1-155238228-A-G

Position:

chr1-155238228-A-G

Variant summary

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

The NM_000157.4(GBA1):c.667T>C(p.Trp223Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,912 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W223C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

GBA1
NM_000157.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8U:1

Conservation

PhyloP100: 8.10

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 4 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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 1-155238228-A-G is Pathogenic according to our data. Variant chr1-155238228-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 93457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155238228-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBA1	NM_000157.4 linkuse as main transcript	c.667T>C	p.Trp223Arg	missense_variant	6/11	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.667T>C	p.Trp223Arg	missense_variant	6/11	1	NM_000157.4	ENSP00000357357.3		P04062-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251106

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461736

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 19, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2023	Functional studies found that W223R is associated with significantly reduced enzyme activity (PMID: 10757640); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9516376, 25435509, 8889578, 11112377, 18078074, 10679038, 27864021, 16396828, 29198828, 26220978, 16418594, 18070135, 24904648, 30606667, 32658388, 34586679, 17059888, 33301762, 10757640) -
Uncertain significance, flagged submission	clinical testing	Revvity Omics, Revvity	Jun 24, 2022	- -

Gaucher disease

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 27, 2017	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 13, 2020	The p.Trp223Arg variant in GBA has been reported in at least 8 individuals with Gaucher disease (PMID: 17059888, 24801745, 27136700, 10679038, 27864021) and has been Identified in 0.002% (2/111560) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs61748906). 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: 93457) as benign by Prevention Genetics, likely pathogenic by Praxis fuer Humangenetik Tuebingen, and pathogenic by Integrated Genetics and EGL Genetic Diagnostics. In vitro functional studies demonstrating very low glucocerebrosidase activity in mutant hiPSC macrophages provide some evidence that the p.Trp223Arg variant may impact protein function (PMID: 24801745). 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 combination with reported pathogenic variants and in 8 individuals with Gaucher disease increases the likelihood that the p.Trp223Arg variant is pathogenic (VariationID: 4288, 4290, 4293; PMID: 17059888, 24801745, 27136700, 10679038, 27864021). 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 affected individuals, functional studies, and the low frequency of the variant in the general population. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PS3_moderate, PP3 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 30, 2017	Variant summary: The GBA c.667T>C (p.Trp223Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide and it is located in the Glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This was confirmed by functional studies showing abrogated Beta-glucosidase catalytic activity (0.0004 total units of specific activity per cross-reacting immunologic material (CRIM SA) (vs. 1 in control) (Amaral_2000, Awad_2015). This variant was found in 3/112128 control chromosomes at a frequency of 0.0000268, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). This variant was reported in multiple patients with Gaucher disease (Choy_1999, Rozenberg_2006) in which pseudogene interference was ruled out. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.667T>C (p.W223R) alteration is located in exon 7 (coding exon 6) of the GBA gene. This alteration results from a T to C substitution at nucleotide position 667, causing the tryptophan (W) at amino acid position 223 to be replaced by an arginine (R). Based on data from gnomAD, the C allele has an overall frequency of <0.01% (2/251106) total alleles studied. The highest observed frequency was <0.01% (2/113588) of European (non-Finnish) alleles. This alteration, also referred to as p.W184R in the literature, has been reported in the compound heterozygous state with a second mutation in multiple patients with Gaucher disease (Amaral, 2000; Choy, 2000; Rozenberg, 2006; Panicker, 2014; Dimitriou, 2020). This amino acid position is highly conserved in available vertebrate species. Expression studies in Sf9 cells showed very low activity and an essentially inactive protein (Amaral, 2000). Human induced pluripotent stem cells from fibroblasts of an affected patient with this alteration and a second alteration showed low levels of beta-glucocerebrosidase activity and widespread lysosomal depletion and dysfunction (Panicker, 2014; Awad, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Gaucher disease type II;C0268251:Gaucher disease type III;C1961835:Gaucher disease type I

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Benign

0.78

DEOGEN2

Pathogenic

0.99

D;D;.;.

Eigen

Benign

0.017

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.57

.;T;T;T

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

M;M;.;.

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-13

D;D;D;D

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Benign

0.074

T;T;T;T

Polyphen

0.99

D;D;.;.

Vest4

0.95

MutPred

0.90

Gain of disorder (P = 0.0057);Gain of disorder (P = 0.0057);.;.;

MVP

0.94

MPC

2.4

ClinPred

0.83

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.97

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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