{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/12aeb683-a044-492f-bbce-7f80ca5be1e9/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/CA173994/MONDO:0014493/122/el/0/1828", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173994/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/CA173994/MONDO:0014493/122/el/0/1828/1830", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA173994/MONDO:0014493/122/ci/EV000001928", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "comments": "Activated T cells from the patient harboring the variant exhibit a partial decrease in expression of CTLA-4, demonstrated by flow cytometry (Figure S2).", "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": "CA173994/MONDO:0014493/122/ci/EV000001928", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/25213377", "type": "CuratorInference" } ], "id": "CG-PCER-VARINT:CA173994/MONDO:0014493/122/0/1828/1830", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA173994/MONDO:0014493/122/1/1829", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA173994/MONDO:0014493/122/0/1828", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173994/MONDO:0014493/122/el/0/1735", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173994/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/CA173994/MONDO:0014493/122/el/0/1735/1737", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA173994/MONDO:0014493/122/ci/CA173994/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 1 proband meeting the VCEP standard for phenotypic criteria (PMID: 25213377), however, PS4_Supporting cannot be applied because the proband has already been counted under the PP4 code.", "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": "CA173994/MONDO:0014493/122/ci/CA173994/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA173994/MONDO:0014493/122/0/1735/1737", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA173994/MONDO:0014493/122/1/1736", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA173994/MONDO:0014493/122/0/1735", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173994/MONDO:0014493/122/el/0/1804", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173994/MONDO:0014493/122/ei/1/1805", "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/CA173994/MONDO:0014493/122/el/0/1804/1806", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA173994/MONDO:0014493/122/ci/CA173994/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 present in gnomAD v4.1.0 at a GrpMax allele frequency of 0.000000847, with 1 allele / 1,179,912 total alleles in the European (non-Finnish) population, which is lower than the BS1 threshold of >0.00000111, so BS1 is not met.", "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": "CA173994/MONDO:0014493/122/ci/CA173994/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA173994/MONDO:0014493/122/0/1804/1806", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA173994/MONDO:0014493/122/1/1805", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA173994/MONDO:0014493/122/0/1804", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173994/MONDO:0014493/122/el/0/1798", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173994/MONDO:0014493/122/ei/1/1799", "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/CA173994/MONDO:0014493/122/el/0/1798/1800", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA173994/MONDO:0014493/122/ci/CA173994/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 present in gnomAD v4.1.0 at an allele frequency of 0.0000006195, with 1 allele / 1,614,092 total alleles across all populations of gnomAD, which is higher than the ClinGen Antibody Deficiencies VCEP PM2_Supporting threshold of <0.000000143, so PM2_Supporting is not met.", "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": "CA173994/MONDO:0014493/122/ci/CA173994/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA173994/MONDO:0014493/122/0/1798/1800", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA173994/MONDO:0014493/122/1/1799", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA173994/MONDO:0014493/122/0/1798", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173994/MONDO:0014493/122/el/0/1594", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173994/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/CA173994/MONDO:0014493/122/el/0/1594/1596", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA173994/MONDO:0014493/122/ci/CA173994/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 is a frameshift variant that introduces a premature stop codon into exon 1 of 4 and is predicted to trigger 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": "CA173994/MONDO:0014493/122/ci/CA173994/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA173994/MONDO:0014493/122/0/1594/1596", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA173994/MONDO:0014493/122/1/1595", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA173994/MONDO:0014493/122/0/1594", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173994/MONDO:0014493/122/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA173994/MONDO:0014493/122/ei/1/1832", "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/CA173994/MONDO:0014493/122/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA173994/MONDO:0014493/122/ci/CA173994/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": "The variant has been observed in at least 1 patient with a phenotype that includes hepatosplenomegaly (2 pts), autoimmune hemolytic anemia and thrombocytopenia (2 pts), pulmonary nodules (4 pts), infiltrative lesions (2 pts) in the cerebrum (1 pt), and activated T cells showing a partial decrease in expression of CTLA-4 by flow cytometry, with genotyping by exome sequencing identifying no alternative basis for disease in other loci, which together are highly specific for CTLA4 insufficiency (11 total pts, PMID: 25213377, PP4_Moderate).", "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": "CA173994/MONDO:0014493/122/ci/CA173994/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA173994/MONDO:0014493/122/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA173994/MONDO:0014493/122/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA173994/MONDO:0014493/122/0/1831", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA173994/MONDO:0014493/122", "metadata": { "created": "2025-12-02T14:38:50.621Z", "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 14:38:50 -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": "12aeb683-a044-492f-bbce-7f80ca5be1e9", "variant": { "@id": "https://reg.genome.network/allele/CA173994", "id": "CAR:CA173994", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_005214.5:c.75del" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_005214.5(CTLA4):c.75del (p.Leu28fs)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-31T20:51:01.382Z" } }, "status": { "code": 200, "name": "OK" } }