1-155237453-C-T

Position:

chr1-155237453-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000157.4(GBA1):c.887G>A(p.Arg296Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000744 in 1,613,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

GBA1
NM_000157.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 5.24

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:

GBA1 (HGNC:):

GBA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000157.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.951

PP5

Variant 1-155237453-C-T is Pathogenic according to our data. Variant chr1-155237453-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBA1	NM_000157.4 linkuse as main transcript	c.887G>A	p.Arg296Gln	missense_variant	7/11	ENST00000368373.8	NP_000148.2	P04062-1A0A068F658

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8 linkuse as main transcript	c.887G>A	p.Arg296Gln	missense_variant	7/11	1	NM_000157.4	ENSP00000357357.3		P04062-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251208

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000780

AC:

114

AN:

1461672

Hom.:

Cov.:

AF XY:

0.0000825

AC XY:

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000980

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 23, 2021	The GBA c.887G>A; p.Arg296Gln variant (rs78973108), also known as Arg257Gln, is reported in the literature in the homozygous and compound heterozygous state in multiple individuals and families affected with Gaucher syndrome (Beutler 1994, Erdos 2007, Kim 2020, Lee 2012, Stone 2000). Functional analyses of the variant protein show a dramatic reduction in GBA enzyme activity (Kim 2020). This variant is also reported in ClinVar (Variation ID: 4328). This variant is found in the general population with an overall allele frequency of 0.004% (10/282590 alleles) in the Genome Aggregation Database. The arginine at codon 296 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.942). Based on available information, this variant is considered to be pathogenic. References: Beutler E et al. Glucocerebrosidase mutations in Gaucher disease. Mol Med. 1994 Nov;1(1):82-92. PMID: 8790604. Erdos M et al. Genetic and clinical features of patients with Gaucher disease in Hungary. Blood Cells Mol Dis. 2007 Jul-Aug;39(1):119-23. PMID: 17395504. Kim YM et al. The GBA p.G85E mutation in Korean patients with non-neuronopathic Gaucher disease: founder and neuroprotective effects. Orphanet J Rare Dis. 2020 Nov 11;15(1):318. PMID: 33176831. Lee JY et al. Clinical and genetic characteristics of Gaucher disease according to phenotypic subgroups. Korean J Pediatr. 2012 Feb;55(2):48-53. PMID: 22375149. Stone DL et al. Type 2 Gaucher disease: the collodion baby phenotype revisited. Arch Dis Child Fetal Neonatal Ed. 2000 Mar;82(2):F163-6. PMID: 10685993. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 11, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2021	Identified in the heterozygous state in patients with Parkinson disease (Neumann et al., 2009; Choi et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Previously reported as R257Q due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 33176831, 27312774, 12791040, 21704274, 10796875, 19286695, 17395504, 21384230, 22772462, 10685993, 8790604, 22387070, 26709268, 29091352, 28506293, 30764785, 27717005) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 14, 2021	In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic (PMID: 33176831, 17395504, 21384230, 28506293, 20729108, 21704274, 32822875, 8790604, 32547927, 30764785, 10685993, 25435509). This variant segregates with disease with disease in multiple families (PMID: 8301495, 29091352). The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). Computational tools yielded predictions that this amino acid change may be damaging to the protein.This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -

Gaucher disease

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 25, 2018	Variant summary: GBA c.887G>A (p.Arg296Gln) results in a conservative amino acid change located in the glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 276952 control chromosomes (gnomAD). c.887G>A has been reported in the literature in multiple individuals affected with Gaucher Disease (Alfonso 2007, Erdos 2007, Lee 2012, Lopez 2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Lee 2012). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 16, 2017	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 14, 2020	The p.Arg296Gln variant in GBA has been reported in at least 15 individuals with Gaucher disease (PMID: 17395504, 20729108, 21384230, 25435509, 29091352, 30764785, 21704274) and has been identified in 0.008% (2/24970) of African chromosomes and 0.006% (8/128908) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs78973108). 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: 4328) as Pathogenic by EGL Genetic Diagnostics, GeneDx, Fulgent Genetics, OMIM, and Integrated Genetics. In vitro functional studies demonstrating nearly undetectable levels of beta-glucosidase in patient fibroblasts provide some evidence that the p.Arg296Gln variant may impact protein function (PMID: 29091352). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in one affected homozygote and in combination with reported pathogenic variants in 11 individuals with Gaucher disease increases the likelihood that the p.Arg296Gln variant is pathogenic (VariationID: 4290, 4321, 4296, 93459, 4301, 4288 PMID: 17395504, 20729108, 21384230, 25435509, 29091352). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the presence of the variant in combination with other pathogenic variants in many individuals, in vitro functional studies, and computational evidence. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PS3_moderate, PP3 (Richards 2015). -
not provided, no classification provided	literature only	GeneReviews	-	- -

Gaucher disease type I

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 21, 2023	The GBA c.887G>A (p.Arg296Gln) missense variant, also referred to as p.Arg257Gln, has been identified in individuals with Gaucher disease. In the majority of affected indivduals, the variant was found in a compound heterozygous state with a second missense variant. In one individual it was found in a compound heterozygous state with a 55 bp deletion and in another in a homozygous state (PMID: 17395504; PMID: 20729108; PMID: 25435509). This variant is reported in the Genome Aggregation Database in eight alleles at a frequency of 0.000062 in the European (non-Finnish) population (version 2.1.1). Functional evidence demonstrated that this variant impacts protein function (PMID: 29091352). Multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the available evidence, the c.887G>A (p.Arg296Gln) variant is classified as pathogenic for Gaucher disease. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Gaucher disease (MIM# 230800, 230900, 231000, 231005, 608013). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Gaucher disease is associated with marked clinical variability, even within the same family (PMID: 31010158). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glycosyl hydrolase family 30 TIM-barrel domain (NCBI). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in multiple individuals with Gaucher disease (ClinVar, PMID: 33176831). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Parkinson disease, late-onset

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 03, 2021

- -

Gaucher disease type II;C0268251:Gaucher disease type III;C0752347:Lewy body dementia;C1842704:Gaucher disease perinatal lethal;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I;C3160718:Parkinson disease, late-onset

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Gaucher disease type II;C0268251:Gaucher disease type III;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

GBA1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Feb 09, 2024

PS3, PM3_Strong, PP3 -

Gaucher disease perinatal lethal

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D;.;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

.;D;D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

M;M;.;.

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.6

D;D;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0090

D;D;D;D

Sift4G

Uncertain

0.025

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.80

MVP

0.96

MPC

2.0

ClinPred

0.92

GERP RS

3.5

Varity_R

0.96

gMVP

0.93

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