{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/69a6766c-2bdd-4588-b3fe-932be6ebc89f/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/CA5923264/MONDO:0015152/188/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5923264/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": "2026/5/7", "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/CA5923264/MONDO:0015152/188/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA5923264/MONDO:0015152/188/ci/CA5923264/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 upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.1 is 0.000019574 (15/1180006 European (non-Finnish) alleles), which is lower than the LGMD VCEP threshold of 0.0001, meeting the criteria for PM2_Supporting. ", "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": "CA5923264/MONDO:0015152/188/ci/CA5923264/MONDO:0015152/188.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5923264/MONDO:0015152/188/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5923264/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": "2026/5/7", "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/CA5923264/MONDO:0015152/188/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA5923264/MONDO:0015152/188/ci/CA5923264/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 also gives a score of 0.689, which is below the threshold of 0.7 (PP3 not met). \n\nSpliceAI: 0.0900", "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": "CA5923264/MONDO:0015152/188/ci/CA5923264/MONDO:0015152/188.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5923264/MONDO:0015152/188/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5923264/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": "2026/5/7", "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/CA5923264/MONDO:0015152/188/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA5923264/MONDO:0015152/188/ci/CA5923264/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 of these patients presented with progressive limb girdle muscle weakness (PP4). ", "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": "CA5923264/MONDO:0015152/188/ci/CA5923264/MONDO:0015152/188.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5923264/MONDO:0015152/188/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5923264/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": "2026/5/7", "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/CA5923264/MONDO:0015152/188/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA5923264/MONDO:0015152/188/ci/CA5923264/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": "Per specs, the REVEL score for the missense variant under curation should be >0.7, but the score for this variant is 0.689, so PM5 is not applicable\n\nc.1451G>A (p.Arg484His)\nLP in ClinVar by Labcorp-Invitae, seemingly based on PM5\nnot in LOVD\nPMID: 36913258 de Bruyn et al. (2023): 1 homozygote, no reported consanguinity (PP4, PM3_Supporting)\n5 alleles in gnomAD v4 (PM2_Supporting)\nREVEL: 0.777 (PP3)\n\n\nc.1450C>A p.(Arg484Ser)\nPMID: 34550615, 34145687\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": "CA5923264/MONDO:0015152/188/ci/CA5923264/MONDO:0015152/188.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5923264/MONDO:0015152/188/el/0/1765", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5923264/MONDO:0015152/188/ei/1/1766", "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/CA5923264/MONDO:0015152/188/el/0/1765/1767", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA5923264/MONDO:0015152/188/ci/CA5923264/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": "Another nucleotide change resulting in the same amino acid change, c.1450C>A p.(Arg484Ser), has been reported in association with LGMD (PMID: 36913258), but this nucleotide change also has insufficient evidence to be classified above VUS. \n \n\nCA379922056 \nnot in ClinVar or LOVD\nreported in unconfirmed phase with c.191dupA p.Asn64Lysfs*15 in PMID: 36913258 de Bruyn et al. (2023). Inclusion criteria: (i) genetically confirmed diagnosis of ANO5-related muscle disease by identification of two heterozygous or one homozygous pathogenic or probably pathogenic variant or VUS in the ANO5 gene; and (ii) sufficient data available in the medical files concerning clinical symptoms at onset and clinical evolution over time, ambulation status and use of walking aids, and presence of cardiac and respiratory symptoms. Patients were categorized according to the clinical phenotype at the individual patient level (thus not at the family level) in four groups: LGMD-R12 (predominant proximal weakness or combined proximal and distal weakness in lower and/or upper extremities), MMD3 (predominant distal weakness in lower and/or upper extremities), pseudometabolic myopathy [persistently elevated serum creatine kinase (CK) levels associated with exercise intolerance and/ or myalgia without significant muscle weakness on neurological examination] or asymptomatic hyperCKaemia (persistently elevated serum-CK levels in the absence of weakness or other symptoms, but clinical signs without patient complaints may be present). (PM3_Supporting, PP4)\nabsent from gnomAD v4 (PM2_Supporting)\nREVEL 0.695 (PP3 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": "CA5923264/MONDO:0015152/188/ci/CA5923264/MONDO:0015152/188.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/0/1765/1767", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/1/1766", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/0/1765", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5923264/MONDO:0015152/188/el/0/1828", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5923264/MONDO:0015152/188/ei/1/1829", "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/CA5923264/MONDO:0015152/188/el/0/1828/1830", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA5923264/MONDO:0015152/188/ci/CA5923264/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" }, "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": "CA5923264/MONDO:0015152/188/ci/CA5923264/MONDO:0015152/188.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/0/1828/1830", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/1/1829", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/0/1828", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5923264/MONDO:0015152/188/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5923264/MONDO:0015152/188/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/CA5923264/MONDO:0015152/188/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA5923264/MONDO:0015152/188/ci/CA5923264/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 NM_213599.3: c.1450C>T variant in ANO5 is a missense variant expected to cause the substitution of arginine at amino acid position 484 with cysteine, p.(Arg484Cys). This variant has been reported in at least three individuals with features consistent with LGMD (PMID: 30564623, 34264321; GRASP-LGMD Consortium, ClinVar SCV001954366.1 internal data communication), including in unconfirmed phase with a pathogenic variant in two patients (c.191dup (p.Asn64LysfsTer15, 0.5 pts, GRASP-LGMD Consortium internal data communication; c.304_308del p.(Lys102ValfsTer2), 0.5 pts, PMID: 34264321) and confirmed in trans with a pathogenic variant in one patient (c.1898+1G>A, 1.0 pt, ClinVar SCV001954366.1 internal data communication) (PM3_Strong). ", "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": "CA5923264/MONDO:0015152/188/ci/CA5923264/MONDO:0015152/188.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188/0/1651", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA5923264/MONDO:0015152/188", "metadata": { "created": "2026-05-07T15:15:29.679Z", "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 15:15:29 -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": "69a6766c-2bdd-4588-b3fe-932be6ebc89f", "variant": { "@id": "https://reg.genome.network/allele/CA5923264", "id": "CAR:CA5923264", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_213599.3:c.1450C>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_213599.3(ANO5):c.1450C>T (p.Arg484Cys)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-03T19:58:56.627Z" } }, "status": { "code": 200, "name": "OK" } }