ClinVar Genomic variation as it relates to human health

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM3,PS3,PP5.

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, http://gnomad.broadinstitute.org; 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).

It is unknown if the H294Q variant is disease causing in the absence of the D448H variant; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Previously reported as H255Q using alternative nomenclature; This variant is associated with the following publications: (PMID: 15605411, 25933391, 29980418, 27094865, 32591474, 15690354, 27717005, 21745757, 19459886, 28727984, 18429048, 29699937, 31160058, 29887346, 32623306, 32702516, 32605119, 32618053, 34426522, 32658388, 33473340, 10649495)

PS1, PM1, PM2, PP2, PP5

The c.882T>G (p.H294Q) alteration is located in exon 8 (coding exon 7) of the GBA gene. This alteration results from a T to G substitution at nucleotide position 882, causing the histidine (H) at amino acid position 294 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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.

GBA1: PM3:Strong, PS4:Moderate, PM2:Supporting

The GBA1 c.882T>G variant is predicted to result in the amino acid substitution p.His294Gln. This patient is heterozygous in the GBA gene for a sequence variant designated c.882T>G, which is predicted to result in the amino acid substitution p.His294Gln (also known as H255Q). This variant is commonly reported as part of a non-pseudogene complex allele with c.1342G>C (p.Asp448His, also known as D409H) in cis and another pathogenic variant in trans as causative for Gaucher disease (Filocamo et al. 2005. PubMed ID: 15690354; Miocić et al. 2005. PubMed ID: 15605411; Michelakakis et al. 2006. PubMed ID: 16830265; Santamaria et al. 2008. PubMed ID: 18429048; Kumar et al. 2013. PubMed ID: 22812582). The c.882T>G variant was presumably observed as an isolated variant in trans with the complex recombinant allele frequently described as RecTL or RecC [c.1342G>C; c.1448T>C; c.1448T>C; c1483G>C; c.1497G>C] in one patient with Gaucher disease (Stone et al. 2000. PubMed ID: 10649495). However, at the time of publication of the Stone et. al. report, the c.882T>G variant had not been previously described and was not known to commonly occur as part of complex allele in cis with c.1342G>C. It is therefore not clear in the Stone et. al. report whether the complex genotype of the patient in question was [c.882T>G;c.1342G>C] + [c.1448T>C, c.1483G>C, c.1497G>C] (aka RecNciI) or [c. 882T>G] + [c.1342G>C, c.1448T>C, c.1483G>C, c.1497G>C] (aka RecTL or RecC). In another report, the c.882T>G variant was reported in the compound heterozygous state in a patient with type 1 Gaucher disease, but the presence or absence of the c.1342G>C variant in this patient is not discussed (Karaca et al. 2012. PubMed ID: 23426826). To our knowledge, there are no other reports of the c.882T>G in the homozygous or compound heterozygous state, without c.1342G>C in cis, in patients affected with Gaucher disease. The c.882T>G variant by itself in the heterozygous state, however, has been reported in patients with Parkinson’s disease (Moraitou et al. 2011. PubMed ID: 21745757; Benitez et al. 2016. PubMed ID: 27094865; Kalinderi et al. 2009. PubMed ID: 19383421). Functional studies of GBA enzymatic activity in vitro reveal that the complex allele [c.882T>G; c.1342G>C] is more severely impaired than either c.882T>G or c.1342G>C in isolation, and that c.1342G>C by itself is more severely impaired than c.882T>G (Santamaria et al. 2008. PubMed ID: 18429048), which is consistent with clinical findings. While the non-pseudogene complex allele [c.882T>G; c.1342G>C] is pathogenic, the clinical significance of the c.882T>G variant in isolation is uncertain at this time due to insufficient functional and genetic evidence.