Submissions for variant NM_000022.4(ADA):c.703C>T (p.Arg235Trp)

dbSNP: rs778809577

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000538818	SCV004102824	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2023-11-14	reviewed by expert panel	curation	The c.703C>T (NM_000022.4) variant in ADA gene is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 235 (p.Arg235Trp). The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 2/113770 observed alleles) is 0.000002920 in gnomAD v2.1.1 which is below than SCID VCEP threshold (<0.0001742) and therefore meets this criterion (PM2_Supporting). This variant has been detected in at least 5 individuals with SCID. Of those individuals, 2 were compound heterozygous: Patient #6, W264X, reported by Dalal I et al. (PMID: 21624848, Pathogenic according to the SCID VCEP specifications, confirmed in trans, 1pt) and Patient #26, p.G74D, reported by Chi ZH et al. (PMID: 30290665, Likey Pathogenic according to the SCID VCEP, confirmed in trans, 1 pt). 3 individuals were homozygous for PMIDs: 26255240, 26376800, and 32307643; reaching the limit for homozygous occurrence = 1 pt). Total = 3 pts, PM3_Strong. Evaluating those 5 probands, three of them had PP4 applied at supporting level: * PMID: 30290665: 171 PID-related genes(NGS panel: 0.5pt); T-B-SCID ( SCID gene panel which ruled out alternative causes 0.5pt); SCID diagnostic (0.5pt); Total 1.5pts. * PMID: 26376800: Diagnostic criteria for SCID: 0,5 pt + Reduced ADA enzyme activity in patient cells: 1pt. TOTAL: 1.5 pts, PP4_Met. * PMID: 26255240: Diagnostic criteria for SCID: 0,5 pt + Reduced ADA enzyme activity in patient cells: 1pt = TOTAL: 1.5 pts = PP4_Met. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_Supporting, PP4, PM3_Strong, and PM5_supporting. (VCEP specifications version 1).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000538818	SCV000644843	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2023-09-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 235 of the ADA protein (p.Arg235Trp). This variant is present in population databases (rs778809577, gnomAD 0.007%). This missense change has been observed in individual(s) with SCID (PMID: 21624848, 26255240). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 468281). 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. Experimental studies have shown that this missense change affects ADA function (PMID: 9361033). This variant disrupts the p.Arg234 amino acid residue in ADA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11313286). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
Counsyl	RCV000538818	SCV000799270	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2018-04-12	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000538818	SCV001977499	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2021-08-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003403304	SCV004110457	pathogenic	ADA-related disorder	2022-12-29	criteria provided, single submitter	clinical testing	The ADA c.703C>T variant is predicted to result in the amino acid substitution p.Arg235Trp. This variant was reported in the compound heterozygous and homozygous states in patients with severe combined immunodeficiency (Dalal et al 2011. PubMed ID: 21624848; Patient 26 in Chi et al 2018. PubMed ID: 30290665; Pajno et al 2020. PubMed ID: 32307643). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-43251547-G-A). Of note, a different variant at the same amino acid (p.Arg235Gln) has also been reported in patients with ADA-related disorder (Ariga et al. 2001. PubMed ID: 11313286). Based on this evidence, we interpret that c.703C>T (p.Arg235Trp) variant as pathogenic.
Baylor Genetics	RCV000538818	SCV004213267	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2023-08-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000538818	SCV002095309	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2021-03-30	no assertion criteria provided	clinical testing