rs367968666

Positions:

• chr1-155237458-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP5 BP4

The NM_000157.4(GBA1):​c.882T>G​(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:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:6 U:8 B:1 O:2
• Conservation: PhyloP100: 0.0990

Genes affected

GBA1 (HGNC:4177): (glucosylceramidase beta 1) This gene encodes a lysosomal membrane protein that cleaves the beta-glucosidic linkage of glycosylceramide, an intermediate in glycolipid metabolism. Mutations in this gene cause Gaucher disease, a lysosomal storage disease characterized by an accumulation of glucocerebrosides. A related pseudogene is approximately 12 kb downstream of this gene on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000157.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-155237458-A-C is Pathogenic according to our data. Variant chr1-155237458-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity, other]. Clinvar id is 242810.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_benign=1, Likely_pathogenic=3, Uncertain_significance=7, not_provided=1, other=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14616036). . Strength limited to SUPPORTING due to the PP5.

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: 26 AN: 152164 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000239 AC: 60 AN: 251214 Hom.: 0 AF XY: 0.000287 AC XY: 39 AN XY: 135774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000180 AC: 263 AN: 1461678 Hom.: 1 Cov.: 33 AF XY: 0.000215 AC XY: 156 AN XY: 727150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000161

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152282 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 12 AN XY: 74474

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.000159

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000327

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity; other

Submissions summary: Pathogenic:6 Uncertain:8 Benign:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:2 Benign:1 Other: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:2 Uncertain: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:2 Other: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	13
DANN	Benign	0.82
DEOGEN2	Uncertain	0.66	D;D;.;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.50	N
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Uncertain	0.00030	D
MutationAssessor	Benign	0.015	N;N;.;.
MutationTaster	Benign	0.51	D;D;D;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.070	N;N;N;N
REVEL	Uncertain	0.61
Sift	Benign	0.60	T;T;T;T
Sift4G	Benign	0.59	T;T;T;T
Polyphen		0.0020	B;B;.;.
Vest4		0.16
MutPred		0.58		Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;.;
MVP		0.83
MPC		0.76
ClinPred		0.010	T
GERP RS		1.6
Varity_R		0.28
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs367968666; hg19: chr1-155207249;