ClinVar Genomic variation as it relates to human health

Variant summary: GLA c.1046G>A (p.Trp349X) 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 183139 control chromosomes. c.1046G>A has been reported in the literature in multiple individuals affected with clinically and biochemically confirmed Fabry Disease (example, Sirrs_2009). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Pereira_2007). The most pronounced variant effect results in <10% of normal GLA enzyme activity. 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.

Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23935525, 11322659, 17713670, 20022777)

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GLA protein in which other variant(s) (p.Pro409Ser) have been determined to be pathogenic (PMID: 8768754, 12428061, 31392112; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 992222). This premature translational stop signal has been observed in individual(s) with Fabry disease (PMID: 11322659). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp349*) in the GLA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 81 amino acid(s) of the GLA protein.