ClinVar Genomic variation as it relates to human health

The p.Phe255Tyr variant in GBA has been reported in at least 6 individuals with Gaucher disease, segregated with disease in 3 affected relatives from 1 family, (PMID: 23811968, 24685312, 12587096, 12587096) and has been identified in 0.004% (5/128154) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs74500255). 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: 4298) as pathogenic by OMIM and as likely pathogenic by GeneDx. In vitro functional studies provide some evidence that the p.Phe255Tyr variant may impact protein function (PMID: 8294487). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with a reported pathogenic variant and in at least 5 individuals with Gaucher disease increases the likelihood that the p.Phe255Tyr variant is pathogenic (VariationID: 4290; PMID: 23635853, 24685312, 23811968, 12587096). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the presence of the variant in combination with other pathogenic variants in affected individuals, functional studies, and co-segregation of the variant with disease. ACMG/AMP Criteria applied: PM3_strong, PM2, PS3_moderate, PP3, PP1 (Richards 2015).

PS3, PM2, PS4_moderate, PP3, PP4

Variant summary: GBA c.764T>A (p.Phe255Tyr) results in a conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249870 control chromosomes. c.764T>A has been reported in the literature in individuals affected with Gaucher Disease (Beutler_1993, DAmore_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <1% of normal activity (Grace_1994). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

GBA1: PM3:Strong, PM1, PM2, PS3:Moderate, PP3

Published functional studies demonstrate that the variant results in less than 0.5% of wild-type enzyme activity and absence of mature GBA peptide (PMID: 8294487); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(F216Y); This variant is associated with the following publications: (PMID: 1974409, 32618053, 32714263, 37152446, 8294487, 23635853, 30302829)