ClinVar Genomic variation as it relates to human health

The R368C variant in the GBA gene has been reported previously (as R329C due to alternative nomenclature) in the heterozygous state in an individual with Parkinson disease whose brain glucocerebrosidase activity was 64% of control activity (Lwin et al., 2004). The R368C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R368C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R368C as a variant of uncertain significance.

Variant summary: GBA c.1102C>T (p.Arg368Cys) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) 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 1.2e-05 in 251484 control chromosomes. In a cross sectional review spanning 2006 through 2020, c.1102C>T has been reported in the literature as a compound heterozygous genotype with other known pathogenic GBA alleles in in at-least two patients with clinically and/or biochemically confirmed Gaucher Disease (example, Rozenberg_2006, Ankleshwaria_2014). It has also been reported as a heterozygous genotype in patients with Parkinsonism (example, Lwin_2004, Petrucci_2020) and at-least one report of a patient with Idiopathic REM sleep behavior disorder (IRBD) (Gamez-Valero_2018). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. In this study, the brain specimen from a Parkinson disease patient with a heterozygous genotype was reported to have 64% of the wild-type levels of GBA enzyme activity (Lwin_2004). However, as presented, in our opinion, this does not allow convincing conclusions about the variant specific enzyme effect as the effect of other preanalytical variables that could have contributed to a compromised activity and/or the genotype effect on the overall activity levels could not be assessed. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

The p.Arg368Cys variant in GBA has been reported in at least 3 individuals with Gaucher disease (PMID: 17059888, 24940364, 24522292), and has been identified in 0.006% (1/16254) of African chromosomes and 0.002% (2/113764) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs374306700). 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: 420153) as a VUS by GeneDx. In vitro functional studies demonstrating 64% of wild-type enzyme activity in extracts from a heterozygous carrier of the variant provide some evidence that the p.Arg368Cys variant may slightly impact protein function (PMID: 14728994). 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 trans with reported pathogenic variants and in 2 individuals with Gaucher disease increases the likelihood that the p.Arg368Cys variant is pathogenic. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_strong, PM2, PP3, PS3_supporting (Richards 2015).

The GBA1 c.1102C>T variant is predicted to result in the amino acid substitution p.Arg368Cys. This variant, also known as R329C, has been reported in at least three individuals with Gaucher disease in the compound heterozygous state with a known pathogenic variant (Ankleshwaria et al. 2014. PubMed ID: 24522292; Sheth et al. 2018. PubMed ID: 30285649; Rozenberg et al. 2006. PubMed ID: 17059888) and it was confirmed to be biparentally inherited in at least one case (Ankleshwaria et al. 2014. PubMed ID: 24522292). This variant has also been reported in at least two individuals with Parkinson disease in the heterozygous state (Lwin et al. 2004. PubMed ID: 14728994; Petrucci et al. 2020. PubMed ID: 32658388). Glucocerebrosidase activity in the brain of patient with Parkinson disease who was heterozygous for this variant, was 64% (Lwin et al. 2004. PubMed ID: 14728994). Enzymatic activity in leukocytes was below normal range in patient with Gaucher disease with this variant in compound heterozygous state with another pathogenic variant p.Leu483Pro, also known as L444P (Sheth et al. 2018. PubMed ID: 30285649). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-155206158-G-A). In summary, this variant is interpreted as likely pathogenic.

PP3, PP4, PM2_moderate, PM3