ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.497A>T (p.Asp166Val) (rs79796061)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780285 SCV000917428 likely pathogenic Gaucher disease 2021-04-16 criteria provided, single submitter clinical testing Variant summary: GBA c.497A>T (p.Asp166Val also known as Asp127Val) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251180 control chromosomes (gnomAD). c.497A>T has been reported in the literature in at least one individual affected with Gaucher Disease and was described as a mild severity allele (Beutler_2005). At least one publication reports experimental evidence showing an impact on protein function, where the variant causes the specific activity, induced activation, and conformation of the enzyme to be significantly reduced/altered compared to controls (Liou_2006). Based on a structural model, Atrial et al predict that Asp 127 contacts the hydroxyl group of the glucosylceramide, stabilizing the location of the substrate for catalysis and therefore this mutation to Valine probably alters the proper geometry of the active locus and modifies enzyme activity (Atrian_2008). No other ClinVar submitters 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.

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