{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/7d577c8a-190f-4025-9e0f-f0496b2ecdd5/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1812076188", "label": "ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ANO5 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/CA224418/MONDO:0015152/188/el/0/1684", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224418/MONDO:0015152/188/ei/1/1685", "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/CA224418/MONDO:0015152/188/el/0/1684/1686", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA224418/MONDO:0015152/188/ci/CA224418/MONDO:0015152/188.002", "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 0.49 (PP3, BP4 not met). \n\nSpliceAI 0.15", "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": "CA224418/MONDO:0015152/188/ci/CA224418/MONDO:0015152/188.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA224418/MONDO:0015152/188/0/1684/1686", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA224418/MONDO:0015152/188/1/1685", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA224418/MONDO:0015152/188/0/1684", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224418/MONDO:0015152/188/el/0/1804", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224418/MONDO:0015152/188/ei/1/1805", "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/CA224418/MONDO:0015152/188/el/0/1804/1806", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA224418/MONDO:0015152/188/ci/CA224418/MONDO:0015152/188.002", "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 FAF (the lower bound of the 95% confidence interval of the maximum credible genetic ancestry group allele frequency) is 0.002635, which is greater than the VCEP threshold of 0.001 for BS1. However, this variant is recognized as one of the most common pathogenic variants in ANO5, and the VCEP opted not to apply this code (BS1 exception). \n\n4 homozygotes in Total population: 1 65-70, 1 40-45", "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": "CA224418/MONDO:0015152/188/ci/CA224418/MONDO:0015152/188.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA224418/MONDO:0015152/188/0/1804/1806", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA224418/MONDO:0015152/188/1/1805", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA224418/MONDO:0015152/188/0/1804", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224418/MONDO:0015152/188/el/0/1798", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224418/MONDO:0015152/188/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": "2026/4/9", "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/CA224418/MONDO:0015152/188/el/0/1798/1800", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA224418/MONDO:0015152/188/ci/CA224418/MONDO:0015152/188.002", "contribution": [ { "agent": { "@id": 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"https://erepo.genome.network/evrepo/api/interpretation/CA224418/MONDO:0015152/188/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224418/MONDO:0015152/188/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/CA224418/MONDO:0015152/188/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA224418/MONDO:0015152/188/ci/CA224418/MONDO:0015152/188.002", "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 0.49 (PP3, BP4 not met). \n\nSpliceAI 0.15", "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": "CA224418/MONDO:0015152/188/ci/CA224418/MONDO:0015152/188.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA224418/MONDO:0015152/188/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA224418/MONDO:0015152/188/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA224418/MONDO:0015152/188/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224418/MONDO:0015152/188/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224418/MONDO:0015152/188/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/CA224418/MONDO:0015152/188/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA224418/MONDO:0015152/188/ci/CA224418/MONDO:0015152/188.002", "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 ANO5 allele exhibited limb girdle muscle weakness and had a clinical diagnosis of LGMD (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": "CA224418/MONDO:0015152/188/ci/CA224418/MONDO:0015152/188.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA224418/MONDO:0015152/188/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA224418/MONDO:0015152/188/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA224418/MONDO:0015152/188/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224418/MONDO:0015152/188/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224418/MONDO:0015152/188/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/CA224418/MONDO:0015152/188/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA224418/MONDO:0015152/188/ci/CA224418/MONDO:0015152/188.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "no other missense variants seem to have been reported at this position", "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": "CA224418/MONDO:0015152/188/ci/CA224418/MONDO:0015152/188.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA224418/MONDO:0015152/188/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA224418/MONDO:0015152/188/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA224418/MONDO:0015152/188/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224418/MONDO:0015152/188/el/0/1669", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224418/MONDO:0015152/188/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": "2026/4/9", "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/CA224418/MONDO:0015152/188/el/0/1669/1671", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA224418/MONDO:0015152/188/ci/CA224418/MONDO:0015152/188.002", "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 data, this variant has been identified in over 20 individuals with features consistent with LGMD (PMID: 34008892, 36575883, 25891276, 32925086, 35628876, 31353849; LOVD ANO5_000005; GRASP-LGMD Consortium internal data communication). These observations include eight unrelated patients in whom it was reported in unconfirmed phase with a pathogenic variant (c.191dup p.(Asn64LysfsTer15) x6, 3.0 pts, PMID: 35628876, 31353849, GRASP-LGMD Consortium internal data communication; c.1898+1G>A, 0.5 pts, GRASP-LGMD Consortium internal data communication; c.2272C>T p.(Arg758Cys), 0.5 pts, GRASP-LGMD Consortium internal data communication). This variant has also been reported in a homozygous state in at least four unrelated patients experiencing muscle weakness and with signs of atrophy or dystrophy on muscle biopsy (PMID: 25891276, 31353849). (PM3_Very Strong) \n\nscored:\nc.191dup x6: 3 pt, predicted on different haplotypes\nc.1898+1G>A: 0.5 pt, predicted on different haplotypes\nc.2272C>T p.(Arg758Cys): 0.5 pt, predicted on different haplotypes\nsymptomatic hom x4\n\nunscored:\nc.2478G>T p.(Trp826Cys) (VUS)\nc.1359G>C p.(Tyr453Ter) x2\nc.2498T>A p.(Met833Lys)\nc.2342T>C p.(Leu781Pro)\nc.40G>A p.(Gly14Arg)\nc.709A>G p.(Ile237Val), confirmed in trans\n\nLOVD ANO5_000005: 49 reported entries", "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": "CA224418/MONDO:0015152/188/ci/CA224418/MONDO:0015152/188.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA224418/MONDO:0015152/188/0/1669/1671", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA224418/MONDO:0015152/188/1/1670", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA224418/MONDO:0015152/188/0/1669", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA224418/MONDO:0015152/188", "metadata": { "created": "2026-04-09T22:59:20.737Z", "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 22:59:19 -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": "7d577c8a-190f-4025-9e0f-f0496b2ecdd5", "variant": { "@id": "https://reg.genome.network/allele/CA224418", "id": "CAR:CA224418", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_213599.3:c.692G>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_213599.3(ANO5):c.692G>T (p.Gly231Val)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-05T15:13:36.532Z" } }, "status": { "code": 200, "name": "OK" } }