ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.1504C>T (p.Arg502Cys) (rs80356771)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000079343 SCV000225256 pathogenic not provided 2012-07-24 criteria provided, single submitter clinical testing
GeneDx RCV000079343 SCV000329942 pathogenic not provided 2018-01-16 criteria provided, single submitter clinical testing The R502C pathogenic variant in the GBA gene has been reported previously (reported as R463C due to alternative nomenclature) in multiple patients with Gaucher disease (Hatton et al., 1997). The R502C variant was not observed with a significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R502C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. Functional studies show that R502C has reduced enzyme activity (Hong et al., 1990; Grace et al., 1994). We interpret R502C as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020151 SCV000697584 pathogenic Gaucher disease 2017-08-25 criteria provided, single submitter clinical testing Variant summary: The GBA c.1504C>T (p.Arg502Cys) variant involves the alteration of a non-conserved nucleotide, resulting in a missense change within the glycosyl hydrolase family 30, beta sandwich domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 7/121382 control chromosomes at a frequency of 0.0000577, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). The variant has been identified in numerous patients with Gaucher disease type I and type III, both as a compound heterozygous and homozygous allele. The variant is considered a recurrent mutation and has been associated with mild and severe Gaucher-related phenotypes in patients. Functional studies showed a significant reduction in enzyme activity (Grace_1994). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000762852 SCV000893212 pathogenic Lewy body dementia; Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease, perinatal lethal; Gaucher disease type 3C; Parkinson disease, late-onset 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000079343 SCV000964939 pathogenic not provided 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 502 of the GBA protein (p.Arg502Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. The frequency data for this variant in the population databases (rs80356771, 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 individuals affected with Gaucher disease and Parkinson's disease (PMID: 1972019, 24482953, 8733893, 17427031, 21704274). This variant is also known as p.Arg463Cys and R463C in the literature. ClinVar contains an entry for this variant (Variation ID: 4295). Experimental studies have shown that this missense change dirups GBA enzyme activity (PMID: 11259172, 8294487). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001004110 SCV001162841 pathogenic Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease type 3C criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000004528 SCV001194027 pathogenic Gaucher disease type I 2019-12-10 criteria provided, single submitter clinical testing NM_001005741.2(GBA):c.1504C>T(R502C, aka R463C) is classified as pathogenic in the context of Gaucher disease, and can be associated with Type 1, 2, or 3 of the disease. Sources cited for classification include the following: PMID 24522292, 12595585, 1348297, 1972019, 24482953, 18586596, 1704891, 8294487, 8118463 and 9279145. Classification of NM_001005741.2(GBA):c.1504C>T(R502C, aka R463C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Baylor Genetics RCV000004528 SCV001527534 pathogenic Gaucher disease type I 2018-03-21 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics,Fulgent Genetics RCV001449608 SCV001652788 pathogenic Hereditary late onset Parkinson disease 2021-05-03 criteria provided, single submitter clinical testing
OMIM RCV000004528 SCV000024702 pathogenic Gaucher disease type I 2009-07-01 no assertion criteria provided literature only
OMIM RCV000004529 SCV000024703 pathogenic Gaucher disease type II 2009-07-01 no assertion criteria provided literature only
OMIM RCV000004530 SCV000024704 pathogenic Gaucher disease type III 2009-07-01 no assertion criteria provided literature only
OMIM RCV000004531 SCV000024705 risk factor Parkinson disease, late-onset 2009-07-01 no assertion criteria provided literature only
GeneReviews RCV000020151 SCV000040478 pathologic Gaucher disease 2011-02-01 no assertion criteria provided curation Converted during submission to Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000004528 SCV001422765 pathogenic Gaucher disease type I 2020-01-22 no assertion criteria provided curation The p.Arg502Cys variant in GBA has been reported in at least 17 individuals with Gaucher disease (PMID: 9279145, 24522292, 18586596) and has been identified in 0.011% (14/128876) of European (non-Finnish) chromosomes, 0.010% (3/30616) of South Asian chromosomes, and 0.008% (2/24964) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs80356771). 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: 4295) as pathogenic by EGL Genetic diagnostics, GeneDx, Counsyl, Integrated Genetics, Fulgent Genetics, and OMIM. 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 variant, resulting in a different amino acid change at the same position, p.Arg502His, has been reported in association with disease in the literature and ClinVar, raising the possibility that a change at this position may not be tolerated (PMID: 21070, PMID: 23332636, 17427031, 28727984). The phenotype of an individual homozygous for this variant is highly specific for Gaucher disease based on Beta-glucosidase activity levels below the diagnostic marker of 8.7 nmol/h/mg protein consistent with disease (PMID: 24522292). Additionally, the homozygous occurrence of this variant in 3 individuals with Gaucher disease and the presence of this variant in combination with reported pathogenic variants in 9 individuals with Gaucher disease increases the likelihood that the p.Arg502Cys variant is pathogenic (VariationID: 4290, 4288, 4293; PMID: 9279145, 24522292, 18586596). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on multiple occurrences of the variant in affected individuals and in a homozygous or compound heterozygous state with other pathogenic variants, computational predictions, and the phenotype of a homozygote being highly specific for the disease. ACMG/AMP Criteria applied: PM3_very-strong, PM2_supporting, PP3, PP4 (Richards 2015).

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