{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/876a5285-037a-4bcc-8487-1a11c1513480/doc/sepio/version/1.0.0", "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/CA226835/MONDO:0010725/126/el/0/1753", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226835/MONDO:0010725/126/ei/1/1754", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50086_EP174775864491222", "id": "CG-PCER-AGENT:CG_50086_EP174775864491222", "type": "Agent" }, "contributionDate": { "date": "2026/9/26", "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/0019", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000330", "id": "SEPIO:0000330", "label": "Pathogenic Strong" }, "id": "0019", "label": "PP3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226835/MONDO:0010725/126/el/0/1753/1755", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226835/MONDO:0010725/126/ci/CA226835/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 0.979, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_strong). 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.", "contributionDate": { "date": "2026/9/26", "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": "CA226835/MONDO:0010725/126/ci/CA226835/MONDO:0010725/126.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226835/MONDO:0010725/126/0/1753/1755", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226835/MONDO:0010725/126/1/1754", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226835/MONDO:0010725/126/0/1753", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226835/MONDO:0010725/126/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226835/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": "2026/9/26", "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/0063", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0063", "label": "PP4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226835/MONDO:0010725/126/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226835/MONDO:0010725/126/ci/CA226835/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 the following phenotypes, including the appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (PMID: 33460243, PP4).", "contributionDate": { "date": "2026/9/26", "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": "CA226835/MONDO:0010725/126/ci/CA226835/MONDO:0010725/126.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226835/MONDO:0010725/126/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226835/MONDO:0010725/126/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226835/MONDO:0010725/126/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226835/MONDO:0010725/126/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226835/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": "2026/9/26", "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/CA226835/MONDO:0010725/126/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226835/MONDO:0010725/126/ci/CA226835/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": "2026/9/26", "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": "CA226835/MONDO:0010725/126/ci/CA226835/MONDO:0010725/126.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226835/MONDO:0010725/126/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226835/MONDO:0010725/126/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226835/MONDO:0010725/126/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226835/MONDO:0010725/126/el/0/1606", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226835/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": "2026/9/26", "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/0032", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0032", "label": "PS4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226835/MONDO:0010725/126/el/0/1606/1608", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226835/MONDO:0010725/126/ci/CA226835/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 one of the PS4 requirements of a male diagnosed with XLRS, as well as a second apparently unrelated proband previously used for the PP4 code (PMIDs: 10450864, PS4_Supporting).", "contributionDate": { "date": "2026/9/26", "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": "CA226835/MONDO:0010725/126/ci/CA226835/MONDO:0010725/126.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226835/MONDO:0010725/126/0/1606/1608", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226835/MONDO:0010725/126/1/1607", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226835/MONDO:0010725/126/0/1606", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226835/MONDO:0010725/126/el/0/1615", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226835/MONDO:0010725/126/ei/1/1616", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50086_EP174775864491222", "id": "CG-PCER-AGENT:CG_50086_EP174775864491222", "type": "Agent" }, "contributionDate": { "date": "2026/9/26", "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/006", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "006", "label": "PM1", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226835/MONDO:0010725/126/el/0/1615/1617", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226835/MONDO:0010725/126/ci/CA226835/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 p. Glu215, of the RS1 gene, is a missense substitution affecting an established residue involved in cross-linking the adjacent RS1 subunit defined by the ClinGen X-linked IRD VCEP (PMID: 27114531). The PP3_strong code is ineligible to be used in combination with the PM1 code at any strength, and therefore, this code was not met.", "contributionDate": { "date": "2026/9/26", "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": "CA226835/MONDO:0010725/126/ci/CA226835/MONDO:0010725/126.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226835/MONDO:0010725/126/0/1615/1617", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226835/MONDO:0010725/126/1/1616", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226835/MONDO:0010725/126/0/1615", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226835/MONDO:0010725/126/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226835/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": "2026/9/26", "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/008", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "008", "label": "PM5", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226835/MONDO:0010725/126/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA226835/MONDO:0010725/126/ci/CA226835/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.643G>C (p.Glu215Gln), (PMIDs: 19324861, 11598108, 9618178, 39462066) 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 (56) than the comparison variant (29), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5).", "contributionDate": { "date": "2026/9/26", "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": "CA226835/MONDO:0010725/126/ci/CA226835/MONDO:0010725/126.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA226835/MONDO:0010725/126/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226835/MONDO:0010725/126/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA226835/MONDO:0010725/126/0/1780", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA226835/MONDO:0010725/126", "metadata": { "created": "2026-10-15T19:05:09.618Z", "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, 15 Oct 2026 19:05:09 -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": "876a5285-037a-4bcc-8487-1a11c1513480", "variant": { "@id": "https://reg.genome.network/allele/CA226835", "id": "CAR:CA226835", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000330.4:c.643G>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000330.4(RS1):c.643G>A (p.Glu215Lys)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-28T08:27:24.277Z" } }, "status": { "code": 200, "name": "OK" } }