Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000810109 | SCV004242236 | uncertain significance | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency | 2024-01-10 | reviewed by expert panel | curation | NM_000022.4(ADA):c.757C>T is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 253 (p.Arg253Trp).The filtering allele frequency (the upper threshold of the 95% CI of 101/1180020) of the c.757C>T variant in ADA is 0.00007452 for European Non-Finnish chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting.However, 1 homozygote was reported (PM2 not met). There are no publications for this variant in the literature. Another missense variant R253P in the same codon has been reported (PMIDs : 8258146,9758612) (not classified by SCID VCEP yet):PM5 not evaluated. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: No criteria met (VCEP specifications version 1). |
| ARUP Laboratories, |
RCV000756973 | SCV000884978 | uncertain significance | not provided | 2017-08-09 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000810109 | SCV000950298 | likely pathogenic | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency | 2022-09-22 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 253 of the ADA protein (p.Arg253Trp). This variant is present in population databases (rs201944717, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ADA-related conditions. ClinVar contains an entry for this variant (Variation ID: 618516). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ADA protein function. This variant disrupts the p.Arg253 amino acid residue in ADA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8258146, 9758612). 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. |
| Gene |
RCV000756973 | SCV001987831 | uncertain significance | not provided | 2019-05-23 | criteria provided, single submitter | clinical testing | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge |
| Genome- |
RCV000810109 | SCV002027193 | uncertain significance | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency | 2021-09-05 | criteria provided, single submitter | clinical testing | |
| Natera, |
RCV000810109 | SCV001460808 | uncertain significance | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency | 2020-09-16 | no assertion criteria provided | clinical testing |