ClinVar

Description

The p.His294Gln variant in GBA has been reported in at least 34 individuals with Gaucher disease (PMID: 19459886, 18429048, 25435509, 26847548) and has been identified in 0.058% (6/10370) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs367968666). 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: 242810) as a VUS by Integrated Genetics and Praxis fuer Humangenetik Tuebingen and as pathogenic by Mayo Clinic Genetic Testing Laboratories. Computational prediction tools do not provide strong support for or against an impact to the protein. The His at position 294 is not highly conserved in mammals and evolutionary distant species, and 16 species (Chinese hamster, the golden hamster, and most birds) carry a Gln, raising the possibility that this change at this position may be tolerated. This variant was found exclusively in cis with another pathogenic variant, suggesting that it may not cause disease independently (PMID: 19459886, 18429048, 25435509, 26847548; Variation ID: 4293). In vitro functional studies provide some evidence that the p.His294Gln variant may not independently impact protein function. Additionally, this variant is shown to further decrease the residual activity of the p.Asp448His variant when the variants are on the same allele, suggesting that the variant may increase disease severity when in cis with the pathogenic p.Asp448His variant (PMID: 18429048). However, these types of assays may not accurately represent biological function. In summary, while the clinical significance of the p.His294Gln variant is uncertain, these data suggest that it is more likely to be benign but is expected to increase disease severity as part of the complex allele [p.Asp448His;p.His294Glln]. ACMG/AMP Criteria applied: BS3, BP2, PM2 (Richards 2015).