ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.887G>A (p.Arg296Gln) (rs78973108)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000079357 SCV000232587 pathogenic not provided 2015-09-11 criteria provided, single submitter clinical testing
GeneDx RCV000079357 SCV000321701 pathogenic not provided 2021-08-04 criteria provided, single submitter clinical testing Identified in the heterozygous state in patients with Parkinson disease (Neumann et al., 2009; Choi et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Previously reported as R257Q due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 33176831, 27312774, 12791040, 21704274, 10796875, 19286695, 17395504, 21384230, 22772462, 10685993, 8790604, 22387070, 26709268, 29091352, 28506293, 30764785, 27717005)
Fulgent Genetics,Fulgent Genetics RCV000762855 SCV000893215 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020159 SCV000917433 pathogenic Gaucher disease 2018-09-25 criteria provided, single submitter clinical testing Variant summary: GBA c.887G>A (p.Arg296Gln) 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 3.2e-05 in 276952 control chromosomes (gnomAD). c.887G>A has been reported in the literature in multiple individuals affected with Gaucher Disease (Alfonso 2007, Erdos 2007, Lee 2012, Lopez 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. The most pronounced variant effect results in 10%-<30% of normal activity (Lee 2012). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV001004125 SCV001162856 pathogenic Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease type 3C criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV001449614 SCV001652794 pathogenic Hereditary late onset Parkinson disease 2021-05-03 criteria provided, single submitter clinical testing
OMIM RCV000004573 SCV000024747 pathogenic Gaucher disease, perinatal lethal 2000-03-01 no assertion criteria provided literature only
GeneReviews RCV000020159 SCV000040486 pathologic Gaucher disease 2011-02-01 no assertion criteria provided curation Converted during submission to Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000020159 SCV001422531 pathogenic Gaucher disease 2020-01-14 no assertion criteria provided curation The p.Arg296Gln variant in GBA has been reported in at least 15 individuals with Gaucher disease (PMID: 17395504, 20729108, 21384230, 25435509, 29091352, 30764785, 21704274) and has been identified in 0.008% (2/24970) of African chromosomes and 0.006% (8/128908) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs78973108). 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: 4328) as Pathogenic by EGL Genetic Diagnostics, GeneDx, Fulgent Genetics, OMIM, and Integrated Genetics. In vitro functional studies demonstrating nearly undetectable levels of beta-glucosidase in patient fibroblasts provide some evidence that the p.Arg296Gln variant may impact protein function (PMID: 29091352). 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 11 individuals with Gaucher disease increases the likelihood that the p.Arg296Gln variant is pathogenic (VariationID: 4290, 4321, 4296, 93459, 4301, 4288 PMID: 17395504, 20729108, 21384230, 25435509, 29091352). 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 many individuals, in vitro functional studies, and computational evidence. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PS3_moderate, PP3 (Richards 2015).

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