chr1-155238174-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000157.4(GBA1):c.721G>A(p.Gly241Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000031 in 1,614,020 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G241E) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

GBA1
NM_000157.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11U:1

Conservation

PhyloP100: 5.20

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.

PM1

In a hotspot region, there are 4 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

PP5

Variant 1-155238174-C-T is Pathogenic according to our data. Variant chr1-155238174-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 93459.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.721G>A	p.Gly241Arg	missense_variant	Exon 6 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.721G>A	p.Gly241Arg	missense_variant	Exon 6 of 11	1	NM_000157.4	ENSP00000357357.3		P04062-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152134

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251482

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6Uncertain:1

May 14, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 12204005, 22429443, 32822875, 32547927, 22964618, 29934114, 11259172, 24022302, 10744424, 29091352, 22247978, 23430543, 8790604). This variant segregates with disease in multiple families (PMID: 29091352, 29934114, 9153297). The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). Assessment of experimental evidence is inconclusive and computational tools yielded discordant predictions regarding the effect of this variant on protein function (PMID: 11259172, 25084554).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. -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GBA1: PM3:Very Strong, PM2, PM5 -

Apr 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 241 of the GBA protein (p.Gly241Arg). 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 individual(s) with Gaucher disease and/or Parkinson's disease (PMID: 12204005, 22173904, 22247978, 23430543, 26117366, 29091352). This variant is also known as p.Gly202Arg or G202R. ClinVar contains an entry for this variant (Variation ID: 93459). 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. Experimental studies have shown that this missense change affects GBA function (PMID: 9153297). This variant disrupts the p.Gly241 amino acid residue in GBA. Other variant(s) that disrupt this residue have been observed in individuals with GBA-related conditions (PMID: 10744424), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Dec 06, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 21, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 21, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 26792850); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(G202R); This variant is associated with the following publications: (PMID: 28727984, 27789132, 11783951, 25188399, 27816428, 27836528, 24022302, 22173904, 18078074, 29091352, 34779914, 34820281, 33301762, 34867278, 19830760, 22247978, 26792850, 27872820, 12204005, 23430543, 9516376, 22623374, 22964618, 17427031, 11259172, 8790604, 30461613, 31996268, 34426522, 31589614, 32677286, 32618053, 32658388, 34308104, 22429443, 33176831, 29934114, 26117366, 37432431, 37198191, 35861376, 36097244) -

Gaucher disease

Pathogenic:2

May 08, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The GBA c.721G>A (p.Gly241Arg) variant (alternatively also known as G202R) involves the alteration of a conserved nucleotide, is located in TIM-barrel domain of the protein (InterPro) and 2/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/121276 control chromosomes from ExAC at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). This variant has been found in several patients with GD mainly from Europe in compound heterozygous state with other known pathogenic variants as well as in homozygous state, including an evidence of cosegregation with disease. In an Italian study, this variant was the third most common pathogenic variant (Filocamo_2002). In vitro functional studies show that this variant leads to severely compromised enzymatic activity and/or trafficking (Grace_1997, Torralba_2001, review by Yu_2009). The functional outcome coupled with severe phenotype (type 2 GD) in patients carrying this variant in homozygous state indicates that it could be a severe mutation. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

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.Gly241Arg variant in GBA has been reported in at least 13 individuals with Gaucher disease (PMID: 22429443, 24022302, 11259172) and has been identified in 0.012% (2/16254) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs409652). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Trio analysis showed this variant to be de novo in one individual (PMID: 24022302). In vitro functional studies demonstrating reduced enzyme activity in transfected COS-7 cells provide some evidence that the p.Gly241Arg variant may impact protein function (PMID: 11259172, 25084554). However, these types of assays may not accurately represent biological function. Computational prediction tools suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The Gly at position 241 is highly conserved in mammals and evolutionary distant species, but 1 mammal (Gorilla) carries an Arg, raising the possibility that this change at this position may be tolerated. The presence of this variant in combination with reported pathogenic variants in 12 individuals with Gaucher disease increases the likelihood that the p.Gly241Arg variant is pathogenic (VariationID: 4288, 4290; PMID: 22429443, 11259172). 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, functional studies, and the occurrence of the variant de novo in a Gaucher disease patient. ACMG/AMP Criteria applied: PM3_very-strong, PS3, PS2, PM2_supporting (Richards 2015). -

Gaucher disease type I

Pathogenic:1

Nov 20, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM3_VSTR,PS3_MOD,PM2_SUP,PP3 -

Parkinson disease, late-onset

Pathogenic:1

Nov 16, 2017

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.91

D;D;.;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.85

.;D;T;T

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.3

M;M;.;.

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-5.1

D;D;D;D

REVEL

Pathogenic

0.80

Sift

Benign

0.12

T;T;T;T

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.77

P;P;.;.

Vest4

0.82

MutPred

0.63

Gain of MoRF binding (P = 0.0179);Gain of MoRF binding (P = 0.0179);.;.;

MVP

0.90

MPC

1.0

ClinPred

0.81

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.63

gMVP

0.93

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