CTLA4 p.Pro136Ser

NM_005214.5(CTLA4):c.406C>T (p.Pro136Ser)is a missense variant encoding the replacement of proline with serine at amino acid 136. This variant is located within the MYPPPY functional domain (residues 134-139), which is required for interaction with CD80 and CD86 (PM1, PMID: 31396201). Another missense variant in the same codon, NM_005214.5(CTLA4):c.406C>G (p.Pro136Ala), has a lower Grantham score (27) than the variant under investigation (74) and has been classified as likely pathogenic for autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency by the ClinGen Antibody Deficiencies VCEP (PM5, PMID: 27379089, PMID: 29729943). Splicing prediction using SpliceAI did not strongly predict an effect on splicing due to either of these variants. This variant is absent from gnomAD v4.1.1 (PM2_Supporting). This variant has been reported in at least 1 proband with a phenotype that includes autoimmune cytopenias (2 pts), recurrent parotitis (4 pts), autoimmune gastrointestinal findings (4 pts), hepatosplenomegaly (2 pts), and recurrent viral infections (2 pts), with genotyping based on exome sequencing to exclude an alternative basis of disease in other loci such as LRBA, which together is highly specific for autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (14 pts, PMID: 32009323, PP4). This variant has been reported in at least one other apparently unrelated patient reaching at least 10 phenotypic points, with a phenotype that includes recurrent upper and lower respiratory tract infections (4 pts), enteropathy and diarrhea (4 pts), T cell infiltration of the lung and gut (1 pt), autoimmune thrombocytopenia and autoimmune hemolytic anemia (2 pts), severe viral infection including skin findings (2 pts), recurrent fungal infections (1 pt), splenomegaly and lymphoproliferative disorder (2 pts), decreased circulating IgG level (2 pts), and post-vaccination measles (1 pt), without genotyping to exclude an alternative basis for disease in other loci (19 pts, PMID: 29729943, PS4_Supporting). The variant has been reported to segregate with autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency through at least 1 affected meiosis from 1 family, with the affected status of the second family member confirmed to include hypogammaglobulinemia (2 pts), markedly decreased B-cells (1 pt), multiple episodes of illness including anemia and/or thrombocytopenia, abnormal lymphocyte subsets (1 pt), viral infection (2 pts), and malignancies (PMID: 32009323, PP1). The computational predictor REVEL gives a score of 0.490, which is below the ClinGen Antibody Deficiencies VCEP threshold of >0.75 and does not predict a damaging effect. The computational predictor CADD gives a PHRED score of 24.9, which is above the ClinGen Antibody Deficiencies VCEP threshold of >20 and predicts a damaging effect on CTLA4 function. Because the two predictors do not agree, PP3 is not met. Additionally, the splicing impact predictor SpliceAI gives a score of 0.02 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. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Antibody Deficiencies VCEP: PM1, PM5, PM2_Supporting, PS4_Supporting, PP1, and PP4. (VCEP specifications version 2.0.0).