rs367968666
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP5BP4
The NM_000157.4(GBA1):āc.882T>Gā(p.His294Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,613,960 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars).
Frequency
Consequence
NM_000157.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GBA1 | NM_000157.4 | c.882T>G | p.His294Gln | missense_variant | 7/11 | ENST00000368373.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GBA1 | ENST00000368373.8 | c.882T>G | p.His294Gln | missense_variant | 7/11 | 1 | NM_000157.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000171 AC: 26AN: 152164Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000239 AC: 60AN: 251214Hom.: 0 AF XY: 0.000287 AC XY: 39AN XY: 135774
GnomAD4 exome AF: 0.000180 AC: 263AN: 1461678Hom.: 1 Cov.: 33 AF XY: 0.000215 AC XY: 156AN XY: 727150
GnomAD4 genome ? AF: 0.000171 AC: 26AN: 152282Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 12AN XY: 74474
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:2Benign:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 23, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 10, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 03, 2022 | 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) - |
other, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 04, 2018 | - Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles). |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | GBA1: PM3:Strong, PS4:Moderate, PM2:Supporting - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
Gaucher disease type I Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 10, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Sep 28, 2022 | PS1, PM1, PM2, PP2, PP5 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
not specified Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 18, 2022 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 21, 2024 | 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. - |
Gaucher disease Uncertain:2Other:1
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 14, 2020 | 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). - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | May 09, 2018 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Gaucher disease type II;C0268251:Gaucher disease type III;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Gaucher disease perinatal lethal Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM3,PS3,PP5. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at