{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/c50ebd08-d4de-4d57-a511-d156aa6c6f67/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/CA350138646/MONDO:0014493/122/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138646/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/CA350138646/MONDO:0014493/122/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138646/MONDO:0014493/122/ci/CA350138646/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": "CA350138646/MONDO:0014493/122/ci/CA350138646/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138646/MONDO:0014493/122/el/0/1606", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138646/MONDO:0014493/122/ei/1/1607", "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/CA350138646/MONDO:0014493/122/el/0/1606/1608", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138646/MONDO:0014493/122/ci/CA350138646/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, with a phenotype that includes splenomegaly and lymphadenopathy (2 pts), autoimmune hemolytic anemia (2 pts), autoimmune thyroiditis (1 pt), hypogammaglobulinemia (2 pts), granulomatous lymphocytic interstitial lung disease (4 pts), and organ infiltration of the bone marrow, kidney, brain, and liver (1 pt), without genotyping that excluded causes in other loci (12 total points, PMID: 25329329, PMID: 34111452, PMID: 27418640, PS4_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": "CA350138646/MONDO:0014493/122/ci/CA350138646/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/0/1606/1608", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/1/1607", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/0/1606", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138646/MONDO:0014493/122/el/0/1684", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138646/MONDO:0014493/122/ei/1/1685", "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/CA350138646/MONDO:0014493/122/el/0/1684/1686", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138646/MONDO:0014493/122/ci/CA350138646/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" }, "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": "CA350138646/MONDO:0014493/122/ci/CA350138646/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/0/1684/1686", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/1/1685", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/0/1684", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138646/MONDO:0014493/122/el/0/1696", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138646/MONDO:0014493/122/ei/1/1697", "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/CA350138646/MONDO:0014493/122/el/0/1696/1698", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138646/MONDO:0014493/122/ci/CA350138646/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": "Transendocytosis and CD80 ligand uptake assays indicate that this variant impacts CD80 ligand capture in the cell. \n\nA transendocytosis assay in CD4+FOXP3+ Treg cells showed that Treg cells from healthy CTLA4+/+ individuals transendocytosed efficiently with 10–25% becoming positive for CD80-GFP; this percentage was reduced to only 2–3% in individuals bearing CTLA4 mutations, indicating a deficit in ligand capture (PMID: 25329329)(PS3_Supporting).\n\nAdditionally, soluble CD80 ligand uptake assays from the same group performed in CHO cells expressing either wild-type or mutant CTLA4 showed that the percentage of CD80-Ig-posititve cells was 5.99% in mutated cells. The percentage of CD80-Ig-posititve cells in wild type cells was 55.4%. These results indicate that this variant impacts protein function by impairing the cells' ability to take up soluble CD80-immunoglobulin fusion protein (PMID: 25329329)(PS3_Supporting).\n\n\n\n\n\n", "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": "CA350138646/MONDO:0014493/122/ci/CA350138646/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/0/1696/1698", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/1/1697", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/0/1696", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138646/MONDO:0014493/122/el/0/1678", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138646/MONDO:0014493/122/ei/1/1679", "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/CA350138646/MONDO:0014493/122/el/0/1678/1680", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138646/MONDO:0014493/122/ci/CA350138646/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": "Family D from PMID: 25329329 has one genotype+/phenotype+ patient. This patient's mother is an unaffected carrier of the mutation. Not applied because the variant needs to be present in the proband + at least 2 more family members. ", "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": "CA350138646/MONDO:0014493/122/ci/CA350138646/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/0/1678/1680", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/1/1679", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/0/1678", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138646/MONDO:0014493/122/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138646/MONDO:0014493/122/ei/1/1748", "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/CA350138646/MONDO:0014493/122/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138646/MONDO:0014493/122/ci/CA350138646/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 computational predictor REVEL gives a score of 0.812 (which is above the threshold of 0.75) and the computational predictor CADD gives a score of 24.7 (which is above the threshold of 20) (PP3). Additionally, the splicing impact predictor SpliceAI gives a score of 0.00, which is below the ClinGen Antibody Deficiencies VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing.", "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": "CA350138646/MONDO:0014493/122/ci/CA350138646/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138646/MONDO:0014493/122/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138646/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/CA350138646/MONDO:0014493/122/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138646/MONDO:0014493/122/ci/CA350138646/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), autoimmune hemolytic anemia (2 pts), interstitial lung disease (4 pts) with granulomatous lymphocytic infiltration (1 pt), lymphadenopathy (2 pts), autoimmune thyroiditis (1 pt), and splenomegaly. However, it is not clear whether genotyping to rule out an alternative basis for disease in LRBA had been performed, so the phenotype was not sufficiently specific for autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency to meet PP4 (PMID: 25329329, PMID: 34111452, PMID: 27418640).", "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": "CA350138646/MONDO:0014493/122/ci/CA350138646/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138646/MONDO:0014493/122/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138646/MONDO:0014493/122/ei/1/1781", "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/CA350138646/MONDO:0014493/122/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138646/MONDO:0014493/122/ci/CA350138646/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": "Thr124Met variant also in this codon. However, this variant is classified as benign by Antibody Deficiencies VCEP. ", "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": "CA350138646/MONDO:0014493/122/ci/CA350138646/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122/0/1780", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138646/MONDO:0014493/122", "metadata": { "created": "2025-12-02T14:13:16.389Z", "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 14:13:15 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA26333-7", "id": "LN:LA26333-7", "label": "Uncertain Significance" }, "type": "VariantPathogenicityInterpretation", "uuid": "c50ebd08-d4de-4d57-a511-d156aa6c6f67", "variant": { "@id": "https://reg.genome.network/allele/CA350138646", "id": "CAR:CA350138646", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_005214.5:c.370A>C" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_005214.5:c.370A>C" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-14T02:34:47.703Z" } }, "status": { "code": 200, "name": "OK" } }