{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/aa5e7a2b-282b-4e07-b134-48139d01bf31/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/94412666", "label": "ClinGen Leber Congenital Amaurosis/early onset Retinal Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for AIPL1 Version 1.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0100438", "id": "MONDO:0100438", "label": "AIPL1-related retinopathy", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA397397299/MONDO:0100438/208/el/0/1696", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA397397299/MONDO:0100438/208/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": "2025/9/29", "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/CA397397299/MONDO:0100438/208/el/0/1696/1698", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA397397299/MONDO:0100438/208/ci/CA397397299/MONDO:0100438/208.002", "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 was associated with ~40% PDE6 enzymatic activity in a cGMP hydrolysis assay relative to the wild-type control, which was comparable to the negative control lacking AIPL1, indicating that it triggers a severe defect in protein function (PMID: 33067476, PS3_Supporting).", "contributionDate": { "date": "2025/9/29", "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": "CA397397299/MONDO:0100438/208/ci/CA397397299/MONDO:0100438/208.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA397397299/MONDO:0100438/208/0/1696/1698", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA397397299/MONDO:0100438/208/1/1697", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA397397299/MONDO:0100438/208/0/1696", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA397397299/MONDO:0100438/208/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA397397299/MONDO:0100438/208/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": "2025/9/29", "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/CA397397299/MONDO:0100438/208/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA397397299/MONDO:0100438/208/ci/CA397397299/MONDO:0100438/208.002", "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 diagnosis of Leber congenital amaurosis (0.5 pts) with genotyping by a next-generation sequencing panel of 163 known inherited retinal disease-associated genes (2 pts), severe visual disturbances in infancy or early childhood (1 pt), visual acuity limited to light perception (1 pt), moderate hypermetropia, kinetic visual field extent not detectable (1 pt), keratoconus (0.5 pts), nystagmus (1 pt), posterior subcapsular cataract (0.5 pts), and nondetectable electroretinogram responses from both rods (0.5 pts) and cones (1 pt), which together are highly specific for AIPL1-related retinopathy (total 9 points, PMID: 20702822, PMID: 23847139, PP4_Moderate).", "contributionDate": { "date": "2025/9/29", "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": "CA397397299/MONDO:0100438/208/ci/CA397397299/MONDO:0100438/208.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA397397299/MONDO:0100438/208/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA397397299/MONDO:0100438/208/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA397397299/MONDO:0100438/208/0/1831", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA397397299/MONDO:0100438/208/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA397397299/MONDO:0100438/208/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": "2025/9/29", "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/CA397397299/MONDO:0100438/208/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA397397299/MONDO:0100438/208/ci/CA397397299/MONDO:0100438/208.002", "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 v4.1.0 (PM2_Supporting).", "contributionDate": { "date": "2025/9/29", "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": "CA397397299/MONDO:0100438/208/ci/CA397397299/MONDO:0100438/208.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA397397299/MONDO:0100438/208/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA397397299/MONDO:0100438/208/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA397397299/MONDO:0100438/208/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA397397299/MONDO:0100438/208/el/0/1690", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA397397299/MONDO:0100438/208/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": "2025/9/29", "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/CA397397299/MONDO:0100438/208/el/0/1690/1692", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA397397299/MONDO:0100438/208/ci/CA397397299/MONDO:0100438/208.002", "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 0.836, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.774 and predicts a damaging effect on AIPL1 protein function (PP3_Moderate). The splicing impact predictor SpliceAI gives a score of 0.01 for 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": "2025/9/29", "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": "CA397397299/MONDO:0100438/208/ci/CA397397299/MONDO:0100438/208.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA397397299/MONDO:0100438/208/0/1690/1692", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA397397299/MONDO:0100438/208/1/1691", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA397397299/MONDO:0100438/208/0/1690", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA397397299/MONDO:0100438/208/el/0/1717", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA397397299/MONDO:0100438/208/ei/1/1718", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166", "id": "CG-PCER-AGENT:CG_50082_EP170326324571166", "type": "Agent" }, "contributionDate": { "date": "2025/9/29", "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/CA397397299/MONDO:0100438/208/el/0/1717/1719", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA397397299/MONDO:0100438/208/ci/CA397397299/MONDO:0100438/208.002", "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 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the M_014336.5(AIPL1):c.265T>C (p.Cys89Arg) variant suspected in trans (PMID: 20702822, PMID: 23847139, PMID: 33067476), which was previously classified likely pathogenic by the ClinGen LCA/eoRD VCEP (0.25 points), so the PM3_Supporting code was not met.", "contributionDate": { "date": "2025/9/29", "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": "CA397397299/MONDO:0100438/208/ci/CA397397299/MONDO:0100438/208.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA397397299/MONDO:0100438/208/0/1717/1719", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA397397299/MONDO:0100438/208/1/1718", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA397397299/MONDO:0100438/208/0/1717", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA397397299/MONDO:0100438/208", "metadata": { "created": "2025-09-29T18:12:32.627Z", "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": "Mon, 29 Sep 2025 18:12:32 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA26332-9", "id": "LN:LA26332-9", "label": "Likely Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "aa5e7a2b-282b-4e07-b134-48139d01bf31", "variant": { "@id": "https://reg.genome.network/allele/CA397397299", "id": "CAR:CA397397299", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_001285403.4:c.214T>C" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_001285403.4:c.214T>C" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-05T04:43:15.086Z" } }, "status": { "code": 200, "name": "OK" } }