{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/8da3ac20-f2f0-43e1-b08a-6d3d7773bda9/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/CA340742486/MONDO:0100368/120/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340742486/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": "2026/9/22", "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/0058", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000330", "id": "SEPIO:0000330", "label": "Pathogenic Strong" }, "id": "0058", "label": "PM3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340742486/MONDO:0100368/120/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340742486/MONDO:0100368/120/ci/CA340742486/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 3 unrelated probands with early-onset severe retinal dystrophy. One proband (PMID:31273949) is compound heterozygous (confirmed in trans) with the c.1399C>G; p.Pro467Ala variant, previously curated as Pathogenic by the LCA/eoRD VCEP (1 point). A second proband is reported in the LOVD database to be found with the c.95-2A>T variant, previously curated as Pathogenic by the LCA/eoRD VCEP. No confirmation of phase available. (0.5 points). A third proband is reported (PMID:29033008) found with p.Pro25Leu variant which does not have confirmation of phase but has been classified by the LCA/eoRD VCEP as Pathogenic (0.5 points) (2.0 total points, PM3_Strong.)", "contributionDate": { "date": "2026/9/22", "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": "CA340742486/MONDO:0100368/120/ci/CA340742486/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340742486/MONDO:0100368/120/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340742486/MONDO:0100368/120/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340742486/MONDO:0100368/120/0/1651", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340742486/MONDO:0100368/120/el/0/1678", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340742486/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": "2026/9/22", "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/0060", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0060", "label": "PP1", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340742486/MONDO:0100368/120/el/0/1678/1680", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340742486/MONDO:0100368/120/ci/CA340742486/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: 31273949).", "contributionDate": { "date": "2026/9/22", "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": "CA340742486/MONDO:0100368/120/ci/CA340742486/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340742486/MONDO:0100368/120/0/1678/1680", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340742486/MONDO:0100368/120/1/1679", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340742486/MONDO:0100368/120/0/1678", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340742486/MONDO:0100368/120/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340742486/MONDO:0100368/120/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166", "id": "CG-PCER-AGENT:CG_50082_EP170326324571166", "type": "Agent" }, "contributionDate": { "date": "2026/9/22", "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/CA340742486/MONDO:0100368/120/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340742486/MONDO:0100368/120/ci/CA340742486/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 0.769, which is above the ClinGen LCA/eoRD VCEP threshold of ≥ 0.644 for PP3_Supporting and predicts a damaging effect on RPE65 function (PP3). The LCA/eoRD VCEP threshold for PP3_Moderate is 0.774 and is almost met. AlphaMissense analysis of the variant predicts \"likely pathogenic\" with a score of 0.9732.\n", "contributionDate": { "date": "2026/9/22", "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": "CA340742486/MONDO:0100368/120/ci/CA340742486/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340742486/MONDO:0100368/120/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340742486/MONDO:0100368/120/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340742486/MONDO:0100368/120/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340742486/MONDO:0100368/120/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340742486/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": "2026/9/22", "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/0063", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0063", "label": "PP4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340742486/MONDO:0100368/120/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340742486/MONDO:0100368/120/ci/CA340742486/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": "Individual P01-II:2 had extinguished rod ERG responses (0.5 pts), fundus albipunctatus/white dots (2 pts), onset between birth and age 5 (1 pt), evidence of cone involvement on ERG (1 pt), and night blindness (0.5 pts) which together are specific for RPE65-related recessive retinopathy (5.0 points, PMID: 31273949, PP4). ", "contributionDate": { "date": "2026/9/22", "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": "CA340742486/MONDO:0100368/120/ci/CA340742486/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340742486/MONDO:0100368/120/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340742486/MONDO:0100368/120/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340742486/MONDO:0100368/120/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340742486/MONDO:0100368/120/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340742486/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": "2026/9/22", "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/CA340742486/MONDO:0100368/120/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340742486/MONDO:0100368/120/ci/CA340742486/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 frequency of 8.475e-7, with 1/ 1179918 alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). In the Middle Eastern genetic ancestry group, the frequency of 1/6062 alleles (0.0001650) is also lower than the threshold.", "contributionDate": { "date": "2026/9/22", "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": "CA340742486/MONDO:0100368/120/ci/CA340742486/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340742486/MONDO:0100368/120/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340742486/MONDO:0100368/120/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340742486/MONDO:0100368/120/0/1636", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340742486/MONDO:0100368/120", "metadata": { "created": "2026-10-15T19:02:30.454Z", "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 19:02:30 -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": "8da3ac20-f2f0-43e1-b08a-6d3d7773bda9", "variant": { "@id": "https://reg.genome.network/allele/CA340742486", "id": "CAR:CA340742486", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000329.3:c.1301C>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000329.3(RPE65):c.1301C>A (p.Ala434Glu)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-31T21:43:33.777Z" } }, "status": { "code": 200, "name": "OK" } }