CTLA4 p.Thr124Pro

NM_005214.5(CTLA4):c.370A>C (p.Thr124Pro) is a missense variant replacing threonine with proline at amino acid 124. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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). 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). 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 predict an impact on CTLA4 splicing. A soluble CD80 ligand uptake assay 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 (PMID: 25329329).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). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Antibody Deficiencies VCEP: PS3_Supporting, PS4_Supporting, PM2_Supporting, and PP3. (VCEP specifications version 1.0.0; date of approval 09/18/2025).