{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/f221734e-c21b-4a55-adf2-8607eb04563f/doc/sepio/version/1.1.0", "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 haploinsufficiency", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1804", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/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": "2026/9/14", "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/0070", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000328", "id": "SEPIO:0000328", "label": "Benign Strong" }, "id": "0070", "label": "BS1", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1804/1806", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138320/MONDO:0014493/122/ci/CA350138320/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 0.00001666, with 1 allele / 60,028 total alleles in the Admixed American population, which is higher than the ClinGen Antibody Deficiencies VCEP BS1 threshold of >0.00000111. However, 1 allele is lower than the BS1 requirement for at least 3 alleles total across all populations in gnomAD, so no population code is met.", "contributionDate": { "date": "2026/9/14", "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": "CA350138320/MONDO:0014493/122/ci/CA350138320/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1804/1806", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/1/1805", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1804", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1798", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/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": "2026/9/14", "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/0011", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "0011", "label": "PM2", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1798/1800", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138320/MONDO:0014493/122/ci/CA350138320/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 total allele frequency of 0.000001239, with 2 alleles / 1,614,188 total alleles across all populations of gnomAD, which is higher than the ClinGen Antibody Deficiencies VCEP PM2_Supporting threshold of <0.000000143.", "contributionDate": { "date": "2026/9/14", "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": "CA350138320/MONDO:0014493/122/ci/CA350138320/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1798/1800", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/1/1799", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1798", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/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": "2026/9/14", "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/0018", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "0018", "label": "PP4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138320/MONDO:0014493/122/ci/CA350138320/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 1 patient with this variant has a phenotype that includes diarrhea/enteropathy (4 pts), decreased circulating antibody level (2 pts), upper and lower respiratory tract infections (4 pts), granulomatous lymphocytic interstitial lung disease (1 pt), splenomegaly and and lymphadenopathy (2 pts), autoimmune thrombocytopenia and hemolytic anemia (2 pts), and CD4+ T cells showing reduced CD80-GFP transendocytosis from co-cultured CHO cells relative to the healthy control patient cells, with genotyping by exome sequencing identifying no alternative basis for disease in other loci, which together are highly specific for autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (15 total pts, PMID: 25329329, PMID: 29729943, PP4_Moderate).", "contributionDate": { "date": "2026/9/14", "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": "CA350138320/MONDO:0014493/122/ci/CA350138320/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1831", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/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": "2026/9/14", "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/0062", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0062", "label": "PP3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138320/MONDO:0014493/122/ci/CA350138320/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 0.864, which is above the ClinGen Antibody Deficiencies VCEP threshold of >0.644. The computational predictor CADD gives a PHRED score of 24.7, which is below the ClinGen Antibody Deficiencies VCEP threshold of >25.3. The two predictors do not agree on a damaging effect on CTLA4 function, so PP3 is not met. The splicing impact predictor SpliceAI gives a score of 0.07 for donor gain, which is below the ClinGen Antibody Deficiencies VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing.", "contributionDate": { "date": "2026/9/14", "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": "CA350138320/MONDO:0014493/122/ci/CA350138320/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/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": "2026/9/14", "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/CA350138320/MONDO:0014493/122/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138320/MONDO:0014493/122/ci/CA350138320/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": "Another missense variant in the same codon, NM_005214.5(CTLA4):c.224G>A (p.Arg75Gln), has been reported in a patient with autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (PMID: 25329329), however, PM5 has not been considered in order to avoid circularity.", "contributionDate": { "date": "2026/9/14", "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": "CA350138320/MONDO:0014493/122/ci/CA350138320/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1684", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/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": "2026/9/14", "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/0080", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000327", "id": "SEPIO:0000327", "label": "Benign Supporting" }, "id": "0080", "label": "BP4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1684/1686", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138320/MONDO:0014493/122/ci/CA350138320/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 0.864, which is above the ClinGen Antibody Deficiencies VCEP threshold of <0.25 and does not predict a benign effect on CTLA4 function. The computational predictor CADD gives a PHRED score of 24.7, which is above the ClinGen Antibody Deficiencies VCEP threshold of <20 and does not predict a benign effect on CTLA4 function. This criterion is not met.", "contributionDate": { "date": "2026/9/14", "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": "CA350138320/MONDO:0014493/122/ci/CA350138320/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1684/1686", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/1/1685", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1684", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1777", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/ei/1/1778", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2026/9/14", "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/0087", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000325", "id": "SEPIO:0000325", "label": "Benign