ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.882T>G (p.His294Gln) (rs367968666)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589369 SCV000697597 uncertain significance not provided 2016-07-28 criteria provided, single submitter clinical testing Variant summary: The GBA c.882T>G (p.His294Gln) variant, alternatively reported as H255Q, involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant was found in 35/122696 control chromosomes at a frequency of 0.0002853, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). This variant is commonly reported in patients with Gaucher disease as a part of complex allele p.[D448H;H294Q]in trans with a known pathogenic mutation. The D448H variant has frequently been reported as an isolated mutation, and its presence in homozygous status has been associated with a less severe phenotype than that observed in the p.[D448H;H294Q] double mutant. The c.881T>G was presumably identified in isolation 1 GD pt, however it is suspected that this pt had a complex genotype [D448H;H294Q]+[RecNciI] instead of [H294Q]+[RecC] that has been initially reported by Stone (2000). A few instances of H294Q variant in isolation has been reported in Parkinsons disease patients (Kalinderi_2009, Benitez_2016). In the expression studies, constructs bearing the H294Q in isolation retained a significant residual enzymatic activity (~ 56.4% and ~76% of the wild type value in two studies, respectively) (Santamaria_2008, Snchez-Oll_2009). The same studies reported that D448H mutant severely reduces the enzymatic activity. Thus D448H could be the driver mutation in the complex allele. Further, one of those studies showed that the double mutant p.[D448H;H294Q] causes more pronounced functional impairment than p.D448H mutant alone (Santamaria_2008), suggesting that the H294Q could be a modifier of D488H variant which is consistent with clinical findings. Another alteration of the same nucleotide, c.882T>A, leads to the same amino acid change (p.His 294Gln). Since no pts homozygous for c.882T>G or in compound heterozygosity with a known pathogenic mutations without D448H in cis, have been reported in the literature, the pathogenicity of the H255Q variant by itself requires further investigatio and additional information needed to classify this variant with confidence. Taking together, the variant was classified as VUS until more information becomes available.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000589369 SCV000854790 other not provided 2018-05-04 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000589369 SCV000891857 uncertain significance not provided 2019-11-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004126 SCV001162857 likely pathogenic Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease type 3C criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001195955 SCV001366382 pathogenic Gaucher disease, perinatal lethal 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM3,PS3,PP5.
Baylor Genetics RCV001329068 SCV001520377 likely pathogenic Gaucher disease type I 2020-07-09 criteria provided, single submitter clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Nilou-Genome Lab RCV001329068 SCV001737355 likely pathogenic Gaucher disease type I 2021-06-10 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000589369 SCV000800929 pathogenic not provided 2017-05-10 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001248861 SCV001422530 uncertain significance Gaucher disease 2020-01-14 no assertion criteria provided curation The p.His294Gln variant in GBA has been reported in at least 34 individuals with Gaucher disease (PMID: 19459886, 18429048, 25435509, 26847548) and has been identified in 0.058% (6/10370) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs367968666). 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: 242810) as a VUS by Integrated Genetics and Praxis fuer Humangenetik Tuebingen and as pathogenic by Mayo Clinic Genetic Testing Laboratories. Computational prediction tools do not provide strong support for or against an impact to the protein. The His at position 294 is not highly conserved in mammals and evolutionary distant species, and 16 species (Chinese hamster, the golden hamster, and most birds) carry a Gln, raising the possibility that this change at this position may be tolerated. This variant was found exclusively in cis with another pathogenic variant, suggesting that it may not cause disease independently (PMID: 19459886, 18429048, 25435509, 26847548; Variation ID: 4293). In vitro functional studies provide some evidence that the p.His294Gln variant may not independently impact protein function. Additionally, this variant is shown to further decrease the residual activity of the p.Asp448His variant when the variants are on the same allele, suggesting that the variant may increase disease severity when in cis with the pathogenic p.Asp448His variant (PMID: 18429048). However, these types of assays may not accurately represent biological function. In summary, while the clinical significance of the p.His294Gln variant is uncertain, these data suggest that it is more likely to be benign but is expected to increase disease severity as part of the complex allele [p.Asp448His;p.His294Glln]. ACMG/AMP Criteria applied: BS3, BP2, PM2 (Richards 2015).

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