{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://erepo.genome.network/evrepo/api/summary/classification/81c411b2-d088-4403-b4e1-80a42a98c302/doc/sepio/version/1.1.1", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/135637588", "label": "ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_mtDNA", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0044970", "id": "MONDO:0044970", "label": "mitochondrial disease", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA913177648/MONDO:0044970/015/el/0/1696", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA913177648/MONDO:0044970/015/ei/1/1697", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50027_EP162030441573574", "id": "CG-PCER-AGENT:CG_50027_EP162030441573574", "type": "Agent" }, "contributionDate": { "date": "2023/1/25", "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/CA913177648/MONDO:0044970/015/el/0/1696/1698", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA913177648/MONDO:0044970/015/ci/CA913177648/MONDO:0044970/015.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50027_EP162030441573574", "id": "CG-PCER-AGENT:CG_50027_EP162030441573574", "type": "Agent" }, "comments": "Single-fiber testing (PMID: 9473477) showed 78% heteroplasmy in COX-negative fibers and 27% in COX-positive fibers. Aminoacylation assays showed that the capacity for aminoacylation of tRNAs with this variant was virtually nil (<0.1%) and the observed aminoacylation deficiency was rescued by an engineered compensatory variant (PMID: 12655007). This and other results led the authors to propose that the functional defect caused by this mutation is due to fragility of the tRNA structure (PS3_supporting). ", "contributionDate": { "date": "2023/1/25", "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": "CA913177648/MONDO:0044970/015/ci/CA913177648/MONDO:0044970/015.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA913177648/MONDO:0044970/015/0/1696/1698", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA913177648/MONDO:0044970/015/1/1697", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA913177648/MONDO:0044970/015/0/1696", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA913177648/MONDO:0044970/015/el/0/1672", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA913177648/MONDO:0044970/015/ei/1/1673", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50027_EP162030441573574", "id": "CG-PCER-AGENT:CG_50027_EP162030441573574", "type": "Agent" }, "contributionDate": { "date": "2023/1/25", "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/CA913177648/MONDO:0044970/015/el/0/1672/1674", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA913177648/MONDO:0044970/015/ci/CA913177648/MONDO:0044970/015.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50027_EP162030441573574", "id": "CG-PCER-AGENT:CG_50027_EP162030441573574", "type": "Agent" }, "comments": "Family member testing was performed in one case and the variant was undetectable in the proband’s mother’s blood, however the variant was also undetectable in the proband’s blood precluding confirmation of a de novo occurrence (PMID: 16120360).", "contributionDate": { "date": "2023/1/25", "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": "CA913177648/MONDO:0044970/015/ci/CA913177648/MONDO:0044970/015.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA913177648/MONDO:0044970/015/0/1672/1674", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA913177648/MONDO:0044970/015/1/1673", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA913177648/MONDO:0044970/015/0/1672", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA913177648/MONDO:0044970/015/el/0/1678", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA913177648/MONDO:0044970/015/ei/1/1679", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50027_EP162030441573574", "id": "CG-PCER-AGENT:CG_50027_EP162030441573574", "type": "Agent" }, "contributionDate": { "date": "2023/1/25", "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/CA913177648/MONDO:0044970/015/el/0/1678/1680", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA913177648/MONDO:0044970/015/ci/CA913177648/MONDO:0044970/015.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50027_EP162030441573574", "id": "CG-PCER-AGENT:CG_50027_EP162030441573574", "type": "Agent" }, "comments": "There are no large families reported in the medical literature to consider for evidence of segregation. ", "contributionDate": { "date": "2023/1/25", "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": "CA913177648/MONDO:0044970/015/ci/CA913177648/MONDO:0044970/015.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA913177648/MONDO:0044970/015/0/1678/1680", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA913177648/MONDO:0044970/015/1/1679", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA913177648/MONDO:0044970/015/0/1678", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA913177648/MONDO:0044970/015/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA913177648/MONDO:0044970/015/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50027_EP162030441573574", "id": "CG-PCER-AGENT:CG_50027_EP162030441573574", "type": "Agent" }, "contributionDate": { "date": "2023/1/25", "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/CA913177648/MONDO:0044970/015/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA913177648/MONDO:0044970/015/ci/CA913177648/MONDO:0044970/015.