Stand Alone" }, "id": "0087", "label": "BA1", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1777/1779", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138320/MONDO:0014493/122/ci/CA350138320/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 0.00001666, with 1 allele / 60,028 total alleles in the Admixed American population, which is higher than the ClinGen Antibody Deficiencies VCEP BA1 threshold of >0.0000111, however, the BA1 requirement is not met for at least 5 alleles total across all populations in gnomAD.", "contributionDate": { "date": "2026/9/14", "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": "CA350138320/MONDO:0014493/122/ci/CA350138320/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1777/1779", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/1/1778", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1777", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1663", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/ei/1/1664", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2026/9/14", "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/0051", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000330", "id": "SEPIO:0000330", "label": "Pathogenic Strong" }, "id": "0051", "label": "PS2", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1663/1665", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138320/MONDO:0014493/122/ci/CA350138320/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 identified as a de novo occurrence with confirmed parental relationships in 1 individual with CTLA4 insufficiency (PMID: 25329329). The 15 phenotype points for this case and genotyping by whole exome sequencing (facilitating exclusion of LRBA variants as an alternative basis for disease) indicate a phenotype highly specific for the gene (2 de novo points, PS2).", "contributionDate": { "date": "2026/9/14", "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": "CA350138320/MONDO:0014493/122/ci/CA350138320/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1663/1665", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/1/1664", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1663", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1828", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/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": "2026/9/14", "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/0052", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000330", "id": "SEPIO:0000330", "label": "Pathogenic Strong" }, "id": "0052", "label": "PS3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1828/1830", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138320/MONDO:0014493/122/ci/EV000001929", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "comments": "Transendocytosis assay performed with patient CD4+ T cells expressing the p.Arg75Trp variant or wild-type CTLA4 showed reduced CD80-GFP uptake from co-cultured CHO cells, indicating that this variant has a damaging effect on protein function. This evidence has been considered for PP4 rather than for PS3_Supporting.", "contributionDate": { "date": "2026/9/14", "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": "CA350138320/MONDO:0014493/122/ci/EV000001929", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/29729943", "type": "CuratorInference" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1828/1830", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/1/1829", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1828", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1699", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/ei/1/1700", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2026/9/14", "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/0057", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "0057", "label": "PS4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1699/1701", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138320/MONDO:0014493/122/ci/CA350138320/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 2 unrelated probands meeting the VCEP standard for phenotypic criteria, with at least 10 phenotype points but without genotyping to exclude causes in other loci such as LRBA (PMID: 29729943, PS4_Moderate). Please note that a third proband from the same publication has been documented in other publications and has already been used for the PP4 code (PMID: 25329329, PMID: 28366794, PMID: 29305966).", "contributionDate": { "date": "2026/9/14", "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": "CA350138320/MONDO:0014493/122/ci/CA350138320/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1699/1701", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/1/1700", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1699", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1648", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/ei/1/1649", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2026/9/14", "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/0023", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000330", "id": "SEPIO:0000330", "label": "Pathogenic Strong" }, "id": "0023", "label": "PP1", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138320/MONDO:0014493/122/el/0/1648/1650", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138320/MONDO:0014493/122/ci/CA350138320/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 reported to segregate with CTLA4 insufficiency through at least 5 affected meioses from 1 family (PP1_Strong; PMID: 29729943). Affected status was counted only for family members with at least 6 phenotype points.", "contributionDate": { "date": "2026/9/14", "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": "CA350138320/MONDO:0014493/122/ci/CA350138320/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1648/1650", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/1/1649", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122/0/1648", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138320/MONDO:0014493/122", "metadata": { "created": "2026-09-14T22:21:02.047Z", "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": "Mon, 14 Sep 2026 22:21:01 -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": "f221734e-c21b-4a55-adf2-8607eb04563f", "variant": { "@id": "https://reg.genome.network/allele/CA350138320", "id": "CAR:CA350138320", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_005214.5:c.223C>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_005214.5(CTLA4):c.223C>T (p.Arg75Trp)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-14T03:27:34.237Z" } }, "status": { "code": 200, "name": "OK" } }