{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/6b75b512-79f7-452a-ae4c-aec715828caf/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/CA8365564/MONDO:0100453/167/el/0/1696", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365564/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": "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/CA8365564/MONDO:0100453/167/el/0/1696/1698", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8365564/MONDO:0100453/167/ci/CA8365564/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": "Gucy2e-knockout mouse retinas injected with an adeno-associated virus-packaged GUCY2D construct encoding the p.Ser248Trp variant showed mRNA levels similar to the wild-type control (Figure 3C) but dramatically reduced protein levels (Figure 3B, Figure 4) and essentially no cGMP production (Figure 3A), indicating that it triggers a severe defect in protein function (PMID: 27881908, PS3_Supporting). The variant exhibited ~125% enzymatic activity in a guanylate cyclase assay relative to the wild-type control, which is higher than the ClinGen LCA / eoRD BS3_Supporting threshold of ≥50% activity, indicating that it preserves normal protein function (PMID: 23035049, Figures 5B and 5D). However, this variant falls within the extracellular domain (occurring between amino acids 52-462), in which variants are known to show no damaging effect in these assays.", "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": "CA8365564/MONDO:0100453/167/ci/CA8365564/MONDO:0100453/167.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8365564/MONDO:0100453/167/0/1696/1698", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8365564/MONDO:0100453/167/1/1697", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8365564/MONDO:0100453/167/0/1696", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365564/MONDO:0100453/167/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365564/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/CA8365564/MONDO:0100453/167/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8365564/MONDO:0100453/167/ci/CA8365564/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), decreased central visual acuity (1 pt) with onset in the first year of life (1 pt), nystagmus (1 pt), decreased peripheral vision (1 pt), retinal vessel attenuation with granularity of peripheral fundus (0.5 pts), outer nuclear layer thickness on OCT within normal limits (1 pt), poor pupillary light response (0.5 pts), and undetectable electroretinogram responses from rods (0.5 pts). and cones (1 pt), which together are highly specific for GUCY2D-related recessive retinopathy (total 8 points but no specific criteria, PMID: 23035049, 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": "CA8365564/MONDO:0100453/167/ci/CA8365564/MONDO:0100453/167.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8365564/MONDO:0100453/167/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8365564/MONDO:0100453/167/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8365564/MONDO:0100453/167/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365564/MONDO:0100453/167/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365564/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/CA8365564/MONDO:0100453/167/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8365564/MONDO:0100453/167/ci/CA8365564/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 0.000001240, with 2 alleles / 1,612,844 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": "CA8365564/MONDO:0100453/167/ci/CA8365564/MONDO:0100453/167.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8365564/MONDO:0100453/167/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8365564/MONDO:0100453/167/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8365564/MONDO:0100453/167/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365564/MONDO:0100453/167/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365564/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/CA8365564/MONDO:0100453/167/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8365564/MONDO:0100453/167/ci/CA8365564/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.743C>T (p.Ser248Leu)) has been reported in association with GUCY2D-related recessive retinopathy by the ClinGen LCA / eoRD VCEP (PMID: 26957854). Splicing prediction using SpliceAI did not strongly predict an effect on splicing due to either of these variants. However, the variant has not yet been classified by the LCA / eoRD VCEP, so the PM5 code 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": "CA8365564/MONDO:0100453/167/ci/CA8365564/MONDO:0100453/167.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8365564/MONDO:0100453/167/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8365564/MONDO:0100453/167/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8365564/MONDO:0100453/167/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365564/MONDO:0100453/167/el/0/1690", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365564/MONDO:0100453/167/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": "2025/1/30", "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/CA8365564/MONDO:0100453/167/el/0/1690/1692", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8365564/MONDO:0100453/167/ci/CA8365564/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 0.878, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RetGC-1 function (PP3_Moderate). The splicing impact predictor SpliceAI gives a delta score of 0.06 for acceptor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not 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": "CA8365564/MONDO:0100453/167/ci/CA8365564/MONDO:0100453/167.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8365564/MONDO:0100453/167/0/1690/1692", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8365564/MONDO:0100453/167/1/1691", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8365564/MONDO:0100453/167/0/1690", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365564/MONDO:0100453/167/el/0/1609", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8365564/MONDO:0100453/167/ei/1/1610", "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/CA8365564/MONDO:0100453/167/el/0/1609/1611", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8365564/MONDO:0100453/167/ci/CA8365564/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 compound heterozygous with the NM_000180.4(GUCY2D):c.3224+1G>C variant suspected in trans (0.5 points, PMID: 23035049, PMID: 23847139), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (0.5 total points, PM3_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": "CA8365564/MONDO:0100453/167/ci/CA8365564/MONDO:0100453/167.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8365564/MONDO:0100453/167/0/1609/1611", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8365564/MONDO:0100453/167/1/1610", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8365564/MONDO:0100453/167/0/1609", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8365564/MONDO:0100453/167", "metadata": { "created": "2025-01-30T17:41:40.889Z", "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 17:41:40 -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": "6b75b512-79f7-452a-ae4c-aec715828caf", "variant": { "@id": "https://reg.genome.network/allele/CA8365564", "id": "CAR:CA8365564", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000180.4:c.743C>G" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000180.4(GUCY2D):c.743C>G (p.Ser248Trp)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-02T06:40:41.634Z" } }, "status": { "code": 200, "name": "OK" } }