{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/bc545cdf-c331-4bcf-b50f-b561a1be3aee/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/CA340747756/MONDO:0100368/120/el/0/1678", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340747756/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/CA340747756/MONDO:0100368/120/el/0/1678/1680", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340747756/MONDO:0100368/120/ci/CA340747756/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 fundus albipunctatus through at least 1 affected meiosis from 1 family, with the variant present in the compound heterozygous state with the p.Pro467Ala variant confirmed in trans (PP1; PMID: 31273949).", "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": "CA340747756/MONDO:0100368/120/ci/CA340747756/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340747756/MONDO:0100368/120/0/1678/1680", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340747756/MONDO:0100368/120/1/1679", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340747756/MONDO:0100368/120/0/1678", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340747756/MONDO:0100368/120/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340747756/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/CA340747756/MONDO:0100368/120/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340747756/MONDO:0100368/120/ci/CA340747756/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 two probands harboring this variant exhibit a phenotype specific for RPE65-related recessive retinopathy (PMID: 23661369, PMID: 31273949), one with a phenotype including nyctalopia (0.5 pts) and reduced visual acuity with childhood onset (1 pt), photophobia (1 pt), pigment deposits in the macula (0.5 pts), attenuation of retinal vessels (0.5 pts), and optic disc pallor (0.5 pts), which together are specific for RPE65-related recessive retinopathy (4 points, PP4).", "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": "CA340747756/MONDO:0100368/120/ci/CA340747756/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340747756/MONDO:0100368/120/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340747756/MONDO:0100368/120/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340747756/MONDO:0100368/120/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340747756/MONDO:0100368/120/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340747756/MONDO:0100368/120/ei/1/1781", "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/CA340747756/MONDO:0100368/120/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340747756/MONDO:0100368/120/ci/CA340747756/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": "Two other missense variants at the same codon have been reported in similarly affected individuals (NM_000329.3(RPE65):c.433G>A (p.Ala145Thr) in PMID: 26906952, and NM_000329.3(RPE65):c.433G>C (p.Ala145Pro) in PMID: 28224992). However, this variant has not been considered for the PM5 code in order to avoid circularity.", "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": "CA340747756/MONDO:0100368/120/ci/CA340747756/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340747756/MONDO:0100368/120/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340747756/MONDO:0100368/120/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340747756/MONDO:0100368/120/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340747756/MONDO:0100368/120/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340747756/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/CA340747756/MONDO:0100368/120/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340747756/MONDO:0100368/120/ci/CA340747756/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 absent from gnomAD v4.1.1 (PM2_Supporting).", "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": "CA340747756/MONDO:0100368/120/ci/CA340747756/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340747756/MONDO:0100368/120/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340747756/MONDO:0100368/120/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340747756/MONDO:0100368/120/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340747756/MONDO:0100368/120/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340747756/MONDO:0100368/120/ei/1/1652", "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/CA340747756/MONDO:0100368/120/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340747756/MONDO:0100368/120/ci/CA340747756/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 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.200T>G (p.Leu67Arg) or the NM_000329.3(RPE65):c.1399C>G (p.Pro467Ala) variants confirmed in trans, which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PMID: 23661369, PMID: 31273949PM3, PM3_Strong).", "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": "CA340747756/MONDO:0100368/120/ci/CA340747756/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340747756/MONDO:0100368/120/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340747756/MONDO:0100368/120/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340747756/MONDO:0100368/120/0/1651", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340747756/MONDO:0100368/120/el/0/1690", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340747756/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/CA340747756/MONDO:0100368/120/el/0/1690/1692", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340747756/MONDO:0100368/120/ci/CA340747756/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 0.929, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate).", "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": "CA340747756/MONDO:0100368/120/ci/CA340747756/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340747756/MONDO:0100368/120/0/1690/1692", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340747756/MONDO:0100368/120/1/1691", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340747756/MONDO:0100368/120/0/1690", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340747756/MONDO:0100368/120", "metadata": { "created": "2026-08-20T19:24:42.593Z", "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 19:24:42 -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": "bc545cdf-c331-4bcf-b50f-b561a1be3aee", "variant": { "@id": "https://reg.genome.network/allele/CA340747756", "id": "CAR:CA340747756", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000329.3:c.434C>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000329.3(RPE65):c.434C>A (p.Ala145Asp)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-03T15:50:13.871Z" } }, "status": { "code": 200, "name": "OK" } }