ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.273_276dup (p.Asp93Ter)

dbSNP: rs1928406808
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Total submissions: 3
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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 RCV001175015 SCV001338527 pathogenic Fabry disease 2020-04-14 criteria provided, single submitter clinical testing Variant summary: GLA c.273_276dupTGAT (p.Asp93X) 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 183388 control chromosomes (gnomAD). c.273_276dupTGAT has been reported in the literature in individuals affected with Fabry Disease (Altarescu_2001, Schiffmann_2015). The variant is reported as having <10% alpha-Gal activity compared to WT, and was not responsive to the pharmacological chaperone (PC) 1-deoxygalactonojirimycin (DGJ) in in vitro studies (Altarescu_2001, Lukas_2013). 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 pathogenic.
Invitae RCV001175015 SCV002242824 pathogenic Fabry disease 2022-07-04 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects GLA function (PMID: 23935525). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 917785). This premature translational stop signal has been observed in individual(s) with clinical features of Fabry disease (PMID: 23935525). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp93*) in the GLA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLA are known to be pathogenic (PMID: 10666480, 12175777).
Revvity Omics, Revvity RCV003142099 SCV003826394 pathogenic not provided 2023-01-20 criteria provided, single submitter clinical testing

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