Description
The p.Arg87Trp variant in GBA has been reported in at least 12 individuals with Gaucher disease, segregated with disease in 4 affected relatives from 2 families (PMID: 28506293, 28727984, 28947706, 7655857, 17574891, 9153297, 9295080, 17059888), and has been identified in 0.012% (2/16234) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1141814). 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: 4321) as pathogenic by OMIM and Integrated Genetics. In vitro functional studies provide some evidence that the p.Arg87Trp variant may slightly impact protein function (PMID: 9153297). 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 one affected homozygote and in combination with reported pathogenic variants in 7 individuals with Gaucher disease increases the likelihood that the p.Arg87Trp variant is pathogenic (VariationID: 4288, 4328, 65570; PMID: 28506293, 28727984, 28947706, 7655857, 17574891, 9295080). The phenotype of individuals compound heterozygous for this variant is highly specific for Gaucher disease based on significantly reduced beta-glucosidase activity in the leukocytes consistent with disease (PMID: 28506293, 9295080). 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, patient's phenotypes being highly specific for the gene, cosegregation with disease, and functional studies. ACMG/AMP Criteria applied: PM3_very-strong, PM2_supporting, PP3, PP4, PS3_supporting, PP1 (Richards 2015).
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
