rs1064644

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM1PP5_Very_StrongBP4

The NM_000157.4(GBA1):c.703T>C(p.Ser235Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GBA1
NM_000157.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.158

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 Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000157.4

PP5

Variant 1-155238192-A-G is Pathogenic according to our data. Variant chr1-155238192-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.31176922).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4 linkuse as main transcript	c.703T>C	p.Ser235Pro	missense_variant	6/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8 linkuse as main transcript	c.703T>C	p.Ser235Pro	missense_variant	6/11	1	NM_000157.4	P1	P04062-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151618

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:

0.0000951

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251456

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000342

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000660

AC:

AN:

151618

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74020

show subpopulations

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:

0.0000951

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000468

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gaucher disease

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 13, 2020	The p.Ser235Pro variant in GBA has been reported in at least 6 individuals with Gaucher disease (PMID: 12204005, 28727984, 22526844, 10796875, 10649495) and has been identified in 0.006% (2/34582) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1064644). 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: 21072) as pathogenic by Integrated Genetics and Shahid Beheshti University of Medical Sciences. In vitro functional studies provide some evidence that the p.Ser235Pro variant may impact protein function (PMID: 22526844). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in 2 affected homozygotes and in combination with reported pathogenic variants in 4 individuals with Gaucher disease increases the likelihood that the p.Ser235Pro variant is pathogenic (VariationID: 4288, 4290, 65570; PMID: 12204005, 28727984, 22526844, 10796875, 10649495). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on its presence in affected homozygotes and compound heterozygotes, functional studies, and low frequency in the general population. ACMG/AMP Criteria applied: PM3_strong, PS3, PM2 (Richards 2015). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 06, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 19, 2017	Variant summary: The GBA c.703T>C (p.Ser235Pro) missense variant (alternatively also known as S196P) involves the alteration of a non-conserved nucleotide, is located in glycosyl hydrolase family 30, TIM-barrel domain of the protein (InterPro) and is predicted to be damaging by 3/4 in silico tools. This variant was found in 1/120788 control chromosomes from ExAC at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). This variant has been reported in at least six patients with Gaucher disease in homozygous as well as in compound heterozygous state with other pathogenic variants (Hodanova_1999, Stone_2000, Koprivica_2000, Filocamo_2002), including evidence of cosegregation with disease in one family. Two homozygous patients had type 2 GD, suggesting it could be a severe mutation. An in-vitro study in recombinant virus system showed that this variant severely reduces enzymatic activity (5.07+/-0.49% of normal activity) without affecting protein expression and such enzymatic deficiency is consistent with that seen in patient cells (Stone_2000, Hodanova_2003). One reputable database (via ClinVar) has classified it as pathogenic. Taken together, this variant is classified as pathogenic. -

not specified

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2016

The p.S235P variant (also known as c.703T>C), located in coding exon 6 of the GBA gene, results from a T to C substitution at nucleotide position 703. The serine at codon 235 is replaced by proline, an amino acid with similar properties. This alteration (referred to as S196P) has been described in individuals with Gaucher disease, who were either homozygous for this alteration or had another alteration in the second allele (Stone DL et al. Hum. Mutat., 2000;15:181-8; Hodanová K et al. Blood Cells Mol. Dis. 1999;25:287-98; Filocamo M et al. Hum. Mutat., 2002 Sep;20:234-5). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Sep 29, 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

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Nov 03, 2021

- -

Gaucher disease perinatal lethal

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.36

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Pathogenic

0.91

D;D;.;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.16

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.31

T;T;T;T

MetaSVM

Uncertain

0.18

MutationAssessor

Uncertain

2.4

M;M;.;.

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.2

N;N;N;N

REVEL

Uncertain

0.62

Sift

Benign

0.031

D;D;T;T

Sift4G

Benign

0.29

T;T;T;T

Polyphen

0.0060

B;B;.;.

Vest4

0.31

MutPred

0.58

Loss of glycosylation at S235 (P = 0.0465);Loss of glycosylation at S235 (P = 0.0465);.;.;

MVP

0.67

MPC

0.96

ClinPred

0.17

GERP RS

-3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.96

gMVP

0.93

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