Submissions for variant NM_000157.4(GBA1):c.259C>T (p.Arg87Trp)

gnomAD frequency: 0.00001  dbSNP: rs1141814

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589792	SCV000697586	pathogenic	Gaucher disease	2016-11-10	criteria provided, single submitter	clinical testing	Variant summary: The GBA c.259C>T (p.Arg87Trp) variant, located in the Glycosyl hydrolase domain, causes a missense change involving a conserved nucleotide with 5/5 in silico tools predict a damaging outcome, which a functional study, Grace_1997, supports these predictions. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency 2/121120 (1/60560), which does not exceed the estimated maximal expected allele frequency for a pathogenic GBA variant of 1/200 (0.005). This variant has been reported in numerous GD patients, who were homozygous and compound heterozygous for the variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000589792	SCV001422687	pathogenic	Gaucher disease	2020-01-22	criteria provided, single submitter	curation	The p.Arg87Trp variant in GBA has been reported in at least 12 individuals with Gaucher disease, segregated with disease in 4 affected relatives from 2 families (PMID: 28506293, 28727984, 28947706, 7655857, 17574891, 9153297, 9295080, 17059888), and has been identified in 0.012% (2/16234) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1141814). 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: 4321) as pathogenic by OMIM and Integrated Genetics. In vitro functional studies provide some evidence that the p.Arg87Trp variant may slightly impact protein function (PMID: 9153297). 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 one affected homozygote and in combination with reported pathogenic variants in 7 individuals with Gaucher disease increases the likelihood that the p.Arg87Trp variant is pathogenic (VariationID: 4288, 4328, 65570; PMID: 28506293, 28727984, 28947706, 7655857, 17574891, 9295080). The phenotype of individuals compound heterozygous for this variant is highly specific for Gaucher disease based on significantly reduced beta-glucosidase activity in the leukocytes consistent with disease (PMID: 28506293, 9295080). 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, patient's phenotypes being highly specific for the gene, cosegregation with disease, and functional studies. ACMG/AMP Criteria applied: PM3_very-strong, PM2_supporting, PP3, PP4, PS3_supporting, PP1 (Richards 2015).
Mayo Clinic Laboratories, Mayo Clinic	RCV001507457	SCV001713036	pathogenic	not provided	2020-02-13	criteria provided, single submitter	clinical testing	PS3, PS4_moderate, PM2, PP1, PP4
Revvity Omics, Revvity	RCV001507457	SCV002024191	pathogenic	not provided	2019-08-23	criteria provided, single submitter	clinical testing
Mendelics	RCV002247245	SCV002516448	pathogenic	Lewy body dementia	2022-05-04	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251874	SCV002523620	pathogenic	See cases	2020-04-02	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PS4, PM2, PM3, PP2
Fulgent Genetics, Fulgent Genetics	RCV002476927	SCV002778933	pathogenic	Lewy body dementia; Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease perinatal lethal; Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome; Parkinson disease, late-onset	2021-11-17	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000004565	SCV004232628	pathogenic	Gaucher disease type I	2024-01-25	criteria provided, single submitter	clinical testing	A compound heterozygous missense variation in exon 3 of the GBA gene that results in the amino acid substitution of Trptophan for Arginine at codon 87 was detected. The observed variant c.259C>T (p.Arg87Trp) has a minor allele frequency of 0.0028% in the gnomAD databases. The in silico prediction of the variant is disease causing by DANN and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a pathogenic.
GeneDx	RCV001507457	SCV005080098	pathogenic	not provided	2023-12-05	criteria provided, single submitter	clinical testing	Functional studies found that R87W is associated with significantly reduced beta-glucosidase activity (PMID: 9153297); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20729108, 9516376, 26018676, 17574891, 9217217, 17059888, 34820281, 33301762, 34867278, 7655857, 24904648, 28947706, 26051481, 30764785, 9295080, 1974409, 9153297, 29699937, 27027900, 28506293, 10796875, 28727984, 27872820, 33176831, 33473340, 35592045, 29625627)
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV004760320	SCV005373873	pathogenic	Parkinson disease, late-onset	2024-09-22	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV002476927	SCV005440575	pathogenic	Lewy body dementia; Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease perinatal lethal; Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome; Parkinson disease, late-onset		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3+PM3_VeryStrong+PP4+PP1_Strong
OMIM	RCV000004565	SCV000024739	pathogenic	Gaucher disease type I	1997-10-03	no assertion criteria provided	literature only
Natera, Inc.	RCV000589792	SCV002086482	pathogenic	Gaucher disease	2017-03-16	no assertion criteria provided	clinical testing