ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.1102C>T (p.Arg368Cys) (rs374306700)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487271 SCV000568801 uncertain significance not provided 2017-03-07 criteria provided, single submitter clinical testing 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.
Baylor Genetics RCV001004120 SCV001162851 likely pathogenic Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease type 3C criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001249080 SCV001423036 likely pathogenic Gaucher disease 2020-01-22 no assertion criteria provided curation 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).

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