{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/d1b42d5c-6dd4-4376-b088-49da0241c349/doc/sepio/version/1.6.0", "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/CA226515/MONDO:0100368/120/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226515/MONDO:0100368/120/ei/1/1832", "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/CA226515/MONDO:0100368/120/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226515/MONDO:0100368/120/ci/CA226515/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 patient harboring the variant exhibited reduced or nondetectable rod ERG (required, 2 pts), decreased central visual acuity (1 pt), symptomatic onset between birth and age 5 years (1 pt), evidence of cone involvement on ERG (1 pt), light staring (1 pt), nyctalopia (1 pt), and positive response to RPE65 gene therapy (8 pts), exceeding the 8 phenotype points required for this criterion (VCEP member-provided data, PP4_Moderate). A second reported patient met the phenotype point threshold as well (PMID: 9501220). A third reported patient with the same genotype exhibited similar phenotypes, but it is not clear whether the patients from PMID: 9501220 and PMID: 27375040 are distinct.", "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": "CA226515/MONDO:0100368/120/ci/CA226515/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226515/MONDO:0100368/120/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226515/MONDO:0100368/120/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226515/MONDO:0100368/120/0/1831", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226515/MONDO:0100368/120/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226515/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/CA226515/MONDO:0100368/120/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226515/MONDO:0100368/120/ci/CA226515/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 0.00002196, with 2 alleles / 91080 total alleles in the South Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (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": "CA226515/MONDO:0100368/120/ci/CA226515/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226515/MONDO:0100368/120/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226515/MONDO:0100368/120/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226515/MONDO:0100368/120/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226515/MONDO:0100368/120/el/0/1777", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226515/MONDO:0100368/120/ei/1/1778", "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/CA226515/MONDO:0100368/120/el/0/1777/1779", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226515/MONDO:0100368/120/ci/CA226515/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 0.00002196, with 2 alleles / 91080 total alleles in the South Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (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": "CA226515/MONDO:0100368/120/ci/CA226515/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226515/MONDO:0100368/120/0/1777/1779", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226515/MONDO:0100368/120/1/1778", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226515/MONDO:0100368/120/0/1777", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226515/MONDO:0100368/120/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226515/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/CA226515/MONDO:0100368/120/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226515/MONDO:0100368/120/ci/CA226515/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 patients meeting the minimum phenotype requirement harbor the p.Val473Asp variant in the homozygous state (PMID: 9501220, SCV001430890.1, 1 pt). An additional report of a homozygous patient is found in PMID: 27375040 and PMID: 19854499, but it is not clear that this patient is unrelated to the first. Two compound heterozygous patients have been described (VCEP members-provided data) harboring the variant in trans with the p.Pro363Thr variant, which has been previously classified as Likely Pathogenic by the ClinGen Leber congenital amaurosis / early-onset retinal dystrophy (2 pts) (3 pt, 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": "CA226515/MONDO:0100368/120/ci/CA226515/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226515/MONDO:0100368/120/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226515/MONDO:0100368/120/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226515/MONDO:0100368/120/0/1651", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226515/MONDO:0100368/120/el/0/1690", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226515/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/CA226515/MONDO:0100368/120/el/0/1690/1692", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226515/MONDO:0100368/120/ci/CA226515/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 meta-predictor REVEL gives a score of 0.992, which is above the ClinGen LCA/eoRP VCEP PP3 threshold of >0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The computational splicing predictor SpliceAI indicates that the variant may impact splicing by disrupting a splice acceptor (change score 0.10) or triggering a splice donor gain (change score 0.08), although these are not high-confidence predictions.", "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": "CA226515/MONDO:0100368/120/ci/CA226515/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226515/MONDO:0100368/120/0/1690/1692", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226515/MONDO:0100368/120/1/1691", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226515/MONDO:0100368/120/0/1690", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226515/MONDO:0100368/120/el/0/1804", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226515/MONDO:0100368/120/ei/1/1805", "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/CA226515/MONDO:0100368/120/el/0/1804/1806", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226515/MONDO:0100368/120/ci/CA226515/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 v2.1.1.", "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": "CA226515/MONDO:0100368/120/ci/CA226515/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226515/MONDO:0100368/120/0/1804/1806", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226515/MONDO:0100368/120/1/1805", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226515/MONDO:0100368/120/0/1804", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226515/MONDO:0100368/120", "metadata": { "created": "2026-08-20T21:00:11.146Z", "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 21:00:10 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.6.0" }, "statementOutcome": { "@id": "https://loinc.org/LA26332-9", "id": "LN:LA26332-9", "label": "Likely Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "d1b42d5c-6dd4-4376-b088-49da0241c349", "variant": { "@id": "https://reg.genome.network/allele/CA226515", "id": "CAR:CA226515", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000329.3:c.1418T>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000329.3(RPE65):c.1418T>A (p.Val473Asp)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-03T21:34:52.527Z" } }, "status": { "code": 200, "name": "OK" } }