{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://erepo.genome.network/evrepo/api/summary/classification/4d66b49c-5789-488a-9be7-7312b3695d19/doc/sepio/version/1.0.0", "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 1.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "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/CA340749010/MONDO:0100368/120/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340749010/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": "2024/2/20", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0018", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "0018", "label": "PP4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340749010/MONDO:0100368/120/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340749010/MONDO:0100368/120/ci/CA340749010/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 harboring this variant has been genotyped by targeted exome sequencing that found no alternative cause of disease among 188 known inherited retinal degeneration genes (2 pts) and exhibited a diagnosis of Leber congenital amaurosis (0.5 pts), onset before the age of 5 years (1 pt), reduced central visual acuity (1 pt), nystagmus (1 pt), hypo-autofluorescence (2 pts), and extinguished rod (0.5 pts) and cone (1 pt) electroretinogram responses, which together are highly specific for RPE65-related recessive retinopathy (9 pts, PMID: 34830511, PP4_Moderate).", "contributionDate": { "date": "2024/2/20", "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": "CA340749010/MONDO:0100368/120/ci/CA340749010/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340749010/MONDO:0100368/120/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340749010/MONDO:0100368/120/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340749010/MONDO:0100368/120/0/1831", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340749010/MONDO:0100368/120/el/0/1678", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340749010/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": "2024/2/20", "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" } ], "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/CA340749010/MONDO:0100368/120/el/0/1678/1680", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340749010/MONDO:0100368/120/ci/CA340749010/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 in two different families, with the variant present in the compound heterozygous state in both instances (PP1; PMID: 22509104, PMID: 23661369).", "contributionDate": { "date": "2024/2/20", "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": "CA340749010/MONDO:0100368/120/ci/CA340749010/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340749010/MONDO:0100368/120/0/1678/1680", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340749010/MONDO:0100368/120/1/1679", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340749010/MONDO:0100368/120/0/1678", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340749010/MONDO:0100368/120/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340749010/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": "2024/2/20", "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" } ], "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/CA340749010/MONDO:0100368/120/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340749010/MONDO:0100368/120/ci/CA340749010/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.2.1.1 at a maximum allele frequency of 0.00005437, with 1 allele / 18392 total alleles in the East Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting).", "contributionDate": { "date": "2024/2/20", "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": "CA340749010/MONDO:0100368/120/ci/CA340749010/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340749010/MONDO:0100368/120/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340749010/MONDO:0100368/120/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340749010/MONDO:0100368/120/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340749010/MONDO:0100368/120/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340749010/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": "2024/2/20", "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" } ], "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/CA340749010/MONDO:0100368/120/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340749010/MONDO:0100368/120/ci/CA340749010/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 unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000329.3(RPE65):c.596dup (p.Asn199LysfsTer?) or NM_000329.3(RPE65):c.893del (Lys298Asnfs*27) variant confirmed in trans, which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 points, PMID: 34830511, PM3_Strong).", "contributionDate": { "date": "2024/2/20", "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": "CA340749010/MONDO:0100368/120/ci/CA340749010/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340749010/MONDO:0100368/120/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340749010/MONDO:0100368/120/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340749010/MONDO:0100368/120/0/1651", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340749010/MONDO:0100368/120/el/0/1690", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340749010/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": "2024/2/20", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0025", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "0025", "label": "PP3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA340749010/MONDO:0100368/120/el/0/1690/1692", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA340749010/MONDO:0100368/120/ci/CA340749010/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 0.98, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0.02 for splice acceptor gain, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing.", "contributionDate": { "date": "2024/2/20", "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": "CA340749010/MONDO:0100368/120/ci/CA340749010/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA340749010/MONDO:0100368/120/0/1690/1692", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340749010/MONDO:0100368/120/1/1691", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA340749010/MONDO:0100368/120/0/1690", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA340749010/MONDO:0100368/120", "metadata": { "created": "2024-09-28T04:04:24.929Z", "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": "Sat, 28 Sep 2024 04:04:24 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA6668-3", "id": "LN:LA6668-3", "label": "Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "4d66b49c-5789-488a-9be7-7312b3695d19", "variant": { "@id": "https://reg.genome.network/allele/CA340749010", "id": "CAR:CA340749010", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000329.3:c.200T>G" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000329.3(RPE65):c.200T>G (p.Leu67Arg)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-04-08T15:50:21.704Z" } }, "status": { "code": 200, "name": "OK" } }