ClinVar Miner

Submissions for variant NM_000022.4(ADA):c.532del (p.Val177_Val178insTer) (rs886041796)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000606716 SCV000712838 likely pathogenic Severe combined immunodeficiency due to ADA deficiency 2017-02-03 criteria provided, single submitter clinical testing The p.Val178X variant in ADA has not been previously reported in individuals wit h adenosine deaminase (ADA) deficiency, but was identified in 2/18938 East Asian individuals by the Genome Aggregation Database (gnomAD, http://gnomad.broadinst itute.org/). This variant is a deletion of 1 nucleotide at position 532, which g enerates a premature termination codon at amino acid position 178. Loss of funct ion of the ADA gene is an established disease mechanism in severe combined immun odeficiency due to adenosine deaminase deficiency. In summary, although addition al studies are required to fully establish its clinical significance, the p.Val1 78X variant is likely pathogenic due to its predicted impact to the protein.
Counsyl RCV000606716 SCV000794217 likely pathogenic Severe combined immunodeficiency due to ADA deficiency 2017-09-20 criteria provided, single submitter clinical testing
Invitae RCV000606716 SCV001216454 pathogenic Severe combined immunodeficiency due to ADA deficiency 2019-03-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val178*) in the ADA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ADA-related conditions. ClinVar contains an entry for this variant (Variation ID: 505549). Loss-of-function variants in ADA are known to be pathogenic (PMID: 26255240, 26376800). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001194147 SCV001363447 likely pathogenic Severe combined immunodeficiency disease 2019-05-10 criteria provided, single submitter clinical testing Variant summary: ADA c.532delG (p.Val178X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.956_960delAAGAG/p.Glu319fsX3). The variant allele was found at a frequency of 4e-06 in 251362 control chromosomes. c.532delG has been reported in the literature in an individual affected with Severe Combined Immunodeficiency Syndrome (Chi_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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 likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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