Submissions for variant NM_000022.4(ADA):c.643G>A (p.Ala215Thr)

gnomAD frequency: 0.00030  dbSNP: rs114025668

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000059112	SCV000796174	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2017-12-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000059112	SCV000958303	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2022-08-19	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 215 of the ADA protein (p.Ala215Thr). This variant is present in population databases (rs114025668, gnomAD 0.07%). This missense change has been observed in individual(s) with partial ADA deficiency without SCID (PMID: 2166947, 9108404, 9225964, 9758612, 14499267). ClinVar contains an entry for this variant (Variation ID: 1967). 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: 2166947, 9108404, 9361033, 11067872). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001280563	SCV001467763	uncertain significance	not specified	2020-12-07	criteria provided, single submitter	clinical testing	Variant summary: ADA c.643G>A (p.Ala215Thr) results in a non-conservative amino acid change located in the Adenosine/AMP deaminase domain (IPR001365) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, at least one publication reports experimental evidence that this variant affects mRNA splicing resulting in induction of exon 7 skipping in approximately 50% of cells (Ozsahin_1997) but a residual low level (10-15%) skipping of exon 7 was also observed in normal cells. Therefore, the exact impact of this splicing phenomenon on ADA activity in-vivo is not clear. The variant allele was found at a frequency of 9.9e-05 in 251422 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ADA causing Severe Combined Immunodeficiency Syndrome (9.9e-05 vs 0.0014), allowing no conclusion about variant significance. c.643G>A has been not been reported in the literature in individuals affected with Severe Combined Immunodeficiency Syndrome, but has been observed in clinically asymptomatic individuals presenting with a partial ADA deficiency in-vitro (example, Hirschhorn_1990, Hirschhorn_1997, Ozsahin_1997). These report(s) do not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal ADA enzyme activity (example, Jiang_1997, Richard_2007, Arredondo-Vega_1998). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000059112	SCV002027194	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
Fulgent Genetics, Fulgent Genetics	RCV000059112	SCV002779383	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2022-04-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000059112	SCV004215830	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2022-03-01	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000059112	SCV004810296	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2024-04-04	criteria provided, single submitter	clinical testing
OMIM	RCV000002044	SCV000022202	pathogenic	Partial adenosine deaminase deficiency	1990-08-01	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000059112	SCV000090638	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