Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000685056 | SCV000812528 | pathogenic | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency | 2023-07-08 | criteria provided, single submitter | clinical testing | This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 104 of the ADA protein (p.Pro104Leu). This missense change has been observed in individuals with clinical features of ADA deficiency (PMID: 7691348, 9758612; Invitae). 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 expected to disrupt ADA protein function. ClinVar contains an entry for this variant (Variation ID: 565486). This variant is also known as 406C>T. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro104 amino acid residue in ADA. Other variant(s) that disrupt this residue have been observed in individuals with ADA-related conditions (PMID: 9758612, 31858364), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects ADA function (PMID: 9758612, 14499267). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003155284 | SCV003844297 | pathogenic | Severe combined immunodeficiency disease | 2023-02-28 | criteria provided, single submitter | clinical testing | Variant summary: ADA c.311C>T (p.Pro104Leu) results in a non-conservative amino acid change located in the Adenosine deaminase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251456 control chromosomes. c.311C>T has been reported in the literature in individuals affected with Severe Combined Immunodeficiency (Atasoy_1993, Arredondo-Vega_1998). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <1% of normal activity (Atasoy_1993, Arredondo-Vega_1998). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV000685056 | SCV004213278 | likely pathogenic | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency | 2023-08-14 | criteria provided, single submitter | clinical testing | |
| Natera, |
RCV000685056 | SCV002095327 | likely pathogenic | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency | 2021-03-18 | no assertion criteria provided | clinical testing |