{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/6fd74226-2024-4f89-b455-5fa657333c4f/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1733815116", "label": "ClinGen Leber Congenital Amaurosis/early onset Retinal Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GUCY2D Version 1.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0100453", "id": "MONDO:0100453", "label": "GUCY2D-related recessive retinopathy", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365964/MONDO:0100453/167/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365964/MONDO:0100453/167/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": "2026/9/9", "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/CA8365964/MONDO:0100453/167/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8365964/MONDO:0100453/167/ci/CA8365964/MONDO:0100453/167.002", "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 0.479, which is below the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RetGC-1 protein function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.04, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing.", "contributionDate": { "date": "2026/9/9", "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": "CA8365964/MONDO:0100453/167/ci/CA8365964/MONDO:0100453/167.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8365964/MONDO:0100453/167/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8365964/MONDO:0100453/167/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8365964/MONDO:0100453/167/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365964/MONDO:0100453/167/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365964/MONDO:0100453/167/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": "2026/9/9", "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/CA8365964/MONDO:0100453/167/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8365964/MONDO:0100453/167/ci/CA8365964/MONDO:0100453/167.002", "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 total allele frequency of 0.000017, with 27 alleles / 1613832 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting).", "contributionDate": { "date": "2026/9/9", "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": "CA8365964/MONDO:0100453/167/ci/CA8365964/MONDO:0100453/167.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8365964/MONDO:0100453/167/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8365964/MONDO:0100453/167/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8365964/MONDO:0100453/167/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365964/MONDO:0100453/167/el/0/1717", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365964/MONDO:0100453/167/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": "2026/9/9", "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/007", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "007", "label": "PM3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365964/MONDO:0100453/167/el/0/1717/1719", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8365964/MONDO:0100453/167/ci/CA8365964/MONDO:0100453/167.002", "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 homozygous for the variant (0.5 points, PMID: 40478561). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000180.4 (GUCY2D):c.2945del (p.Gly982ValfsTer39) variant suspected in trans (0.5 points, PMID: 29559409), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1.0 total points, PM3).", "contributionDate": { "date": "2026/9/9", "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": "CA8365964/MONDO:0100453/167/ci/CA8365964/MONDO:0100453/167.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8365964/MONDO:0100453/167/0/1717/1719", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8365964/MONDO:0100453/167/1/1718", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8365964/MONDO:0100453/167/0/1717", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365964/MONDO:0100453/167/el/0/1696", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365964/MONDO:0100453/167/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": "2026/9/9", "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/CA8365964/MONDO:0100453/167/el/0/1696/1698", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8365964/MONDO:0100453/167/ci/CA8365964/MONDO:0100453/167.002", "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 guanylate cyclase assay relative to the wild-type control, which is lower than the ClinGen LCA/eoRD VCEP PS3_Supporting threshold of ≤10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 33109612).", "contributionDate": { "date": "2026/9/9", "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": "CA8365964/MONDO:0100453/167/ci/CA8365964/MONDO:0100453/167.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8365964/MONDO:0100453/167/0/1696/1698", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8365964/MONDO:0100453/167/1/1697", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8365964/MONDO:0100453/167/0/1696", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365964/MONDO:0100453/167/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365964/MONDO:0100453/167/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": "2026/9/9", "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/CA8365964/MONDO:0100453/167/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8365964/MONDO:0100453/167/ci/CA8365964/MONDO:0100453/167.002", "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 congenital stationary night blindness (0.5 pts), vision loss in dim light since early infancy (1 pt), normal retinal structure by optical coherence tomography (1 pt), a non-detectable rod isolating electroretinogram (0.5 pts), evidence of cone involvement on ERG (1 pt) and genotyping by exome sequencing that did not provide an alternative explanation for visual impairment (4 pts), which together are highly specific for GUCY2D-related recessive retinopathy (8 total points, PMID: 29559409, PP4_Moderate).", "contributionDate": { "date": "2026/9/9", "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": "CA8365964/MONDO:0100453/167/ci/CA8365964/MONDO:0100453/167.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8365964/MONDO:0100453/167/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8365964/MONDO:0100453/167/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8365964/MONDO:0100453/167/0/1831", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8365964/MONDO:0100453/167", "metadata": { "created": "2026-09-09T16:44:06.436Z", "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": "Wed, 09 Sep 2026 16:44:06 -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": "6fd74226-2024-4f89-b455-5fa657333c4f", "variant": { "@id": "https://reg.genome.network/allele/CA8365964", "id": "CAR:CA8365964", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000180.4:c.1996C>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000180.4(GUCY2D):c.1996C>T (p.Arg666Trp)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-05T10:31:10.130Z" } }, "status": { "code": 200, "name": "OK" } }