{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/94439f89-b156-4b35-8610-3e93493f1cb1/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/CA8328593/MONDO:0100438/208/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8328593/MONDO:0100438/208/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": "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/CA8328593/MONDO:0100438/208/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8328593/MONDO:0100438/208/ci/CA8328593/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 a diagnosis of Leber congenital amaurosis (0.5 pts) received before age 5 years (1 pt), severely reduced central visual acuity (1 pt), kinetic visual field extent (V-4e) undetectable (1 pt), nystagmus (1 pt), and nondetectable electroretinogram responses from both rods (0.5 pts) and cones (1 pt), which together are specific for AIPL1-related retinopathy (total 6 points, PMID: 20702822, PP4).", "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": "CA8328593/MONDO:0100438/208/ci/CA8328593/MONDO:0100438/208.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8328593/MONDO:0100438/208/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8328593/MONDO:0100438/208/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8328593/MONDO:0100438/208/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8328593/MONDO:0100438/208/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8328593/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/CA8328593/MONDO:0100438/208/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8328593/MONDO:0100438/208/ci/CA8328593/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 present in gnomAD v.4.1.0 at a total allele frequency of 0.000001239, with 2 / 1,614,150 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (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": "CA8328593/MONDO:0100438/208/ci/CA8328593/MONDO:0100438/208.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8328593/MONDO:0100438/208/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8328593/MONDO:0100438/208/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8328593/MONDO:0100438/208/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8328593/MONDO:0100438/208/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8328593/MONDO:0100438/208/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": "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/CA8328593/MONDO:0100438/208/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8328593/MONDO:0100438/208/ci/CA8328593/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 2 probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 15024725, PMID: 20079931, PMID: 20702822, PMID: 26306921, VCEP member-provided data, PM3). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_014336.5(AIPL1):c.216G>A (p.Trp72Ter) variant likely confirmed in trans due to their physical proximity (1 point, PMID: 20702822), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). The variant has been reported in an additional proband with early-onset severe retinal dystrophy (PMID: 38880373) who was compound heterozygous with the NM_014336.5(AIPL1):c.730GAG[1] (p.Glu245del) variant suspected in trans, which has not yet been classified by the ClinGen LCA/eoRD VCEP. The variant has been reported in an additional proband with a potentially compatible diagnosis (VCEP member-provided data) who was compound heterozygous with the NM_014336.5(AIPL1):c.1127del (p.Pro376Argfs*42) suspected in trans, which has not yet been classified by the ClinGen LCA/eoRD VCEP.", "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": "CA8328593/MONDO:0100438/208/ci/CA8328593/MONDO:0100438/208.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8328593/MONDO:0100438/208/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8328593/MONDO:0100438/208/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8328593/MONDO:0100438/208/0/1651", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8328593/MONDO:0100438/208/el/0/1690", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8328593/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/CA8328593/MONDO:0100438/208/el/0/1690/1692", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8328593/MONDO:0100438/208/ci/CA8328593/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 0.780, 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 0.02 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": "CA8328593/MONDO:0100438/208/ci/CA8328593/MONDO:0100438/208.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8328593/MONDO:0100438/208/0/1690/1692", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8328593/MONDO:0100438/208/1/1691", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8328593/MONDO:0100438/208/0/1690", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8328593/MONDO:0100438/208/el/0/1696", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8328593/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/CA8328593/MONDO:0100438/208/el/0/1696/1698", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8328593/MONDO:0100438/208/ci/CA8328593/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": "Co-expression of the variant with PDE6C and Pγ resulted in less than 10% of cGMP hydrolysis activity relative to the wild-type AIPL1 control (PMID: 27268253), while X-ray crystal structures of the wild-type and variant AIPL1 identified an inability of the variant to bind prenyl groups, which are relevant to AIPL1 interaction with the isoprenylated C-terminus of PDE6 (PMID: 28973376). ", "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": "CA8328593/MONDO:0100438/208/ci/CA8328593/MONDO:0100438/208.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8328593/MONDO:0100438/208/0/1696/1698", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8328593/MONDO:0100438/208/1/1697", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8328593/MONDO:0100438/208/0/1696", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8328593/MONDO:0100438/208", "metadata": { "created": "2025-09-29T17:57:39.529Z", "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 17:57:39 -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": "94439f89-b156-4b35-8610-3e93493f1cb1", "variant": { "@id": "https://reg.genome.network/allele/CA8328593", "id": "CAR:CA8328593", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_014336.5:c.211G>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_014336.5(AIPL1):c.211G>T (p.Val71Phe)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-14T02:43:36.251Z" } }, "status": { "code": 200, "name": "OK" } }