Background and objectives: Fabry disease (FD) is a multisystemic disorder caused by pathogenic variants in the α-galactosidase (GLA) gene. There is ongoing debate on the disease-causing properties of the GLA variant NM_000169.3: c.937G > T, p.Asp313Tyr (D313Y). Like many others, we recently reclassified this variant from "variant of uncertain significance" to "benign."
Methods: By leveraging Centogene's Biodatabank, we reassessed our classification and analyzed all samples (n = 38,242) molecularly tested for FD from Germany between 2015 and 2020 for GLA genotypes, clinical presentations, and biochemical phenotypes.
Results: The allele frequency of GLA variant p.Asp313Tyr in our cohort was increased compared with gnomAD v4.1.0 data for European (non-Finnish) population resulting in an odds ratio of 2.13 (95% CI 1.94-2.33; p < 0.0001). Compared with individuals without any GLA variant, there was no specific clinical nor biochemical phenotype in this group, supporting a diagnosis of FD.
Discussion: GLA variant p.Asp313Tyr is to be classified as a benign variant and does not cause FD. Because an enrichment of patients with this variant in specific high-risk populations has been seen in this cohort and by other groups, properly designed case-control studies are needed to clarify a potential role of p.Asp313Tyr as risk factor or modifier of a FD-independent dysfunction.
Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.