Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000215113 | SCV000271204 | likely pathogenic | Severe combined immunodeficiency due to ADA deficiency | 2015-11-09 | criteria provided, single submitter | clinical testing | The p.Arg235Gln variant in ADA has been reported in 3 individuals with SCID due to adenosine deaminase deficiency, confirmed by decreased ADA enzyme activity in patient cells (Ariga 2001a, Baffelli 2015). All of these individuals were compo und heterozygous and two of them had a second ADA variant predicted to cause los s of function of the gene on the other allele. The p.Arg235Gln variant was absen t from large population studies. Computational prediction tools and conservation analyses suggest that the variant may impact the protein, though this informati on is not predictive enough to determine pathogenicity. Furthermore, in vitro fu nctional studies provide some evidence that this variant impacts protein functio n (Ariga 2001b), although these types of assays may not accurately represent bio logical function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. |
| Counsyl | RCV000215113 | SCV000794032 | likely pathogenic | Severe combined immunodeficiency due to ADA deficiency | 2017-09-06 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000215113 | SCV000813414 | pathogenic | Severe combined immunodeficiency due to ADA deficiency | 2020-05-04 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with glutamine at codon 235 of the ADA protein (p.Arg235Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in combination with other ADA variants in several individuals affected with adenosine deaminase deficiency (PMID: 11313286, 26376800). In two individuals with ADA enzyme deficiency, this variant was observed on the opposite chromosome (in trans) from another pathogenic ADA variant (PMID: 11313286). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 228244). Experimental studies have shown that this missense change impairs ADA enzyme activity in vitro (PMID: 11160213). The p.Arg235Trp amino acid residue in ADA has been determined to be clinically significant (PMID: 21624848, 26255240, 26376800, Invitae). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. |