ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.667T>C (p.Trp223Arg) (rs61748906)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000079351 SCV000232103 pathogenic not provided 2012-12-19 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000243066 SCV000305642 likely pathogenic Gaucher disease type I; Gaucher disease type II; Gaucher disease type III 2019-06-06 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000079351 SCV000608495 likely pathogenic not provided 2017-04-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588402 SCV000697591 pathogenic Gaucher disease 2017-06-30 criteria provided, single submitter clinical testing Variant summary: The GBA c.667T>C (p.Trp223Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide and it is located in the Glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This was confirmed by functional studies showing abrogated Beta-glucosidase catalytic activity (0.0004 total units of specific activity per cross-reacting immunologic material (CRIM SA) (vs. 1 in control) (Amaral_2000, Awad_2015). This variant was found in 3/112128 control chromosomes at a frequency of 0.0000268, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). This variant was reported in multiple patients with Gaucher disease (Choy_1999, Rozenberg_2006) in which pseudogene interference was ruled out. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000588402 SCV001422957 pathogenic Gaucher disease 2020-01-13 no assertion criteria provided curation The p.Trp223Arg variant in GBA has been reported in at least 8 individuals with Gaucher disease (PMID: 17059888, 24801745, 27136700, 10679038, 27864021) and has been Identified in 0.002% (2/111560) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs61748906). 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: 93457) as benign by Prevention Genetics, likely pathogenic by Praxis fuer Humangenetik Tuebingen, and pathogenic by Integrated Genetics and EGL Genetic Diagnostics. In vitro functional studies demonstrating very low glucocerebrosidase activity in mutant hiPSC macrophages provide some evidence that the p.Trp223Arg variant may impact protein function (PMID: 24801745). 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 reported pathogenic variants and in 8 individuals with Gaucher disease increases the likelihood that the p.Trp223Arg variant is pathogenic (VariationID: 4288, 4290, 4293; PMID: 17059888, 24801745, 27136700, 10679038, 27864021). 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 the low frequency of the variant in the general population. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PS3_moderate, PP3 (Richards 2015).

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