ClinVar Miner

Submissions for variant NM_000022.4(ADA):c.396dup (p.Val133fs) (rs1555844617)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665672 SCV000789831 likely pathogenic Severe combined immunodeficiency due to ADA deficiency 2017-02-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780819 SCV000918393 likely pathogenic Severe combined immunodeficiency disease 2018-11-23 criteria provided, single submitter clinical testing Variant summary: ADA c.396dupA (p.Val133SerfsX38) 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. A truncation downstream of this position, c.956_960delAAGAG (p.Glu319fsX3), has been classified as pathogenic by our laboratory. The variant was absent in 29100 control chromosomes (gnomAD). c.396dupA has been reported in the literature in a compound heterozygote individual affected with Severe Combined Immunodeficiency Syndrome (Felgentreff_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000665672 SCV001203216 pathogenic Severe combined immunodeficiency due to ADA deficiency 2020-01-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val133Serfs*38) 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 been observed in an individual affected with atypical severe combined immunodeficiency deficiency (PMID: 21664875). ClinVar contains an entry for this variant (Variation ID: 550821). Loss-of-function variants in ADA are known to be pathogenic (PMID: 26255240, 26376800). For these reasons, this variant has been classified as Pathogenic.

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