{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/6bae432c-d50d-40d9-b150-a7e15d26fa0e/doc/sepio/version/1.1.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1566365955", "label": "ClinGen Leber Congenital Amaurosis/early onset Retinal Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPE65 Version 1.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0100368", "id": "MONDO:0100368", "label": "RPE65-related recessive retinopathy", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340745829/MONDO:0100368/120/el/0/1678", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340745829/MONDO:0100368/120/ei/1/1679", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166", "id": "CG-PCER-AGENT:CG_50082_EP170326324571166", "type": "Agent" }, "contributionDate": { "date": "2026/8/20", "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/CA340745829/MONDO:0100368/120/el/0/1678/1680", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340745829/MONDO:0100368/120/ci/CA340745829/MONDO:0100368/120.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166", "id": "CG-PCER-AGENT:CG_50082_EP170326324571166", "type": "Agent" }, "comments": "The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PP1; PMID: 28130426).", "contributionDate": { "date": "2026/8/20", "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": "CA340745829/MONDO:0100368/120/ci/CA340745829/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340745829/MONDO:0100368/120/0/1678/1680", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340745829/MONDO:0100368/120/1/1679", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340745829/MONDO:0100368/120/0/1678", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340745829/MONDO:0100368/120/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340745829/MONDO:0100368/120/ei/1/1634", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166", "id": "CG-PCER-AGENT:CG_50082_EP170326324571166", "type": "Agent" }, "contributionDate": { "date": "2026/8/20", "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/CA340745829/MONDO:0100368/120/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340745829/MONDO:0100368/120/ci/CA340745829/MONDO:0100368/120.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166", "id": "CG-PCER-AGENT:CG_50082_EP170326324571166", "type": "Agent" }, "comments": "At least one proband (RF.T.111, patient II-I) harboring this variant exhibits a phenotype including severely decrease ERG responses (0.5), optic disc pallor (0.5), pigmentary retinopathy with attenuated vessels (0.5), symptomatic onset between birth an age five years (1), decreased peripheral vision (1), abnormal color vision (1), decreased central visual acuity (1), and nystagmus (1), which together are specific for RPE65-related recessive retinopathy (6.5 points, PMID: 28130426, PP4).\n", "contributionDate": { "date": "2026/8/20", "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": "CA340745829/MONDO:0100368/120/ci/CA340745829/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340745829/MONDO:0100368/120/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340745829/MONDO:0100368/120/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340745829/MONDO:0100368/120/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340745829/MONDO:0100368/120/el/0/1717", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340745829/MONDO:0100368/120/ei/1/1718", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166", "id": "CG-PCER-AGENT:CG_50082_EP170326324571166", "type": "Agent" }, "contributionDate": { "date": "2026/8/20", "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/CA340745829/MONDO:0100368/120/el/0/1717/1719", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340745829/MONDO:0100368/120/ci/CA340745829/MONDO:0100368/120.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166", "id": "CG-PCER-AGENT:CG_50082_EP170326324571166", "type": "Agent" }, "comments": "This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who is compound heterozygous with the NM_000329.3(RPE65):c.1360del (p.Thr454LeufsTer?) variant confirmed in trans (1 point, PMIDs:28130426), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1 total point, PM3).\n", "contributionDate": { "date": "2026/8/20", "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": "CA340745829/MONDO:0100368/120/ci/CA340745829/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340745829/MONDO:0100368/120/0/1717/1719", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340745829/MONDO:0100368/120/1/1718", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340745829/MONDO:0100368/120/0/1717", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340745829/MONDO:0100368/120/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340745829/MONDO:0100368/120/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166", "id": "CG-PCER-AGENT:CG_50082_EP170326324571166", "type": "Agent" }, "contributionDate": { "date": "2026/8/20", "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/CA340745829/MONDO:0100368/120/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340745829/MONDO:0100368/120/ci/CA340745829/MONDO:0100368/120.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166", "id": "CG-PCER-AGENT:CG_50082_EP170326324571166", "type": "Agent" }, "comments": "This variant is present in gnomAD v.4.1.1 at a GrpMax allele frequency of 0.00000068, with 3 / 1179970 total alleles in the European Non-Finnish population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting).\n", "contributionDate": { "date": "2026/8/20", "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": "CA340745829/MONDO:0100368/120/ci/CA340745829/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340745829/MONDO:0100368/120/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340745829/MONDO:0100368/120/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340745829/MONDO:0100368/120/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340745829/MONDO:0100368/120/el/0/1690", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340745829/MONDO:0100368/120/ei/1/1691", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166", "id": "CG-PCER-AGENT:CG_50082_EP170326324571166", "type": "Agent" }, "contributionDate": { "date": "2026/8/20", "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/CA340745829/MONDO:0100368/120/el/0/1690/1692", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340745829/MONDO:0100368/120/ci/CA340745829/MONDO:0100368/120.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166", "id": "CG-PCER-AGENT:CG_50082_EP170326324571166", "type": "Agent" }, "comments": "The computational predictor REVEL gives a score of 0.986, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on RPE65 function (PP3_Moderate).\n", "contributionDate": { "date": "2026/8/20", "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": "CA340745829/MONDO:0100368/120/ci/CA340745829/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340745829/MONDO:0100368/120/0/1690/1692", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340745829/MONDO:0100368/120/1/1691", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340745829/MONDO:0100368/120/0/1690", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340745829/MONDO:0100368/120", "metadata": { "created": "2026-08-20T19:10:30.688Z", "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, 20 Aug 2026 19:10:30 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.1.0" }, "statementOutcome": { "@id": "https://loinc.org/LA26332-9", "id": "LN:LA26332-9", "label": "Likely Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "6bae432c-d50d-40d9-b150-a7e15d26fa0e", "variant": { "@id": "https://reg.genome.network/allele/CA340745829", "id": "CAR:CA340745829", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000329.3:c.755T>C" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000329.3(RPE65):c.755T>C (p.Phe252Ser)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-02T11:41:23.723Z" } }, "status": { "code": 200, "name": "OK" } }