1-155235196-G-A

Position:

chr1-155235196-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000157.4(GBA1):c.1504C>T(p.Arg502Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,612,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R502H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000073 ( 0 hom., cov: 25)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

GBA1
NM_000157.4 missense, splice_region

Scores

Splicing: ADA: 0.6296

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:23O:2

Conservation

PhyloP100: 1.05

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 Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-155235195-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

PP5

Variant 1-155235196-G-A is Pathogenic according to our data. Variant chr1-155235196-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4 linkuse as main transcript	c.1504C>T	p.Arg502Cys	missense_variant, splice_region_variant	10/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8 linkuse as main transcript	c.1504C>T	p.Arg502Cys	missense_variant, splice_region_variant	10/11	1	NM_000157.4	P1	P04062-1

Frequencies

GnomAD3 genomes

AF:

0.0000728

AC:

AN:

151108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000731

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000717

AC:

AN:

251166

Hom.:

AF XY:

0.0000958

AC XY:

AN XY:

135744

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:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000246

AC:

359

AN:

1461270

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

196

AN XY:

726950

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000308

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000728

AC:

AN:

151108

Hom.:

Cov.:

AF XY:

0.0000679

AC XY:

AN XY:

73672

show subpopulations

Gnomad4 AFR

AF:

0.0000731

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000154

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gaucher disease type I

Pathogenic:7

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 05, 2021	The GBA c.1504C>T (p.Arg502Cys) variant is a missense variant, also described in the literature as p.Arg463Cys, and is associated with Gaucher disease (GD). Across a selection of the available literature, the p.Arg502Cys variant is reported in a homozygous state in two individuals with GD, and in a compound heterozygous state in 37 individuals with GD patients (Hatton et al. 1997; Koprivica et al. 2000; Emre et al 2008; Huang et al. 2020). The phenotypes and age of onset in affected individuals is variable and includes type 1 and type 3 Gaucher disease. The p.Arg502Cys variant is reported at a frequency of 0.000118 in the European (non-Finnish) population of the Genome Aggregation Database (version 3.1.1). In vitro functional studies have demonstrated reduced enzymatic activity for the p.Arg502Cys variant protein compared to wild-type (Grace et al. 1994). Based on the evidence, the p.Arg502Cys variant is classified as pathogenic for Gaucher disease. -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jul 30, 2022	A homozygous missense variation in exon 10 of the GBA gene that results in the amino acid substitution of Argenine for Cytosine at codon502 was detected. The observed variant c.1504C>T (p.Arg502Cys) has not been reported in the 1000 genomes and has a MAF of 0.007% in the gnomAD databases. The in silico prediction of the variant is by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 10, 2019	NM_001005741.2(GBA):c.1504C>T(R502C, aka R463C) is classified as pathogenic in the context of Gaucher disease, and can be associated with Type 1, 2, or 3 of the disease. Sources cited for classification include the following: PMID 24522292, 12595585, 1348297, 1972019, 24482953, 18586596, 1704891, 8294487, 8118463 and 9279145. Classification of NM_001005741.2(GBA):c.1504C>T(R502C, aka R463C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Nov 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 21, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg502Cys variant in GBA has been reported in at least 17 individuals with Gaucher disease (PMID: 9279145, 24522292, 18586596) and has been identified in 0.011% (14/128876) of European (non-Finnish) chromosomes, 0.010% (3/30616) of South Asian chromosomes, and 0.008% (2/24964) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs80356771). 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: 4295) as pathogenic by EGL Genetic diagnostics, GeneDx, Counsyl, Integrated Genetics, Fulgent Genetics, and OMIM. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional variant, resulting in a different amino acid change at the same position, p.Arg502His, has been reported in association with disease in the literature and ClinVar, raising the possibility that a change at this position may not be tolerated (PMID: 21070, PMID: 23332636, 17427031, 28727984). The phenotype of an individual homozygous for this variant is highly specific for Gaucher disease based on Beta-glucosidase activity levels below the diagnostic marker of 8.7 nmol/h/mg protein consistent with disease (PMID: 24522292). Additionally, the homozygous occurrence of this variant in 3 individuals with Gaucher disease and the presence of this variant in combination with reported pathogenic variants in 9 individuals with Gaucher disease increases the likelihood that the p.Arg502Cys variant is pathogenic (VariationID: 4290, 4288, 4293; PMID: 9279145, 24522292, 18586596). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on multiple occurrences of the variant in affected individuals and in a homozygous or compound heterozygous state with other pathogenic variants, computational predictions, and the phenotype of a homozygote being highly specific for the disease. ACMG/AMP Criteria applied: PM3_very-strong, PM2_supporting, PP3, PP4 (Richards 2015). -

