ClinVar Miner

Submissions for variant NM_000157.4(GBA1):c.593C>T (p.Pro198Leu)

gnomAD frequency: 0.00001  dbSNP: rs80222298
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mayo Clinic Laboratories, Mayo Clinic RCV001507456 SCV001713035 likely pathogenic not provided 2020-02-13 criteria provided, single submitter clinical testing PS3, PM2, PM5
Revvity Omics, Revvity RCV001507456 SCV003808644 uncertain significance not provided 2020-06-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004587170 SCV005077235 uncertain significance not specified 2024-04-18 criteria provided, single submitter clinical testing Variant summary: GBA1 c.593C>T (p.Pro198Leu), also reported as "P159L", 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 2e-06 in 983702 control chromosomes. c.593C>T has been reported as homozygous in the literature in at least one individual affected with type 1 Gaucher Disease (Demina_1998, Petrides_1998). It has also been reported in the heterozygous state in at least one individual with Parkinson's disease (Peterschmitt_2022). These data indicate that the variant may be associated with disease. At least one publication reports that patient cells had ~39% beta-glucocerebrosidase activity vs. control cell minimums (Petrides_1998). The following publications have been ascertained in the context of this evaluation (PMID: 9554454, 34897099, 9723584, 24022302, 12204005). ClinVar contains an entry for this variant (Variation ID: 1162851). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx RCV001507456 SCV005324980 likely pathogenic not provided 2024-02-22 criteria provided, single submitter clinical testing In vitro assays support that this variant results in impaired beta-glucocerebrosidase binding with the lysosomal integral membrane protein type-2 (LIMP-2) resulting in defective intercellular targeting to lysosomes. (PMID: 27001828); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(P159L); This variant is associated with the following publications: (PMID: 9516376, 9554454, 27001828)

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