Description
Variant summary: GBA1 c.882T>G (p.His294Gln) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 1613960 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in GBA1 causing Gaucher Disease (0.00018 vs 0.005), allowing no conclusion about variant significance. c.882T>G (also known as H255Q) is commonly reported in patients with Gaucher disease as a part of complex allele (examples: Miocic_2005, Santamaria_2008, Kumar_2013, Kumar_2013, Gragnaniello_2023). A few instances of H294Q variant in isolation has been reported in Parkinsons disease patients (Kalinderi_2009, Benitez_2016, Palomba_ 2023). 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) (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. The following publications have been ascertained in the context of this evaluation (PMID: 10649495, 15605411, 18429048, 21745757, 22812582, 19383421, 27094865, 37009750, 36609826, 19167250). ClinVar contains an entry for this variant (Variation ID: 242810). Based on the evidence outlined above, the variant was classified as uncertain significance.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
