{ "data": [ { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://erepo.genome.network/evrepo/api/summary/classification/69b90ad5-3495-4624-b0dd-489f167402a1/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/CA226531/MONDO:0100368/120/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226531/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": "2024/7/23", "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/008", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "008", "label": "PM5", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226531/MONDO:0100368/120/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226531/MONDO:0100368/120/ci/CA226531/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": "Another missense variant in the same codon (p.Arg91Gln) has been classified as Pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP (PM5). Splicing prediction using SpliceAI are equivalent for both of these variants.", "contributionDate": { "date": "2024/7/23", "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": "CA226531/MONDO:0100368/120/ci/CA226531/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226531/MONDO:0100368/120/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226531/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": "2024/7/23", "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/CA226531/MONDO:0100368/120/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226531/MONDO:0100368/120/ci/CA226531/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.4.1.0 at a GrpMax allele frequency of 0.0001329, with 16 alleles / 74990 total alleles in the African / African-American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting).", "contributionDate": { "date": "2024/7/23", "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": "CA226531/MONDO:0100368/120/ci/CA226531/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226531/MONDO:0100368/120/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226531/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": "2024/7/23", "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/CA226531/MONDO:0100368/120/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226531/MONDO:0100368/120/ci/CA226531/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 4 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 35129589, 18722466). This variant has also been reported in at least 2 proband(s) with early-onset severe retinal dystrophy who were compound heterozygous with the variants c.11+5G>A and c.272G>A (p.Arg91Gln), suspected in trans (1 point, PMIDs: 35129589, 33952291), which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong).\n", "contributionDate": { "date": "2024/7/23", "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": "CA226531/MONDO:0100368/120/ci/CA226531/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/0/1651", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226531/MONDO:0100368/120/el/0/1690", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226531/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": "2024/7/23", "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/CA226531/MONDO:0100368/120/el/0/1690/1692", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226531/MONDO:0100368/120/ci/CA226531/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 splicing impact predictor SpliceAI gives a score of [0.22], which is above the ClinGen LCA / eoRD VCEP recommended threshold of ≥ 0.2 and predicts a damaging impact on splicing (PP3).\n\nThe computational predictor REVEL gives a score of [0.852], which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). ", "contributionDate": { "date": "2024/7/23", "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": "CA226531/MONDO:0100368/120/ci/CA226531/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/0/1690/1692", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/1/1691", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/0/1690", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226531/MONDO:0100368/120/el/0/1630", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226531/MONDO:0100368/120/ei/1/1631", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166", "id": "CG-PCER-AGENT:CG_50082_EP170326324571166", "type": "Agent" }, "contributionDate": { "date": "2024/7/23", "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/0040", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "0040", "label": "PP1", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226531/MONDO:0100368/120/el/0/1630/1632", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226531/MONDO:0100368/120/ci/CA226531/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 2 similarly affected relatives, with the variant present in the homozygous state (PP1_Moderate; PMID: 31925606).", "contributionDate": { "date": "2024/7/23", "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": "CA226531/MONDO:0100368/120/ci/CA226531/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/0/1630/1632", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/1/1631", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/0/1630", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226531/MONDO:0100368/120/el/0/1696", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226531/MONDO:0100368/120/ei/1/1697", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166", "id": "CG-PCER-AGENT:CG_50082_EP170326324571166", "type": "Agent" }, "contributionDate": { "date": "2024/7/23", "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/0045", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0045", "label": "PS3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226531/MONDO:0100368/120/el/0/1696/1698", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226531/MONDO:0100368/120/ci/CA226531/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 exhibited 0% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 16754667).\n", "contributionDate": { "date": "2024/7/23", "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": "CA226531/MONDO:0100368/120/ci/CA226531/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/0/1696/1698", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/1/1697", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/0/1696", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226531/MONDO:0100368/120/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226531/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": "2024/7/23", "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/CA226531/MONDO:0100368/120/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226531/MONDO:0100368/120/ci/CA226531/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 exhibits a phenotype including congenital onset (1 pt), abnormal best corrected visual acuity test (1 pt), Mild myopia, extinguished scotopic (0.5 pts) and photopic (1 pt) ERG responses, bone spicule pigmentation of the fundus (0.5 pts), white or yellow dots in fundus (2 pts), and nystagmus (1 pt), and genotyping performed by next-generation sequencing analysis of 586 candidate genes which did not provide an alternative explanation for visual impairment (2 pts). (PMID: 31925606). These 9 total phenotype points are sufficient to meet PP4_Moderate.", "contributionDate": { "date": "2024/7/23", "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": "CA226531/MONDO:0100368/120/ci/CA226531/MONDO:0100368/120.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120/0/1831", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226531/MONDO:0100368/120", "metadata": { "created": "2024-09-28T05:08:44.464Z", "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 05:08:43 -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": "69b90ad5-3495-4624-b0dd-489f167402a1", "variant": { "@id": "https://reg.genome.network/allele/CA226531", "id": "CAR:CA226531", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000329.3:c.271C>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000329.3(RPE65):c.271C>T (p.Arg91Trp)" } ], "type": "CAR" } } ], "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-04-04T13:38:41.929Z" } }, "status": { "code": 200, "name": "OK" } }