A Retrospective Cohort Study of the GLA c.937G > T, p.Asp313Tyr Variant With No Evidence of an Association With Fabry Disease.

BACKGROUND AND OBJECTIVES

Fabry disease (FD) is a multisystemic disorder caused by pathogenic variants in the α-galactosidase () gene. There is ongoing debate on the disease-causing properties of the 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 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; < 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

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.