ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.721G>A (p.Gly241Arg) (rs409652)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000675275 SCV000232101 pathogenic not provided 2016-12-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589250 SCV000697594 pathogenic Gaucher disease 2017-05-08 criteria provided, single submitter clinical testing Variant summary: The GBA c.721G>A (p.Gly241Arg) variant (alternatively also known as G202R) involves the alteration of a conserved nucleotide, is located in TIM-barrel domain of the protein (InterPro) and 2/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/121276 control chromosomes from ExAC at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). This variant has been found in several patients with GD mainly from Europe in compound heterozygous state with other known pathogenic variants as well as in homozygous state, including an evidence of cosegregation with disease. In an Italian study, this variant was the third most common pathogenic variant (Filocamo_2002). In vitro functional studies show that this variant leads to severely compromised enzymatic activity and/or trafficking (Grace_1997, Torralba_2001, review by Yu_2009). The functional outcome coupled with severe phenotype (type 2 GD) in patients carrying this variant in homozygous state indicates that it could be a severe mutation. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000675275 SCV000960918 pathogenic not provided 2020-10-03 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 241 of the GBA protein (p.Gly241Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. The frequency data for this variant in the population databases (rs409652, ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been observed in several individuals affected with Gaucher disease (PMID: 23430543, 22247978, 12204005, 29091352) and Parkinson's disease (PMID: 26117366, 22173904). ClinVar contains an entry for this variant (Variation ID: 93459). This variant is also known as p.Gly202Arg or G202R in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Experimental studies have shown that this missense change disrupts GBA enzyme activity (PMID: 9153297). Variants that disrupt the p.Gly241 amino acid residue in GBA have been observed in affected individuals (PMID: 10744424). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001004128 SCV001162859 pathogenic Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease type 3C criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000675275 SCV001500840 pathogenic not provided 2020-08-01 criteria provided, single submitter clinical testing
GeneDx RCV000675275 SCV001792358 likely pathogenic not provided 2021-06-02 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32658388, 33176831, 32618053, 32677286, 31589614, 27535533, 31996268, 30461613, 29934114, 26117366, 8790604, 11259172, 17427031, 22964618, 22623374, 29091352, 9516376, 22173904, 18078074, 24022302, 27836528, 27816428, 27789132, 22247978, 25188399, 28727984, 23430543, 11783951, 12204005, 27872820, 26792850, 19830760)
Mayo Clinic Laboratories, Mayo Clinic RCV000675275 SCV000800930 uncertain significance not provided 2015-12-16 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000589250 SCV001423050 pathogenic Gaucher disease 2020-01-22 no assertion criteria provided curation The p.Gly241Arg variant in GBA has been reported in at least 13 individuals with Gaucher disease (PMID: 22429443, 24022302, 11259172) and has been identified in 0.012% (2/16254) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs409652). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Trio analysis showed this variant to be de novo in one individual (PMID: 24022302). In vitro functional studies demonstrating reduced enzyme activity in transfected COS-7 cells provide some evidence that the p.Gly241Arg variant may impact protein function (PMID: 11259172, 25084554). However, these types of assays may not accurately represent biological function. Computational prediction tools suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The Gly at position 241 is highly conserved in mammals and evolutionary distant species, but 1 mammal (Gorilla) carries an Arg, raising the possibility that this change at this position may be tolerated. The presence of this variant in combination with reported pathogenic variants in 12 individuals with Gaucher disease increases the likelihood that the p.Gly241Arg variant is pathogenic (VariationID: 4288, 4290; PMID: 22429443, 11259172). 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, functional studies, and the occurrence of the variant de novo in a Gaucher disease patient. ACMG/AMP Criteria applied: PM3_very-strong, PS3, PS2, PM2_supporting (Richards 2015).

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