Submissions for variant NM_000022.4(ADA):c.872C>T (p.Ser291Leu)

gnomAD frequency: 0.00005  dbSNP: rs121908721

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000002048	SCV000800041	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2018-05-18	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000788574	SCV000927730	likely pathogenic	not provided	2018-06-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000002048	SCV000935377	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 291 of the ADA protein (p.Ser291Leu). This variant is present in population databases (rs121908721, gnomAD 0.01%). This missense change has been observed in individual(s) with adenosine deaminase deficiency (PMID: 1284479, 26255240, 26376800). ClinVar contains an entry for this variant (Variation ID: 1971). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADA protein function. Experimental studies have shown that this missense change affects ADA function (PMID: 9758612). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000002048	SCV001977493	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
Fulgent Genetics, Fulgent Genetics	RCV000002048	SCV002786417	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2022-04-21	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000002048	SCV003829432	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2022-09-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000002048	SCV004216626	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2024-03-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004766976	SCV005381321	pathogenic	Severe combined immunodeficiency disease	2024-08-06	criteria provided, single submitter	clinical testing	Variant summary: ADA c.872C>T (p.Ser291Leu) results in a non-conservative amino acid change located in the Adenosine deaminase domain (IPR001365) 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 2.4e-05 in 251496 control chromosomes. c.872C>T has been reported in the literature in individuals affected with Severe Combined Immunodeficiency (Hirschhorn_1992, Aiuti_2009, Adams_2015, Baffelli_2015). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Arredondo-Vega_1998). The following publications have been ascertained in the context of this evaluation (PMID: 1401934, 26255240, 19179314, 9758612, 26376800). ClinVar contains an entry for this variant (Variation ID: 1971). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000002048	SCV000022206	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	1992-01-01	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000002048	SCV000090642	not provided	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency		no assertion provided	not provided
Natera, Inc.	RCV000002048	SCV001460806	pathogenic	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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000788574	SCV001954898	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000788574	SCV001968177	pathogenic	not provided		no assertion criteria provided	clinical testing