rs367968666

Positions:

chr1-155237458-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP5BP4

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:6U:9B:1O:2

Conservation

PhyloP100: 0.0990

Variant links:

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]

GBA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {not_provided=1, Likely_pathogenic=3, Likely_benign=1, Pathogenic=2, Uncertain_significance=7, 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 linkuse as main transcript	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 linkuse as main transcript	c.882T>G	p.His294Gln	missense_variant	7/11	1	NM_000157.4	P1	P04062-1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

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:

AN:

251214

Hom.:

AF XY:

0.000287

AC XY:

AN XY:

135774

show subpopulations

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.:

Cov.:

AF XY:

0.000215

AC XY:

156

AN XY:

727150

show subpopulations

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:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74474

show subpopulations

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.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000280

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity; other

Submissions summary: Pathogenic:6Uncertain:9Benign:1Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:2Benign:1Other:1

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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	GBA1: PM3:Strong, PS4:Moderate, PM2:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 23, 2020	- -
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).
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 10, 2017	- -
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	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. -
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. -

Gaucher disease

Uncertain:2Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
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	- -

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. -

GBA1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 30, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Uncertain

0.66

D;D;.;.

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.82

.;T;T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.15

T;T;T;T

MetaSVM

Uncertain

0.00030

MutationAssessor

Benign

0.015

N;N;.;.

MutationTaster

Benign

0.51

D;D;D;N;N

PrimateAI

Benign

0.38

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over