ClinVar Genomic variation as it relates to human health

Variant summary: GBA c.508C>T (p.Arg170Cys) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251172 control chromosomes. c.508C>T has been reported in the literature as homozygous or compound heterozygous genotypes in multiple individuals affected with Gaucher Disease (example, Miano_2020, Costa_2020, D'Amore_2021, Filocamo_2002, Schuler_2016). These data indicate that the variant is very likely to be associated with disease. No direct experimental evidence demonstrating an impact on protein function has been ascertained in the context of this evaluation although at-least one study reports non-primary evidence supporting a diagnosis of Gaucher Disease by enzyme analysis in a preterm infant homozygous for this variant (Schuler_2016). The following publications have been ascertained in the context of this evaluation (PMID: 31816052, 34649574, 12204005, 32702516, 27922757). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.Arg170Cys variant in GBA has been reported in at least 10 individuals with Gaucher disease (PMID: 29602947, 23430543, 27008851, 17427031, 20946052, 27922757, 22623374, 20880730) and has been identified in 0.005% (1/21648) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123530). 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 as pathogenic by EGL Genetic Diagnostics (VariationID: 93453). 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 phenotype of 2 individuals homozygous or compound heterozygous for this variant is highly specific for Gaucher disease based on null or very low beta-glucosidase activity levels consistent with disease (PMID: 22623374, 29602947). The presence of this variant in 3 affected homozygotes and in combination with reported pathogenic variants in 6 individuals with Gaucher disease increases the likelihood that the p.Arg170Cys variant is pathogenic (VariationID: 65570, 4290, 4297, 4288; PMID: 29602947, 23430543, 27008851, 17427031, 20946052, 27922757, 22623374). 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 affected homozygotes and compound heterozygotes with pathogenic variants, the low frequency of the variant in the general population, and the phenotype of patients with the variant being highly specific for the gene. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP3, PP4 (Richards 2015).

GBA1: PM3:Very Strong, PM1, PM2, PM5, PS3:Supporting