rs747506979

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM5PP3PP5_Very_Strong

The NM_000157.4(GBA1):c.1603C>T(p.Arg535Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R535H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 11)

Exomes 𝑓: 0.0000073 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GBA1
NM_000157.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 3.06

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 11 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-155235002-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.816

PP5

Variant 1-155235003-G-A is Pathogenic according to our data. Variant chr1-155235003-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 242383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBA1	NM_000157.4 link	c.1603C>T	p.Arg535Cys	missense_variant	Exon 11 of 11	ENST00000368373.8	NP_000148.2	P04062-1A0A068F658

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8 link	c.1603C>T	p.Arg535Cys	missense_variant	Exon 11 of 11	1	NM_000157.4	ENSP00000357357.3		P04062-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

91008

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000116

AC:

AN:

172274

Hom.:

AF XY:

0.0000109

AC XY:

AN XY:

91600

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000389

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000412

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000728

AC:

AN:

686718

Hom.:

Cov.:

AF XY:

0.00000844

AC XY:

AN XY:

355634

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000304

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000311

Gnomad4 SAS exome

AF:

0.0000503

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

91008

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

41426

Gnomad4 AFR

AF:

0.00

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:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000171

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gaucher disease type I

Pathogenic:2

Jun 10, 2016

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

USG abdomen s/o. storage disease; Bone-marrow s/o. Storage disease; Anaemia (Hb: 8.6 g%); Plasma Chitotriosidase: 11755.7 nmol/hr/ml plasma (N.R.: 28.66 - 62.94); Beta-Glucosidase: 1.45 nmol/hr/mg protein (N.R.: 4.0 - 32.0) -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg535Cys variant in GBA has been reported at least 10 individuals with Gaucher disease (PMID: 27865684, 30637984, 30764785) and has been identified in 0.004% (1/24272) of South Asian chromosomes and 0.004% (1/25702) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs747506979). 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: 242383) as likely pathogenic by the Institute of Human Genetics. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg535His, has been reported in association with the disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 17059888, 24756352, 17427031, 20629126, 7655857, 28947706, 23430543, 8432537; VariationID: 4311). The phenotype of an individual compound heterozygous for this variant is highly specific for Gaucher disease based on the levels of beta-glucosidase detected in the BGL test being significantly below 8.7 nmol/mg/h consistent with disease (PMID: 27865684). Additionally, the homozygous occurrence of this variant in two affected individuals and the presence of this variant in combination with reported pathogenic variants (VariationID: 4288, 4295, 4290; PMID: 30764785, 27865684, 30637984) and in five individuals with Gaucher disease increases the likelihood that the p.Arg535Cys variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the detection of the variant in combination with other pathogenic variants in affected individuals, the presence of another pathogenic variant at the same location, and the presence of the variant in an individual with a phenotype specific for the disease. ACMG/AMP Criteria applied: PM3_very-Strong, PM2, PM5, PP4 (Richards, 2015). -

not provided

Pathogenic:2

Sep 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs747506979, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 535 of the GBA protein (p.Arg535Cys). This missense change has been observed in individual(s) with Gaucher disease and/or Parkinson's disease (PMID: 1487244, 24522292, 28727984, 29140481). This variant is also known as p.Arg496Cys or R496C. ClinVar contains an entry for this variant (Variation ID: 242383). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GBA protein function. This variant disrupts the p.Arg535 amino acid residue in GBA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16293621, 27735925). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jun 01, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gaucher disease

Pathogenic:2

Mar 01, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GBA c.1603C>T (p.Arg535Cys) also widely reported as p.Arg496Cys, results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 172274 control chromosomes. c.1603C>T has been well reported in the literature in multiple individuals from diverse ethnicities affected with Gaucher Disease (example, Kawame_1992, Karaca_2012, Ankleshwaria_2014 and Feng_2018). These data indicate that the variant is very likely to be associated with disease. No experimental evidence demonstrating an impact on protein function was ascertained. Although at-least one publication reported its identification in a enzymatically and clinically diagnosed Gaucher disease homozygous individual with no primary data provided (Kawame_1992). One researcher has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. This submitter cites an overlapping publication utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -

May 04, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Parkinson disease, late-onset

Pathogenic:1

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.1603C>T(p.Arg535Cys) in GBA gene has been reported previously in homozygous, compound heterozygous and heterozygous state in individuals with Gaucher disease and/or Parkinson's disease (Dimitriou E, et al., 2020. Sheth J, et al., 2019, Ankleshwaria C, et al., 2014). This variant disrupts the p.Arg535 amino acid residue in GBA and the other variant(s) that disrupt this residue have been determined to be pathogenic (Yang AC, et al., 2017). The c.1603C>T variant has 0.001% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic / Likely Pathogenic.The amino acid Arginine at position 535 is changed to a Cystiene changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen, SIFT and MutationTaster) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Arg535Cys in GBA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Gaucher disease type II

Pathogenic:1

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.1603C>T(p.Arg535Cys) variant in GBA gene has been reported previously in homozygous and compound heterozygous states in multiple individuals affected with Gaucher disease (Sheth J, et al., 2019, Leija-Salazar M, et al., 2019; Zampieri S, et al., 2017). The p.Arg535Cys variant is present with allele frequency of 0.001% in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position on GBA gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 535 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. Another missense variant [c.1604G>A (p.Arg535His)] on the same residue of this gene has previously been reported to be disease causing (Yang AC, et al., 2017), suggesting that this residue might be of clinical significance. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;D;.;.

Eigen

Benign

0.066

Eigen_PC

Benign

0.0045

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.96

.;D;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.82

D;D;D;D

MetaSVM

Uncertain

0.73

MutationAssessor

Benign

0.81

L;L;.;.

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.7

D;D;D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0070

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.77

MVP

0.91

MPC

2.1

ClinPred

0.79

GERP RS

3.2

Varity_R

0.53

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

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