ClinVar Miner

Submissions for variant NM_000022.4(ADA):c.632G>A (p.Arg211His) (rs121908716)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000002034 SCV000693972 pathogenic Severe combined immunodeficiency due to ADA 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 due to ADA 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 due to ADA deficiency 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 211 of the ADA protein (p.Arg211His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs121908716, ExAC 0.03%). This variant has been observed as homozygous or compound heterozygous with other variants in ADA in many individuals affected with adenosine deaminase deficiency (PMID: 9758612, 1974554, 9414266, 26376800). ClinVar contains an entry for this variant (Variation ID: 1957). Experimental studies have shown that this missense change reduces expression of the ADA protein (PMID: 9758612). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000002034 SCV000022192 pathogenic Severe combined immunodeficiency due to ADA deficiency 1998-01-01 no assertion criteria provided literature only
UniProtKB/Swiss-Prot RCV000002034 SCV000090637 not provided Severe combined immunodeficiency due to ADA deficiency no assertion provided not provided

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