{ "data": [ { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://erepo.genome.network/evrepo/api/summary/classification/fc5056f3-86f2-497e-a21d-16e5e8850843/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 1.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "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/CA226122/MONDO:0100453/167/el/0/1678", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226122/MONDO:0100453/167/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": "2025/1/30", "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/CA226122/MONDO:0100453/167/el/0/1678/1680", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226122/MONDO:0100453/167/ci/CA226122/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 has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 31704230, PP1).", "contributionDate": { "date": "2025/1/30", "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": "CA226122/MONDO:0100453/167/ci/CA226122/MONDO:0100453/167.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226122/MONDO:0100453/167/0/1678/1680", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226122/MONDO:0100453/167/1/1679", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226122/MONDO:0100453/167/0/1678", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226122/MONDO:0100453/167/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226122/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": "2025/1/30", "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/CA226122/MONDO:0100453/167/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226122/MONDO:0100453/167/ci/CA226122/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 0.547, which is below the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RetGC-1 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.00, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing.", "contributionDate": { "date": "2025/1/30", "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": "CA226122/MONDO:0100453/167/ci/CA226122/MONDO:0100453/167.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226122/MONDO:0100453/167/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226122/MONDO:0100453/167/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226122/MONDO:0100453/167/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226122/MONDO:0100453/167/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226122/MONDO:0100453/167/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": "2025/1/30", "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/CA226122/MONDO:0100453/167/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226122/MONDO:0100453/167/ci/CA226122/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 Leber congenital amaurosis (0.5 pts) with onset before age 5 (1 pt), nystagmus (1), photophobia (1 pt), reduced visual acuity (1 pt), undetectable light-adapted ERG responses (1 pt), reduced or undetectable dark-adapted ERG responses (0.5 pts), and central retinal pigment epithelium atrophy (0.5 pts), which together are specific for GUCY2D-related recessive retinopathy (total 6.5 points, PMID: 31704230, PP4).", "contributionDate": { "date": "2025/1/30", "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": "CA226122/MONDO:0100453/167/ci/CA226122/MONDO:0100453/167.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226122/MONDO:0100453/167/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226122/MONDO:0100453/167/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226122/MONDO:0100453/167/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226122/MONDO:0100453/167/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226122/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": "2025/1/30", "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/CA226122/MONDO:0100453/167/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226122/MONDO:0100453/167/ci/CA226122/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.4.1.0 at a total allele frequency of 0.0001749, with 257 alleles / 1,469,548 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting).", "contributionDate": { "date": "2025/1/30", "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": "CA226122/MONDO:0100453/167/ci/CA226122/MONDO:0100453/167.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226122/MONDO:0100453/167/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226122/MONDO:0100453/167/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226122/MONDO:0100453/167/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226122/MONDO:0100453/167/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226122/MONDO:0100453/167/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": "2025/1/30", "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/CA226122/MONDO:0100453/167/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226122/MONDO:0100453/167/ci/CA226122/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": "Another missense variant in the same codon (NM_000180.4(GUCY2D):c.308A>T (p.Glu103Val)) has been reported in association with GUCY2D-related recessive retinopathy (PMID: 21602930), and splicing prediction using SpliceAI did not strongly predict an effect on splicing due to either of these variants. However, this second variant has not yet been classified by the ClinGen LCA / eoRD VCEP, so PM5 is not met.", "contributionDate": { "date": "2025/1/30", "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": "CA226122/MONDO:0100453/167/ci/CA226122/MONDO:0100453/167.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226122/MONDO:0100453/167/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226122/MONDO:0100453/167/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226122/MONDO:0100453/167/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226122/MONDO:0100453/167/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226122/MONDO:0100453/167/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": "2025/1/30", "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/CA226122/MONDO:0100453/167/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226122/MONDO:0100453/167/ci/CA226122/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 2 apparently unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000180.4(GUCY2D):c.2595del (p.Lys866fs) variant or the NM_000180.4(GUCY2D):c.91dup (p.Arg31fs) variant confirmed in trans, which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 points, PMID: 29178642, PM3_Strong).", "contributionDate": { "date": "2025/1/30", "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": "CA226122/MONDO:0100453/167/ci/CA226122/MONDO:0100453/167.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226122/MONDO:0100453/167/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226122/MONDO:0100453/167/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226122/MONDO:0100453/167/0/1651", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226122/MONDO:0100453/167", "metadata": { "created": "2025-01-30T17:52:16.369Z", "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": "Thu, 30 Jan 2025 17:52:16 -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": "fc5056f3-86f2-497e-a21d-16e5e8850843", "variant": { "@id": "https://reg.genome.network/allele/CA226122", "id": "CAR:CA226122", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000180.4:c.307G>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000180.4(GUCY2D):c.307G>A (p.Glu103Lys)" } ], "type": "CAR" } } ], "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-04-08T11:11:50.510Z" } }, "status": { "code": 200, "name": "OK" } }