). \n\nIf AD/AR included: 5 pts, PM3_Very Strong\nc.146G>A, p.(Arg49His), 0.5 pts, ClinVar SCV000766735.7 internal data communication\nc.550del p.(Thr184ArgfsTer36), 0.5 pts, PMID: 30564623, LOVD Individual #00220543)\nc.598_612del15 p.(Phe200_Leu204del), 0.5 pts, PMID: 3056462\nc.598_612del15 p.(Phe200_Leu204del), 0.5 pts, Athena/Quest \nc.1333G>A p.(Gly445Arg), 1.0 pt, PMID: 30919934, 10330340, LOVD Individual #00214106\nc.759_761del p.(Lys254del), 0.5 pts, (Athena/Quest)\nc.643_663del21, (p.S215_G221del), 0.5 pts, GeneDx #1\nc.643_663del21, (p.S215_G221del), 0.5 pts, GeneDx #2\nc.145C>T (p.Arg49Cys), 0.5 pts, Athena/Quest\n\nIf AD/AR not included: 1.5 pts, PM3\nc.146G>A, p.(Arg49His), 0.5 pts, ClinVar SCV000766735.7 internal data communication\nc.550del p.(Thr184ArgfsTer36), 0.5 pts, PMID: 30564623, LOVD Individual #00220543)\nc.145C>T(p.Arg49Cys), 0.5 pts, Athena/Quest\n\nAD/AR cases: up to 3.5 pts\nc.598_612del15 p.(Phe200_Leu204del) x2 (Athena/Quest, PMID: 3056462)\nc.1333G>A p.(Gly445Arg) x1 (PMID: 30919934, 10330340)\nc.759_761del(p.Lys254del) x1 (Athena/Quest)\nc.643_663del21, (p.S215_G221del) x2 (GeneDx)\n\noptions for more PM3 pts \nin unknown phase with c.1745+5G>C (not yet curated, at best 0.5 pts): LP by Eurofins Ntd Llc, no citations in ClinVar, 1x in LOVD\nin unknown phase with c.802-9G>A (not yet curated, at best 0.5 pts): looks like clear P based on ClinVar\nc.1327T>C p.Ser443Pro x3, PMID: 26810512, 39258114, 35135626: VUS without evidence from cases with this variant\n\n", "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": "CA7511375/MONDO:0015152/187/ci/CA7511375/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA7511375/MONDO:0015152/187/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511375/MONDO:0015152/187/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA7511375/MONDO:0015152/187/0/1651", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511375/MONDO:0015152/187", "metadata": { "created": "2026-05-07T16:17:44.746Z", "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 16:17:44 -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": "f77e66d1-d86f-4674-8e90-d2b2c50e7803", "variant": { "@id": "https://reg.genome.network/allele/CA7511375", "id": "CAR:CA7511375", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000070.3:c.1505T>C" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000070.3(CAPN3):c.1505T>C (p.Ile502Thr)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-29T22:38:09.175Z" } }, "status": { "code": 200, "name": "OK" } }