{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/db6797b3-b077-422c-9623-a5443a6e0d3a/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/CA224411/MONDO:0015152/188/el/0/1597", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224411/MONDO:0015152/188/ei/1/1598", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/2/17", "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/CA224411/MONDO:0015152/188/el/0/1597/1599", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA224411/MONDO:0015152/188/ci/CA224411/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": "This variant has been reported in a heterozygous state in an individual with clinically suspected LGMD who was apparently homozygous for the pathogenic variant c.191dup p.(Asn64LysfsTer15), suggesting the variants occurred in cis on one allele (PMID: 30564623, LOVD Individual #00220749; BP2). \n\nThese variants are predicted on different haplotypes in gnomAD v2.1.1", "contributionDate": { "date": "2026/2/17", "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": "CA224411/MONDO:0015152/188/ci/CA224411/MONDO:0015152/188.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/0/1597/1599", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/1/1598", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/0/1597", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224411/MONDO:0015152/188/el/0/1678", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224411/MONDO:0015152/188/ei/1/1679", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/2/17", "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/CA224411/MONDO:0015152/188/el/0/1678/1680", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA224411/MONDO:0015152/188/ci/CA224411/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": "Two affected family members of a proband with this variant and a second presumed diagnostic ANO5 allele were shown to have the same two variants but phase was not confirmed (PMID: 22980763; PP1 not met).", "contributionDate": { "date": "2026/2/17", "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": "CA224411/MONDO:0015152/188/ci/CA224411/MONDO:0015152/188.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/0/1678/1680", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/1/1679", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/0/1678", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224411/MONDO:0015152/188/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224411/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": "2026/2/17", "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/CA224411/MONDO:0015152/188/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA224411/MONDO:0015152/188/ci/CA224411/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 0.851, which exceeds the threshold of ≥0.70, evidence that correlates with impact to ANO5 function (PP3). ", "contributionDate": { "date": "2026/2/17", "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": "CA224411/MONDO:0015152/188/ci/CA224411/MONDO:0015152/188.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224411/MONDO:0015152/188/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224411/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": "2026/2/17", "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/CA224411/MONDO:0015152/188/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA224411/MONDO:0015152/188/ci/CA224411/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 displayed progressive limb girdle muscle weakness (PMID: 31395899, 22402862; PP4). ", "contributionDate": { "date": "2026/2/17", "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": "CA224411/MONDO:0015152/188/ci/CA224411/MONDO:0015152/188.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224411/MONDO:0015152/188/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224411/MONDO:0015152/188/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": "2026/2/17", "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/CA224411/MONDO:0015152/188/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA224411/MONDO:0015152/188/ci/CA224411/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 filtering allele frequency for this variant is 0.00006 in gnomAD v4.1.0 (the upper bound of the 95% confidence interval of 57/1178734 European (non-Finnish) alleles), which is lower than the VCEP threshold of 0.0001 for PM2_Supporting, meeting this criterion (PM2_Supporting).\n\nThe highest MAF is in the European (Finnish) population, but we do not use that bottlenecked group. \n\n", "contributionDate": { "date": "2026/2/17", "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": "CA224411/MONDO:0015152/188/ci/CA224411/MONDO:0015152/188.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224411/MONDO:0015152/188/el/0/1669", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224411/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": "2026/2/17", "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/CA224411/MONDO:0015152/188/el/0/1669/1671", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA224411/MONDO:0015152/188/ci/CA224411/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": "This variant has been detected in at least 13 unrelated individuals with features consistent with LGMD or anoctaminopathy (PMID: 30564623, 29970176, 23047743, 22980763, 31395899, 22402862; ClinVar SCV001574736.5, SCV000582412.4 internal data communication), including in unconfirmed phase with a pathogenic variant in six unrelated cases (c.989dup p.(Leu330PhefsTer6) x2, 1.0 pt, PMID: 30564623, LOVD Individual #00220727, ClinVar SCV001574736.5 internal data communication; c.191dup p.(Asn64LysfsTer15) x2, 1.0 pt, PMID: 30564623, LOVD Individual #00221127, ClinVar SCV000582412.4 internal data communication; c.2272C>T p.(Arg758Cys) x2, 1.0 pt, PMID: 31395899, 22402862). It has also been confirmed in trans with a pathogenic variant in one patient (c.191dup p.(Asn64LysfsTer15), 1.0 pt, ClinVar SCV001574736.5 internal data communication) (PM3_Very Strong). \n\nindependently P variants scored in unknown phase:\nc.989dup p.(Leu330PhefsTer6): predicted on different haplotypes\nc.191dup p.(Asn64LysfsTer15): predicted on different haplotypes\nc.2272C>T p.(Arg758Cys) (x2): predicted on different haplotypes\n\nto potentially curate:\nc.2498T>A p.(Met833Lys) (0.5 if P): predicted on different haplotypes, solidly P in ClinVar (Variation ID 285338) but PM3_Very Strong or segregation OR PM5 required for full P classification; not on our curation list\nc.1631-7_1631-3del (0.25 if LP but seems like VUS): not in gnomAD v2 but 2 alleles in v4, VUS by Eurofins in ClinVar (Variation ID: 498336) with no citations, SpliceAI 0.3 for Acceptor Loss\nc.1097A>G p.(Asn366Ser) (0.25 if LP but seems like VUS): not in gnomAD v2, REVEL 0.201, not in ClinVar (CA379921132), no other cases aside from Sarkozy in LOVD, no other missense changes at same position\nc.1203G>A p.(Trp401Ter) (0.25 if LP): not in gnomAD v2 or v4, not in ClinVar (CA379921398), no other cases aside from Fichna in LOVD\nc.479G>A (p.Arg160His) (1.0 if LP): looks like VUS based on ClinVar\n\n\n", "contributionDate": { "date": "2026/2/17", "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": "CA224411/MONDO:0015152/188/ci/CA224411/MONDO:0015152/188.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/0/1669/1671", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/1/1670", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/0/1669", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224411/MONDO:0015152/188/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA224411/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": "2026/2/17", "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/CA224411/MONDO:0015152/188/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA224411/MONDO:0015152/188/ci/CA224411/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": "NM_213599.3(ANO5):c.241G>T (p.Asp81Tyr)\nVariation ID: 3752955\nLP by Labcorp Genetics (formerly Invitae) but no literature cases", "contributionDate": { "date": "2026/2/17", "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": "CA224411/MONDO:0015152/188/ci/CA224411/MONDO:0015152/188.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188/0/1780", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA224411/MONDO:0015152/188", "metadata": { "created": "2026-02-17T18:26:44.015Z", "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": "Tue, 17 Feb 2026 18:26:43 -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": "db6797b3-b077-422c-9623-a5443a6e0d3a", "variant": { "@id": "https://reg.genome.network/allele/CA224411", "id": "CAR:CA224411", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_213599.3:c.242A>G" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_213599.3(ANO5):c.242A>G (p.Asp81Gly)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-29T04:05:06.201Z" } }, "status": { "code": 200, "name": "OK" } }