{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/f5d6278d-646f-48b4-acb0-f06875d81687/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/CA7511448/MONDO:0015152/187/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511448/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": "2026/1/12", "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/CA7511448/MONDO:0015152/187/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA7511448/MONDO:0015152/187/ci/CA7511448/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 0.896, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function.\n\n0.896", "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": "CA7511448/MONDO:0015152/187/ci/CA7511448/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA7511448/MONDO:0015152/187/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511448/MONDO:0015152/187/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA7511448/MONDO:0015152/187/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511448/MONDO:0015152/187/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511448/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/CA7511448/MONDO:0015152/187/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA7511448/MONDO:0015152/187/ci/CA7511448/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 (PP4).\n\nNote that Fanin et al. (2009) (PMID: 18854869) report absent calpain-3 protein expression in skeletal muscle by Western blot in a patient with a clinical diagnosis of LGMD, but the 2nd CAPN3 variant is c.598_612del in unknown phase, which is also a proposed AD. Because we don't really need this phenotype specificity evidence to reach P, I opted to apply PP1_Moderate for segregation evidence instead.\n\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": "CA7511448/MONDO:0015152/187/ci/CA7511448/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA7511448/MONDO:0015152/187/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511448/MONDO:0015152/187/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA7511448/MONDO:0015152/187/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511448/MONDO:0015152/187/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511448/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/CA7511448/MONDO:0015152/187/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA7511448/MONDO:0015152/187/ci/CA7511448/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 variant allele frequency in gnomAD v4.1.0 for is 0.00004455 (2/44898 East Asian chromosomes), which is is lower than the LGMD VCEP threshold (<0.0001) for PM2_Supporting.\n\ncriterion also met if upper bound of the 95% CI for the European (non-Finnish) population used: 0.00003 (22/1179964).\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": "CA7511448/MONDO:0015152/187/ci/CA7511448/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA7511448/MONDO:0015152/187/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511448/MONDO:0015152/187/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA7511448/MONDO:0015152/187/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511448/MONDO:0015152/187/el/0/1669", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511448/MONDO:0015152/187/ei/1/1670", "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/CA7511448/MONDO:0015152/187/el/0/1669/1671", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA7511448/MONDO:0015152/187/ci/CA7511448/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": "Across a selection of the available literature, this variant has been reported in at least 11 unrelated patients with features of LGMD (PMID: 19556129, 18854869, 32576226, 30919934, 25214167, 16100770, 36575883, 31066050), including in a homozygous state in two unrelated probands without reported consanguinity (0.5 pts x2; PMID: 31066050, 30919934), confirmed in trans with a pathogenic variant in three probands (c.701G>A p.(Gly234Glu), 1.0 pt, PMID: 3657588; c.550del p.(Thr184ArgfsTer36), 1.0 pt, PMID: 16100770; c.598_612del p.(Phe200_Leu204del), 1.0 pt, PMID: 16100770), and in unconfirmed phase with a pathogenic variant in two probands (c.550del p.(Thr184ArgfsTer36), 0.5 pts, PMID: 16100770; c.598_612del p.(Phe200_Leu204del), 0.5 pts, PMID: 18854869) (PM3_Very Strong). \n\nin gnomAD v2, predicted on a different haplotype from c.550del p.(Thr184ArgfsTer36) and c.598_612del p.(Phe200_Leu204del)\n\nIn practice, only 0.5 pts out of the 4 needed for Very_Strong are coming from the c.598_612del p.(Phe200_Leu204del) proposed dominant variant, and it is for a family where the carrier parent was considered unaffected despite \"special emphasis put on intensive search for new secondary cases in the family of the proband in order to determine the mode of inheritance\" (PMID: 16100770).\n\nThere are also unscored cases with presumed diagnostic variants that we haven't curated yet\n\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": "CA7511448/MONDO:0015152/187/ci/CA7511448/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA7511448/MONDO:0015152/187/0/1669/1671", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511448/MONDO:0015152/187/1/1670", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA7511448/MONDO:0015152/187/0/1669", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511448/MONDO:0015152/187/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511448/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": "2026/1/12", "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/CA7511448/MONDO:0015152/187/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA7511448/MONDO:0015152/187/ci/CA7511448/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": "Other amino acid changes at this position have been reported, but this code is not needed for a P classification and this variant seems to have the most evidence compared to the other missense changes.", "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": "CA7511448/MONDO:0015152/187/ci/CA7511448/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA7511448/MONDO:0015152/187/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511448/MONDO:0015152/187/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA7511448/MONDO:0015152/187/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511448/MONDO:0015152/187/el/0/1630", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA7511448/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/CA7511448/MONDO:0015152/187/el/0/1630/1632", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA7511448/MONDO:0015152/187/ci/CA7511448/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": "Two affected family members of a homozygous proband were also shown to be homozygous for this variant (PMID: 30919934; 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": "CA7511448/MONDO:0015152/187/ci/CA7511448/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA7511448/MONDO:0015152/187/0/1630/1632", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511448/MONDO:0015152/187/1/1631", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA7511448/MONDO:0015152/187/0/1630", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA7511448/MONDO:0015152/187", "metadata": { "created": "2026-01-12T15:36:30.521Z", "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 15:36:30 -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": "f5d6278d-646f-48b4-acb0-f06875d81687", "variant": { "@id": "https://reg.genome.network/allele/CA7511448", "id": "CAR:CA7511448", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000070.3:c.1621C>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000070.3(CAPN3):c.1621C>T (p.Arg541Trp)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-14T05:30:19.023Z" } }, "status": { "code": 200, "name": "OK" } }