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50027_EP162030441573574", "id": "CG-PCER-AGENT:CG_50027_EP162030441573574", "type": "Agent" }, "comments": "The computational predictor MitoTIP suggests this variant is pathogenic, scoring in the 63.5 percentile; HmtVAR also predicts it to be pathogenic, scoring in the 75.0 percentile (PP3). ", "contributionDate": { "date": "2023/1/25", "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": "CA913177648/MONDO:0044970/015/ci/CA913177648/MONDO:0044970/015.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA913177648/MONDO:0044970/015/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA913177648/MONDO:0044970/015/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA913177648/MONDO:0044970/015/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA913177648/MONDO:0044970/015/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA913177648/MONDO:0044970/015/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50027_EP162030441573574", "id": "CG-PCER-AGENT:CG_50027_EP162030441573574", "type": "Agent" }, "contributionDate": { "date": "2023/1/25", "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/CA913177648/MONDO:0044970/015/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA913177648/MONDO:0044970/015/ci/CA913177648/MONDO:0044970/015.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50027_EP162030441573574", "id": "CG-PCER-AGENT:CG_50027_EP162030441573574", "type": "Agent" }, "comments": "The m.4298G>A variant is absent in the GenBank dataset, the Helix dataset, and gnomAD v3.1.2 (PM2_supporting). \n", "contributionDate": { "date": "2023/1/25", "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": "CA913177648/MONDO:0044970/015/ci/CA913177648/MONDO:0044970/015.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA913177648/MONDO:0044970/015/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA913177648/MONDO:0044970/015/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA913177648/MONDO:0044970/015/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA913177648/MONDO:0044970/015/el/0/1606", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA913177648/MONDO:0044970/015/ei/1/1607", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50027_EP162030441573574", "id": "CG-PCER-AGENT:CG_50027_EP162030441573574", "type": "Agent" }, "contributionDate": { "date": "2023/1/25", "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/CA913177648/MONDO:0044970/015/el/0/1606/1608", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA913177648/MONDO:0044970/015/ci/CA913177648/MONDO:0044970/015.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50027_EP162030441573574", "id": "CG-PCER-AGENT:CG_50027_EP162030441573574", "type": "Agent" }, "comments": "The m.4298G>A variant in MT-TI has been reported in two unrelated adults with primary mitochondrial disease. Chronic progressive external ophthalmoplegia (CPEO) and multiple sclerosis (MS) were seen in one individual (PMID: 9473477) and the second individual had rhabdomyolysis, myoglobinuria, and myalgia after fasting or exercise in addition to muscle weakness and unstable gait (PMID: 16120360). This variant was seen in varying degrees of heteroplasmy in these individuals in muscle, urine, and hair roots by PCR/RFLP, but was not observed in blood (PS4_supporting). ", "contributionDate": { "date": "2023/1/25", "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": "CA913177648/MONDO:0044970/015/ci/CA913177648/MONDO:0044970/015.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA913177648/MONDO:0044970/015/0/1606/1608", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA913177648/MONDO:0044970/015/1/1607", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA913177648/MONDO:0044970/015/0/1606", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA913177648/MONDO:0044970/015", "metadata": { "created": "2025-10-23T17:56:21.950Z", "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, 23 Oct 2025 17:56:21 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.1.1" }, "statementOutcome": { "@id": "https://loinc.org/LA26333-7", "id": "LN:LA26333-7", "label": "Uncertain Significance" }, "type": "VariantPathogenicityInterpretation", "uuid": "81c411b2-d088-4403-b4e1-80a42a98c302", "variant": { "@id": "https://reg.genome.network/allele/CA913177648", "id": "CAR:CA913177648", "relatedContextualAllele": [ { "alleleName": [ { "name": "NC_012920.1:m.4298G>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NC_012920.1:m.4298G>A" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-04-08T14:09:36.708Z" } }, "status": { "code": 200, "name": "OK" } }