ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America 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 2018-07-01 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000589369 SCV000800929 pathogenic not provided 2017-05-10 no assertion criteria provided clinical testing

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