Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV004697021 | SCV001158248 | likely pathogenic | not provided | 2024-08-19 | criteria provided, single submitter | clinical testing | The CTLA4 c.209G>A; p.Arg70Gln variant (rs1581573705, ClinVar Variation ID:811325) is reported in the literature in individuals affected with CTLA4-related disorders (Egg 2022, Egg 2018, Similuk 2022, Thaventhiran 2020). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, other variants at this codon (c.208C>T, p.Arg70Trp) have been reported in individuals with CTLA4- related disorders and are considered to be disease causing (Egg 2018, Schubert 2014). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.409). In vitro functional analyses in CHO and Jurkat T cells demonstrate reduced CD86 binding disrupting CD86 transendocytosis (Kennedy 2022). Based on available information, this variant is considered to be likely pathogenic. References: Egg D et al. Therapeutic options for CTLA-4 insufficiency. J Allergy Clin Immunol. 2022 Feb;149(2):736-746. PMID: 34111452. Egg D et al. Increased Risk for Malignancies in 131 Affected CTLA4 Mutation Carriers. Front Immunol. 2018 Sep 10;9:2012. PMID: 30250467. Kennedy A et al. Differences in CD80 and CD86 transendocytosis reveal CD86 as a key target for CTLA-4 immune regulation. Nat Immunol. 2022 Sep;23(9):1365-1378. PMID: 35999394. Schubert D et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014 Dec;20(12):1410-1416. doi: 10.1038/nm.3746. Epub 2014 Oct 20. PMID: 25329329. Similuk MN et al. Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations. J Allergy Clin Immunol. 2022 Oct;150(4):947-954. PMID: 35753512. Thaventhiran JED et al. Whole-genome sequencing of a sporadic primary immunodeficiency cohort. Nature. 2020 Jul;583(7814):90-95. PMID: 32499645. |
| NIHR Bioresource Rare Diseases, |
RCV001027565 | SCV001190135 | likely pathogenic | Inherited Immunodeficiency Diseases | 2019-01-01 | criteria provided, single submitter | research | |
| Labcorp Genetics |
RCV001208574 | SCV001379969 | likely pathogenic | Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency | 2025-01-11 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 70 of the CTLA4 protein (p.Arg70Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features consistent with autosomal dominant CTLA4 haploinsufficiency (PMID: 30250467, 32499645, 35753512). ClinVar contains an entry for this variant (Variation ID: 811325). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CTLA4 function (PMID: 35999394). This variant disrupts the p.Arg70 amino acid residue in CTLA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25329329, 30250467). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Clinical Genetics Laboratory, |
RCV004697021 | SCV005197660 | likely pathogenic | not provided | 2023-12-18 | criteria provided, single submitter | clinical testing |