Submissions for variant NM_000157.4(GBA1):c.476G>A (p.Arg159Gln)

gnomAD frequency: 0.00001  dbSNP: rs79653797

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000020154	SCV001423035	pathogenic	Gaucher disease	2020-01-22	criteria provided, single submitter	curation	The p.Arg159Gln variant in GBA has been reported in at least 6 individuals with Gaucher disease (PMID: 15214004, 17560820, 17059888, 22658918) and has been identified in 0.002891% (1/34592) of Latino chromosomes and 0.0008814% (1/113462) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs79653797). 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: 4291) as pathogenic by OMIM. In vitro functional studies showing that fibroblasts cultured from a patient with Gaucher disease had <1% wild-type activity provide some evidence that the p.Arg159Gln variant may impact protein function (PMID: 15214004). 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. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg159Trp, has been reported in association with Gaucher disease in the literature and ClinVar, supporting that this variant may be pathogenic (VariationID: 65570; PMID: 28727984, 22623374, 17395504, 27865684, 29685539, 30764785, 23936319). Additionally, the presence of this variant in combination with reported pathogenic and likely pathogenic variants and in 4 individuals with Gaucher disease increases the likelihood that the p.Arg159Gln variant is pathogenic (VariationID: 4290, 4333; PMID: 15214004, 17560820, 17059888). 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 reported pathogenic variants, the significantly reduced activity of the protein in fibroblasts derived from a proband, and the presence of a pathogenic variant at the same position. ACMG/AMP Criteria applied: PM3_strong, PM2, PS3_moderate, PM5, PP3 (Richards 2015).
Johns Hopkins Genomics, Johns Hopkins University	RCV001250522	SCV001425323	likely pathogenic	Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome	2020-05-06	criteria provided, single submitter	clinical testing	GBA c.476G>A has been reported in multiple individuals presenting with Gaucher disease. This GBA variant (rs79653797) is rare (<0.1%) in a large population dataset (gnomAD: 2/251180 total alleles; 0.0008%; no homozygotes). This variant is located within a mutational hotpspot, which is in proximity to glucocerebrosidase catalytic sites. An alternate pathogenic missense change (p.Arg159Trp) has been reported at the same amino acid residue. This variant has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is highly evolutionarily conserved across most species assessed. We consider this variant to be likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020154	SCV001737811	pathogenic	Gaucher disease	2021-05-23	criteria provided, single submitter	clinical testing	Variant summary: GBA c.476G>A (p.Arg159Gln) results in a 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 8e-06 in 251180 control chromosomes. c.476G>A has been reported in the literature as p.Arg120Gln in multiple individuals affected with Gaucher Disease (example, Theophilus_1989, Beutler_1993, Koprivica_2000, Felderhoff-Meuser_2004, Rozenberg_2006, Mercimek-Mahmutoglu_2007, Sonder_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in compound heterozygosity with a 12 nucleotide insertion. The most pronounced variant effect results in <1% of normal activity in the patient derived fibroblast homogenate (Felderhoff-Mueser_2004). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV001781178	SCV002018401	pathogenic	not provided	2022-06-22	criteria provided, single submitter	clinical testing
GeneDx	RCV001781178	SCV005440760	pathogenic	not provided	2024-06-24	criteria provided, single submitter	clinical testing	Functional studies found this variant is associated with significantly reduced enzyme activity compared to wild-type (PMID: 16293621); 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.R120Q; This variant is associated with the following publications: (PMID: 34867278, 23588557, 17560820, 16293621, 31589614, 32677286, 35861376, 37750340, 37312046, 35810474, 34779914, 32507414, 15214004, 16546416, 33977031, 32613234, 34820281, 3180993, 10796875, 37198191, 1899336, 17059888)
OMIM	RCV000004518	SCV000024692	pathogenic	Gaucher disease type I	2004-07-15	no assertion criteria provided	literature only
OMIM	RCV000004519	SCV000024693	pathogenic	Gaucher disease perinatal lethal	2004-07-15	no assertion criteria provided	literature only
GeneReviews	RCV000020154	SCV000040481	not provided	Gaucher disease		no assertion provided	literature only
Natera, Inc.	RCV000020154	SCV002086479	pathogenic	Gaucher disease	2017-05-06	no assertion criteria provided	clinical testing