ClinVar Miner

Submissions for variant NM_000022.4(ADA):c.632G>A (p.Arg211His)

gnomAD frequency: 0.00009  dbSNP: rs121908716
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000002034 SCV000693972 pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency 2016-06-30 criteria provided, single submitter clinical testing Variant summary: The ADA c.632G>A (p.Arg211His) variant involves the alteration of a conserved nucleotide. Variant is located at the metal-dependent hydrolase domain and the Adenosine/AMP deaminase domain of the protein. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 8/121106 control chromosomes at a frequency of 0.0000661, which does not exceed the estimated maximal expected allele frequency of a pathogenic ADA variant (0.001633). This variant has been reported in many ADA deficient patients and functional studies showed that variant leads to enzyme activity deficiency. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Counsyl RCV000002034 SCV000790018 likely pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency 2017-03-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756972 SCV000884977 pathogenic not provided 2018-01-30 criteria provided, single submitter clinical testing The ADA c.632G>A; p.Arg211His variant has been repeatedly found in patients with ADA deficiency-dependent severe combined immunodeficiency (SCID), including 4 unrelated homozygotes (Arredondo-Vega 1998) and 6 homozygotes from a Romani population, four of whom were related (Baffelli 2015). It has also been reported in the compound heterozygous state, in which this variant was found along with another pathogenic ADA variant, in at least 8 other SCID patients (Arredondo-Vega 1998, Bell 2011, Engel 2007, Onodera 1998). Functional studies have demonstrated that although genes carrying this variant produce full-length mRNA, ADA protein activity is severely reduced or absent (Akeson 1988, Arredondo-Vega 1998). Reduced ADA activity is an established cause of SCID (Hershfield 2003). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.006% (identified on 18 out of 277,060 chromosomes), and is classified as pathogenic in ClinVar (ID: 1957). Based on the available information, this variant is classified as pathogenic.
Blueprint Genetics RCV000756972 SCV000927581 pathogenic not provided 2018-03-08 criteria provided, single submitter clinical testing
Invitae RCV000002034 SCV000949035 pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency 2021-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 211 of the ADA protein (p.Arg211His). This variant is present in population databases (rs121908716, gnomAD 0.02%). This missense change has been observed in individual(s) with adenosine deaminase deficiency (PMID: 1974554, 9414266, 9758612, 26376800). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1957). 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. Studies have shown that this missense change alters ADA gene expression (PMID: 9758612). For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University RCV000002034 SCV001425437 pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency 2020-02-20 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000002034 SCV001977504 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
Neuberg Supratech Reference Laboratories Pvt Ltd,Neuberg Centre for Genomic Medicine RCV000002034 SCV002073241 pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency criteria provided, single submitter clinical testing The missense variant p.R211H in ADA (NM_000022.4) has been reported previously in affected patients (Baffelli 2015 et al). Functional studies demonstrate a damaging effect. The variant has been submitted to ClinVar as Pathogenic. The variant is damaging by in silico prediction tools. The nucleotide c.632 in ADA is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic
OMIM RCV000002034 SCV000022192 pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency 1998-01-01 no assertion criteria provided literature only
UniProtKB/Swiss-Prot RCV000002034 SCV000090637 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. RCV000002034 SCV001461842 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

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