{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/40bed26c-a1bb-481d-a1b5-de875d47e07c/doc/sepio/version/1.1.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1570648177", "label": "ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0010725", "id": "MONDO:0010725", "label": "X-linked retinoschisis", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA412376057/MONDO:0010725/126/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA412376057/MONDO:0010725/126/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50086_EP174775864491222", "id": "CG-PCER-AGENT:CG_50086_EP174775864491222", "type": "Agent" }, "contributionDate": { "date": "2025/10/3", "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/CA412376057/MONDO:0010725/126/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA412376057/MONDO:0010725/126/ci/CA412376057/MONDO:0010725/126.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50086_EP174775864491222", "id": "CG-PCER-AGENT:CG_50086_EP174775864491222", "type": "Agent" }, "comments": "The computational predictor REVEL gives a score of 0.868, which is within the ClinGen X-linked IRD VCEP range between 0.931 to 0.773 and predicts a damaging effect on RS1 function. The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. The PM1_strong code is ineligible to be combined with PP3 at any strength, therefore, the PP3 code was not met.", "contributionDate": { "date": "2025/10/3", "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": "CA412376057/MONDO:0010725/126/ci/CA412376057/MONDO:0010725/126.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA412376057/MONDO:0010725/126/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA412376057/MONDO:0010725/126/ei/1/1634", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50086_EP174775864491222", "id": "CG-PCER-AGENT:CG_50086_EP174775864491222", "type": "Agent" }, "contributionDate": { "date": "2025/10/3", "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/CA412376057/MONDO:0010725/126/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA412376057/MONDO:0010725/126/ci/CA412376057/MONDO:0010725/126.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50086_EP174775864491222", "id": "CG-PCER-AGENT:CG_50086_EP174775864491222", "type": "Agent" }, "comments": "At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 34645606, PMID: 33460243, PP4).", "contributionDate": { "date": "2025/10/3", "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": "CA412376057/MONDO:0010725/126/ci/CA412376057/MONDO:0010725/126.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA412376057/MONDO:0010725/126/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA412376057/MONDO:0010725/126/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50086_EP174775864491222", "id": "CG-PCER-AGENT:CG_50086_EP174775864491222", "type": "Agent" }, "contributionDate": { "date": "2025/10/3", "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/CA412376057/MONDO:0010725/126/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA412376057/MONDO:0010725/126/ci/CA412376057/MONDO:0010725/126.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50086_EP174775864491222", "id": "CG-PCER-AGENT:CG_50086_EP174775864491222", "type": "Agent" }, "comments": "This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting).", "contributionDate": { "date": "2025/10/3", "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": "CA412376057/MONDO:0010725/126/ci/CA412376057/MONDO:0010725/126.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA412376057/MONDO:0010725/126/el/0/1606", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA412376057/MONDO:0010725/126/ei/1/1607", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50086_EP174775864491222", "id": "CG-PCER-AGENT:CG_50086_EP174775864491222", "type": "Agent" }, "contributionDate": { "date": "2025/10/3", "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/CA412376057/MONDO:0010725/126/el/0/1606/1608", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA412376057/MONDO:0010725/126/ci/CA412376057/MONDO:0010725/126.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50086_EP174775864491222", "id": "CG-PCER-AGENT:CG_50086_EP174775864491222", "type": "Agent" }, "comments": "This variant has been reported in at least 1 proband meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis, as well as a second apparently unrelated proband previously used for the PP4 code (PMIDs: 30652005, PS4_Supporting).", "contributionDate": { "date": "2025/10/3", "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": "CA412376057/MONDO:0010725/126/ci/CA412376057/MONDO:0010725/126.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/0/1606/1608", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/1/1607", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/0/1606", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA412376057/MONDO:0010725/126/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA412376057/MONDO:0010725/126/ei/1/1781", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50086_EP174775864491222", "id": "CG-PCER-AGENT:CG_50086_EP174775864491222", "type": "Agent" }, "contributionDate": { "date": "2025/10/3", "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/CA412376057/MONDO:0010725/126/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA412376057/MONDO:0010725/126/ci/CA412376057/MONDO:0010725/126.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50086_EP174775864491222", "id": "CG-PCER-AGENT:CG_50086_EP174775864491222", "type": "Agent" }, "comments": "Another missense variant in the same codon, NM_000330.4(RS1):c.175T>A (p.Cys59Ser), (PMIDs: 31174210, 10450864, 17987333, 9618178) has been classified as pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (159) than the comparison variant (112), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5).\n", "contributionDate": { "date": "2025/10/3", "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": "CA412376057/MONDO:0010725/126/ci/CA412376057/MONDO:0010725/126.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA412376057/MONDO:0010725/126/el/0/1648", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA412376057/MONDO:0010725/126/ei/1/1649", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50086_EP174775864491222", "id": "CG-PCER-AGENT:CG_50086_EP174775864491222", "type": "Agent" }, "contributionDate": { "date": "2025/10/3", "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/CA412376057/MONDO:0010725/126/el/0/1648/1650", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA412376057/MONDO:0010725/126/ci/CA412376057/MONDO:0010725/126.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50086_EP174775864491222", "id": "CG-PCER-AGENT:CG_50086_EP174775864491222", "type": "Agent" }, "comments": "The variant has been reported to segregate with X-linked retinoschisis through at least 3 meioses in two families with multiple affected brothers (PP1_Strong; PMID: 30652005).", "contributionDate": { "date": "2025/10/3", "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": "CA412376057/MONDO:0010725/126/ci/CA412376057/MONDO:0010725/126.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/0/1648/1650", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/1/1649", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/0/1648", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA412376057/MONDO:0010725/126/el/0/1585", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA412376057/MONDO:0010725/126/ei/1/1586", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50086_EP174775864491222", "id": "CG-PCER-AGENT:CG_50086_EP174775864491222", "type": "Agent" }, "contributionDate": { "date": "2025/10/3", "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/CA412376057/MONDO:0010725/126/el/0/1585/1587", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA412376057/MONDO:0010725/126/ci/CA412376057/MONDO:0010725/126.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50086_EP174775864491222", "id": "CG-PCER-AGENT:CG_50086_EP174775864491222", "type": "Agent" }, "comments": "This variant is a missense substitution affecting a critical amino acid residue involved in disulfide bridge formation as defined by the ClinGen X-linked IRD VCEP (PMID: 26812435, PM1_Strong).", "contributionDate": { "date": "2025/10/3", "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": "CA412376057/MONDO:0010725/126/ci/CA412376057/MONDO:0010725/126.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/0/1585/1587", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/1/1586", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126/0/1585", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA412376057/MONDO:0010725/126", "metadata": { "created": "2025-10-03T23:02:16.254Z", "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": "Fri, 03 Oct 2025 23:02:15 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.1.0" }, "statementOutcome": { "@id": "https://loinc.org/LA6668-3", "id": "LN:LA6668-3", "label": "Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "40bed26c-a1bb-481d-a1b5-de875d47e07c", "variant": { "@id": "https://reg.genome.network/allele/CA412376057", "id": "CAR:CA412376057", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000330.4:c.175T>G" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000330.4(RS1):c.175T>G (p.Cys59Gly)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-04T13:56:38.138Z" } }, "status": { "code": 200, "name": "OK" } }