ClinVar Miner

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

dbSNP: rs1555844617
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen RCV000665672 SCV004102818 pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency 2023-11-14 reviewed by expert panel curation The c.396dup (p.Val133Serfs*38) (NM_000022.4) variant in ADA is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 5/12 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one patient with this variant displayed Diagnostic criteria for Leaky SCID (0.5pt) + T-B-NK- lymphocyte subset profile (0.5pt) = 1 point TOTAL, which is highly specific for SCID (PP4_Met, PMID: 21664875). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1, PM2_Supporting, and PP4. (VCEP specifications version 1).
Counsyl RCV000665672 SCV000789831 likely pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase 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 2022-04-15 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 184218 control chromosomes. 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. Three 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000665672 SCV001203216 pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency 2022-10-24 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. Loss-of-function variants in ADA are known to be pathogenic (PMID: 26255240, 26376800). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with atypical severe combined immunodeficiency deficiency (PMID: 21664875). ClinVar contains an entry for this variant (Variation ID: 550821). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab RCV000665672 SCV001977515 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
Baylor Genetics RCV000665672 SCV004213367 pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency 2023-06-20 criteria provided, single submitter clinical testing

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