Gaucher disease

Pathogenic:5Other:1

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. The 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 cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (19 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 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 beta sandwich domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is also known as p.(Arg463Cys) in the literature. It has previously been reported in >20 Gaucher disease type 1 and 3 patients, however the phenotypic consequence of this variant has been suggested as being particularly inconsistent (ClinVar, PMIDs: 10796875; 33334373; 30764785). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies demonstrated that this variant results in reduced GBA enzymatic activity (PMID: 11259172). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 08, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 25, 2017	Variant summary: The GBA c.1504C>T (p.Arg502Cys) variant involves the alteration of a non-conserved nucleotide, resulting in a missense change within the glycosyl hydrolase family 30, beta sandwich domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 7/121382 control chromosomes at a frequency of 0.0000577, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). The variant has been identified in numerous patients with Gaucher disease type I and type III, both as a compound heterozygous and homozygous allele. The variant is considered a recurrent mutation and has been associated with mild and severe Gaucher-related phenotypes in patients. Functional studies showed a significant reduction in enzyme activity (Grace_1994). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant is also known as p.Arg463Cys in the literature (PMID: 23588557). This variant has been previously reported as a compound heterozygous change most commonly in patients with Gaucher disease, but also among patients with Parkinson disease and renal cell carcinoma (PMID: 1972019, 24482953, 8733893, 17427031, 21704274, 29625052, 30537300). Functional studies indicate that this variant impairs the GBA enzyme activity (PMID: 11259172, 8294487). The frequency data for variants in the GBA gene in population databases may be unreliable due to the presence of pseudogenes and paralogs (PMID: 20301446). In silico analyses support a deleterious effect of the c.1504C>T (p.Arg502Cys) variant on protein function. Based on the available evidence, the c.1504C>T (p.Arg502Cys) variant is classified as Pathogenic. -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2022	Published functional studies demonstrate that R502C has reduced enzyme activity (Hong et al., 1990; Grace et al., 1994); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Previously reported as R463C due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 12595585, 30537300, 10796875, 23413260, 22975760, 23588557, 24482953, 16293621, 8294487, 1972019, 1348297, 19286695, 27717005, 29140481, 8733893, 26008600, 9279145, 29625052, 34426522, 32658388) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 502 of the GBA protein (p.Arg502Cys). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individuals with Gaucher disease and Parkinson's disease (PMID: 1972019, 8733893, 17427031, 21704274, 24482953). This variant is also known as p.Arg463Cys or R463C. ClinVar contains an entry for this variant (Variation ID: 4295). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GBA function (PMID: 8294487, 11259172). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 23, 2021	The GBA c.1504C>T; p.Arg502Cys variant (rs80356771), also known as Arg463Cys, is reported in the literature in the homozygous and compound heterozygous state in multiple individuals affected with Gaucher syndrome (Alfonso 2007, Chauhan 2013, Hatton 1997, Tayebi 1996). Functional analyses of the variant protein show a dramatic reduction in GBA enzyme activity (Grace 1994, Liou 2006). This variant is also reported in ClinVar (Variation ID: 4295). This variant is found in the non-Finnish European population with an allele frequency of 0.011% (14/128876 alleles) in the Genome Aggregation Database. The arginine at codon 502 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.817). Additionally, other amino acid substitutions at this codon (His, Pro, Cys, Gln, Ser) have been reported in individuals with Gaucher syndrome (Alfonso 2007, Liou 2006, Beutler 1994, Jurecka 2011). Based on available information, this variant is considered to be pathogenic. References: Alfonso P et al. Mutation analysis and genotype/phenotype relationships of Gaucher disease patients in Spain. J Hum Genet. 2007;52(5):391-396.PMID: 17427031. Beutler E et al. Glucocerebrosidase mutations in Gaucher disease. Mol Med. 1994 Nov;1(1):82-92. PMID: 8790604. Chauhan V et al. Adult type 3 Gaucher disease as manifestation of R463C/Rec Nci I mutation: first reported case in the world literature. J Assoc Physicians India. 2013 May;61(5):346-8. PMID: 24482953. Grace ME et al. Analysis of human acid beta-glucosidase by site-directed mutagenesis and heterologous expression. J Biol Chem. 1994 Jan 21;269(3):2283-91. PMID: 8294487. Hatton CE et al. Mutation analysis in 46 British and Irish patients with Gaucher's disease. Arch Dis Child. 1997 Jul;77(1):17-22. PMID: 9279145. Jurecka A et al. Gaucher disease and dysgammaglobulinemia: a report of 61 patients, including 18 with GD type III. Blood Cells Mol Dis. 2011 Jan 15;46(1):85-7. PMID: 20729110. Liou B et al. Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations. J Biol Chem. 2006 Feb 17;281(7):4242-53. PMID: 16293621. Tayebi N et al. Genotype D399N/R463C in a patient with type 3 Gaucher disease previously assigned genotype N370S/R463C. Biochem Mol Med. 1996 Apr;57(2):149-51. PMID: 8733893. -

Parkinson disease, late-onset

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 03, 2021	- -
risk factor, no assertion criteria provided	literature only	OMIM	Jul 01, 2009	- -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2015

The p.R502C pathogenic mutation (also known as c.1504C>T and p.R463C in the literature), located in coding exon 10 of the GBA gene, results from a C to T substitution at nucleotide position 1504. The arginine at codon 502 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was originally identified in combination with p.L444P in a non-Jewish patient with Gaucher disease type 1 and results in a significant reduction of normal enzyme activity (Hong CM et al. DNA Cell Biol. 1990;9(4):233-241) This mutation was also observed in 10 patients, 9 of whom were non-Ashkenazi Jewish, and affected with either Gaucher disease type 1 or type 3 (subacute nueronopathic type) (Koprivica V, Am. J. Hum. Genet. 2000 Jun; 66(6):1777-86). Another functional study found this mutation inactivated the enzyme function completely by rapid degredation (Liou B, J. Biol. Chem. 2006 Feb; 281(7):4242-53). Based on the supporting evidence, p.R502C is interpreted as a disease-causing mutation. -

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

Dec 01, 2021

- -

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

- -

Gaucher disease type II

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2009

- -

Gaucher disease type III

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;D;.;.

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.83

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;M;.;.

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.3

D;D;D;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0090

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.90

MVP

0.91

MPC

1.9

ClinPred

0.71

GERP RS

2.1

Varity_R

0.81

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.63

dbscSNV1_RF

Benign

0.60

SpliceAI score (max)

0.0

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