Submissions for variant NM_000022.4(ADA):c.226C>T (p.Arg76Trp)

gnomAD frequency: 0.00081  dbSNP: rs121908736

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482569	SCV000568505	uncertain significance	not provided	2023-12-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28471432, 9225964, 35914665, 21228398, 1346349, 8433873, 2166947)
Illumina Laboratory Services, Illumina	RCV000059096	SCV001303124	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000059096	SCV001419110	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2022-10-24	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 76 of the ADA protein (p.Arg76Trp). This variant is present in population databases (rs121908736, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with partial adenosine deaminase deficiency (PMID: 2166947). ClinVar contains an entry for this variant (Variation ID: 1962). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV000059096	SCV002027196	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
CeGaT Center for Human Genetics Tuebingen	RCV000482569	SCV004811731	uncertain significance	not provided	2024-03-01	criteria provided, single submitter	clinical testing	ADA: PS3:Supporting
Breakthrough Genomics, Breakthrough Genomics	RCV000482569	SCV005194992	uncertain significance	not provided		criteria provided, single submitter	not provided
OMIM	RCV000002039	SCV000022197	pathogenic	Partial adenosine deaminase deficiency	1990-08-01	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000059096	SCV000090617	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.	RCV000059096	SCV002095332	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2020-10-20	no assertion criteria provided	clinical testing