{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/2d89e149-6f8f-4828-9aaa-025bc0c6e0f3/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1615403520", "label": "ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACTA1 Version 2.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "2.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0100084", "id": "MONDO:0100084", "label": "alpha-actinopathy", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA345147066/MONDO:0100084/147/el/0/1837", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA345147066/MONDO:0100084/147/ei/1/1838", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50031_EP172779037880653", "id": "CG-PCER-AGENT:CG_50031_EP172779037880653", "type": "Agent" }, "contributionDate": { "date": "2026/9/28", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0061", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0061", "label": "PP2", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA345147066/MONDO:0100084/147/el/0/1837/1839", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA345147066/MONDO:0100084/147/ci/CA345147066/MONDO:0100084/147.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50031_EP172779037880653", "id": "CG-PCER-AGENT:CG_50031_EP172779037880653", "type": "Agent" }, "comments": "ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The missense Z-score in gnomAD v4.1.1 is 6.63. ", "contributionDate": { "date": "2026/9/28", "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": "CA345147066/MONDO:0100084/147/ci/CA345147066/MONDO:0100084/147.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA345147066/MONDO:0100084/147/0/1837/1839", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA345147066/MONDO:0100084/147/1/1838", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA345147066/MONDO:0100084/147/0/1837", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA345147066/MONDO:0100084/147/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA345147066/MONDO:0100084/147/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50031_EP172779037880653", "id": "CG-PCER-AGENT:CG_50031_EP172779037880653", "type": "Agent" }, "contributionDate": { "date": "2026/9/28", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0062", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0062", "label": "PP3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA345147066/MONDO:0100084/147/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA345147066/MONDO:0100084/147/ci/CA345147066/MONDO:0100084/147.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50031_EP172779037880653", "id": "CG-PCER-AGENT:CG_50031_EP172779037880653", "type": "Agent" }, "comments": "The computational predictor REVEL gives a score of 0.94, which is above the VCEP threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). ", "contributionDate": { "date": "2026/9/28", "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": "CA345147066/MONDO:0100084/147/ci/CA345147066/MONDO:0100084/147.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA345147066/MONDO:0100084/147/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA345147066/MONDO:0100084/147/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA345147066/MONDO:0100084/147/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA345147066/MONDO:0100084/147/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA345147066/MONDO:0100084/147/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50031_EP172779037880653", "id": "CG-PCER-AGENT:CG_50031_EP172779037880653", "type": "Agent" }, "contributionDate": { "date": "2026/9/28", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0030", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0030", "label": "PM2", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA345147066/MONDO:0100084/147/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA345147066/MONDO:0100084/147/ci/CA345147066/MONDO:0100084/147.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50031_EP172779037880653", "id": "CG-PCER-AGENT:CG_50031_EP172779037880653", "type": "Agent" }, "comments": "This variant is absent from gnomAD (PM2_Supporting). Coverage of the gene in this region is adequate. ", "contributionDate": { "date": "2026/9/28", "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": "CA345147066/MONDO:0100084/147/ci/CA345147066/MONDO:0100084/147.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA345147066/MONDO:0100084/147/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA345147066/MONDO:0100084/147/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA345147066/MONDO:0100084/147/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA345147066/MONDO:0100084/147/el/0/1735", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA345147066/MONDO:0100084/147/ei/1/1736", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50031_EP172779037880653", "id": "CG-PCER-AGENT:CG_50031_EP172779037880653", "type": "Agent" }, "contributionDate": { "date": "2026/9/28", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0053", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000330", "id": "SEPIO:0000330", "label": "Pathogenic Strong" }, "id": "0053", "label": "PS4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA345147066/MONDO:0100084/147/el/0/1735/1737", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA345147066/MONDO:0100084/147/ci/CA345147066/MONDO:0100084/147.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50031_EP172779037880653", "id": "CG-PCER-AGENT:CG_50031_EP172779037880653", "type": "Agent" }, "comments": "There were not enough affected individuals with the variant to apply PS4 at any level. ", "contributionDate": { "date": "2026/9/28", "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": "CA345147066/MONDO:0100084/147/ci/CA345147066/MONDO:0100084/147.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA345147066/MONDO:0100084/147/0/1735/1737", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA345147066/MONDO:0100084/147/1/1736", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA345147066/MONDO:0100084/147/0/1735", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA345147066/MONDO:0100084/147/el/0/1621", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA345147066/MONDO:0100084/147/ei/1/1622", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50031_EP172779037880653", "id": "CG-PCER-AGENT:CG_50031_EP172779037880653", "type": "Agent" }, "contributionDate": { "date": "2026/9/28", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0056", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000330", "id": "SEPIO:0000330", "label": "Pathogenic Strong" }, "id": "0056", "label": "PM5", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA345147066/MONDO:0100084/147/el/0/1621/1623", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA345147066/MONDO:0100084/147/ci/CA345147066/MONDO:0100084/147.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50031_EP172779037880653", "id": "CG-PCER-AGENT:CG_50031_EP172779037880653", "type": "Agent" }, "comments": "Three missense variants, [c.686T>C (p.Met229Thr), c.685A>T (p.Met229Leu), and c.685A>G (p.Met229Val); SCV007612356.1, SCV007612355.1, SCV007612357.1, respectively] in the same codon have been classified as pathogenic/likely pathogenic/pathogenic for autosomal dominant alpha-actinopathy by the ClinGen Congenital Myopathies VCEP (PM5_Strong).", "contributionDate": { "date": "2026/9/28", "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": "CA345147066/MONDO:0100084/147/ci/CA345147066/MONDO:0100084/147.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA345147066/MONDO:0100084/147/0/1621/1623", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA345147066/MONDO:0100084/147/1/1622", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA345147066/MONDO:0100084/147/0/1621", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA345147066/MONDO:0100084/147/el/0/1660", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA345147066/MONDO:0100084/147/ei/1/1661", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50031_EP172779037880653", "id": "CG-PCER-AGENT:CG_50031_EP172779037880653", "type": "Agent" }, "contributionDate": { "date": "2026/9/28", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0022", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0022", "label": "PM6", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA345147066/MONDO:0100084/147/el/0/1660/1662", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA345147066/MONDO:0100084/147/ci/CA345147066/MONDO:0100084/147.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50031_EP172779037880653", "id": "CG-PCER-AGENT:CG_50031_EP172779037880653", "type": "Agent" }, "comments": "This variant has been identified as a de novo occurrence with unconfirmed parental relationships in one individual with features of RYR1-related myopathy (PM6_Supporting, 0.5 points; Synnovis internal data). ", "contributionDate": { "date": "2026/9/28", "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": "CA345147066/MONDO:0100084/147/ci/CA345147066/MONDO:0100084/147.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA345147066/MONDO:0100084/147/0/1660/1662", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA345147066/MONDO:0100084/147/1/1661", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA345147066/MONDO:0100084/147/0/1660", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA345147066/MONDO:0100084/147", "metadata": { "created": "2026-10-15T19:07:57.583Z", "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, 15 Oct 2026 19:07:57 -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": "2d89e149-6f8f-4828-9aaa-025bc0c6e0f3", "variant": { "@id": "https://reg.genome.network/allele/CA345147066", "id": "CAR:CA345147066", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_001100.4:c.686T>G" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_001100.4:c.686T>G" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-03T19:11:01.931Z" } }, "status": { "code": 200, "name": "OK" } }