ClinVar

Description

The p.Leu483Arg variant in GBA has been reported in two Brazilian individuals with Gaucher disease (PMID: 27825739) and has been identified in 0.005% (1/18388) of East Asian chromosomes and 0.003% (1/34386) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs421016). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 93449) as likely pathogenic by GeneDx, Integrated Genetics, and the Foundation for Research In Genetics and Endocrinology, and as pathogenic by EGL Genetic Diagnostics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Leu483Pro, has been reported in association with disease in ClinVar and the literature, supporting that a change at this position may not be tolerated (VariationID: 4288; PMID: 17427031, 23719189, 30662625, 28686011). The presence of this variant in combination with a reported pathogenic variant and in 2 individuals with Gaucher disease increases the likelihood that the p.Leu483Arg variant is pathogenic (VariationID: 4290, PMID: 27825739). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PM3, PP3 (Richards 2015).