{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/2f2bab08-120b-49e8-8a2e-881ea23294d0/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1567102241", "label": "ClinGen Antibody Deficiencies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CTLA4 Version 1.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0014493", "id": "MONDO:0014493", "label": "autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173992/MONDO:0014493/122/el/0/1828", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173992/MONDO:0014493/122/ei/1/1829", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2025/12/2", "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/CA173992/MONDO:0014493/122/el/0/1828/1830", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA173992/MONDO:0014493/122/ci/CA173992/MONDO:0014493/122.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "comments": "Flow cytometery in patient regulatory T cells showed aberrations in expression indicating that this variant impacts protein function (PMID: 29200144). Since this experiment was performed in proband cells, the evidence was considered for PP4 rather than for PS3_Supporting.", "contributionDate": { "date": "2025/12/2", "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": "CA173992/MONDO:0014493/122/ci/CA173992/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA173992/MONDO:0014493/122/0/1828/1830", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA173992/MONDO:0014493/122/1/1829", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA173992/MONDO:0014493/122/0/1828", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173992/MONDO:0014493/122/el/0/1735", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173992/MONDO:0014493/122/ei/1/1736", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2025/12/2", "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/CA173992/MONDO:0014493/122/el/0/1735/1737", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA173992/MONDO:0014493/122/ci/CA173992/MONDO:0014493/122.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "comments": "This variant has been reported in at least 3 apparently unrelated probands meeting the VCEP standard for phenotypic criteria. In 1 case, the proband exceeded 6 phenotypic points with genotyping that excluded causes in other loci (PMID: 25213377, PMID: 29200144). In 2 cases, the proband exceeded 10 phenotype points without genotyping that excluded causes in other loci (PS4_Moderate; PMID: 29729943, PMID:29330115, PMID: 32499327).", "contributionDate": { "date": "2025/12/2", "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": "CA173992/MONDO:0014493/122/ci/CA173992/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA173992/MONDO:0014493/122/0/1735/1737", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA173992/MONDO:0014493/122/1/1736", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA173992/MONDO:0014493/122/0/1735", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173992/MONDO:0014493/122/el/0/1594", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173992/MONDO:0014493/122/ei/1/1595", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2025/12/2", "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/CA173992/MONDO:0014493/122/el/0/1594/1596", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA173992/MONDO:0014493/122/ci/CA173992/MONDO:0014493/122.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "comments": "NM_005214.5(CTLA4):c.151C>T (p.Arg51Ter) is a nonsense variant that introduces a premature stop codon into exon 2 of 4 and is predicted to lead to nonsense-mediated decay in CTLA4, in which loss-of-function is an established mechanism of disease (PVS1).", "contributionDate": { "date": "2025/12/2", "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": "CA173992/MONDO:0014493/122/ci/CA173992/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA173992/MONDO:0014493/122/0/1594/1596", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA173992/MONDO:0014493/122/1/1595", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA173992/MONDO:0014493/122/0/1594", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173992/MONDO:0014493/122/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173992/MONDO:0014493/122/ei/1/1634", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2025/12/2", "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/CA173992/MONDO:0014493/122/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA173992/MONDO:0014493/122/ci/CA173992/MONDO:0014493/122.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "comments": "At least one patient harboring this variant had a phenotype that included hypogammaglobulinemia (2 pts), thrombocytopenia (1 pt), respiratory involvement with pulmonary infiltrates (4 pts), brain infiltrates (1 pts), splenomegaly (2 pts), and eczema (1 pt), but lacked sufficient genotyping to rule out an alternative basis for disease in LRBA, which together were not sufficiently specific to meet PP4 for autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (11 total points, PMID: 29729943).", "contributionDate": { "date": "2025/12/2", "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": "CA173992/MONDO:0014493/122/ci/CA173992/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA173992/MONDO:0014493/122/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA173992/MONDO:0014493/122/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA173992/MONDO:0014493/122/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173992/MONDO:0014493/122/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173992/MONDO:0014493/122/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2025/12/2", "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/CA173992/MONDO:0014493/122/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA173992/MONDO:0014493/122/ci/CA173992/MONDO:0014493/122.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "comments": "This variant is absent from gnomAD v4.1.0 (PM2_Supporting).", "contributionDate": { "date": "2025/12/2", "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": "CA173992/MONDO:0014493/122/ci/CA173992/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA173992/MONDO:0014493/122/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA173992/MONDO:0014493/122/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA173992/MONDO:0014493/122/0/1636", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA173992/MONDO:0014493/122", "metadata": { "created": "2025-12-02T14:38:28.529Z", "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": "Tue, 02 Dec 2025 14:38:27 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA6668-3", "id": "LN:LA6668-3", "label": "Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "2f2bab08-120b-49e8-8a2e-881ea23294d0", "variant": { "@id": "https://reg.genome.network/allele/CA173992", "id": "CAR:CA173992", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_005214.5:c.151C>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_005214.5(CTLA4):c.151C>T (p.Arg51Ter)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-14T02:48:17.021Z" } }, "status": { "code": 200, "name": "OK" } }