ClinVar Miner

Submissions for variant NM_000022.4(ADA):c.646G>A (p.Gly216Arg) (rs121908723)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000256171 SCV000321380 pathogenic not provided 2017-07-10 criteria provided, single submitter clinical testing The G216R missense variant in the ADA gene has been reported previously in association with adenosine adeaminase deficiency in patients of varied ancestries (Hirschhorn et al., 1991; Arredondo-Vega et al., 1998; Adams et al., 2015; Baffelli et al., 2015). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. G216R is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (R211H/C, V213F, A215T, E217K) have been reported in the Human Gene Mutation Database in association with ADA-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In addition, functional studies have shown that the G216R variant results in reduced catalytic activity and early clinical presentation of the disorder (Arredondo-Vega et al., 1998). Therefore, we consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000002045 SCV000693973 pathogenic Severe combined immunodeficiency due to ADA deficiency 2017-08-27 criteria provided, single submitter clinical testing Variant summary: The c.646G>A (p.Gly216Arg) in ADA gene is a missense change that involves a highly conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant of interest is located within the active site of conserved domain and mutations were proven to lead to severe SCID presentation due to complete abolishment of all residual enzyme activity. The variant is present in the large control population dataset of ExAC at a frequency 1.65e-05 (2/121232 chrs tested). The variant has been identified homozygously or in the compound heterozygous state in numerous affected individuals with severe presentation. Lastly, multiple reputable databases/diagnostic centers classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic.
Counsyl RCV000002045 SCV000789553 pathogenic Severe combined immunodeficiency due to ADA deficiency 2017-02-14 criteria provided, single submitter clinical testing
Invitae RCV000002045 SCV000952135 pathogenic Severe combined immunodeficiency due to ADA deficiency 2019-09-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 216 of the ADA protein (p.Gly216Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs121908723, ExAC 0.003%). This variant has been observed in homozygous and compound heterozygous individuals affected with adenosine deaminase deficiency (PMID: 9108404, 9758612, 1680289, 1346349, 26255240). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 1968). Experimental studies have shown that this missense change disrupts ADA protein function (PMID: 9758612, 9108404, 8258146). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000002045 SCV000022203 pathogenic Severe combined immunodeficiency due to ADA deficiency 1991-10-01 no assertion criteria provided literature only
UniProtKB/Swiss-Prot RCV000002045 SCV000090639 not provided Severe combined immunodeficiency due to ADA deficiency no assertion provided not provided

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