rs381427

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_ModeratePM1PM2PM5PP3PP5_Moderate

The NM_000157.4(GBA1):c.689T>G(p.Val230Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,832 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V230E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

GBA1
NM_000157.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.23

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.

PS1

Transcript NM_000157.4 (GBA1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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, 0.804

PP5

Variant 1-155238206-A-C is Pathogenic according to our data. Variant chr1-155238206-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 928835.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBA1	NM_000157.4 link	c.689T>G	p.Val230Gly	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 link	c.689T>G	p.Val230Gly	missense_variant	6/11	1	NM_000157.4	ENSP00000357357.3		P04062-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251390

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151988

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Gaucher disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 28, 2024

Variant summary: GBA1 c.689T>G (p.Val230Gly) results in a non-conservative amino acid change located in the TIM-barrel domain (IPR033453) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-06 in 1606838 control chromosomes in the gnomAD database (v4.0 dataset), however the variant is located in a region that is known to be highly homologous to the GBA pseudogene, therefore these data might not be reliable. The variant, c.689T>G, has been reported in the literature in compound heterozygote individuals affected with Gaucher Disease (e.g. Choy_1997, Giraldo_2011, Narita_2014, Huang_2020, Kim_2020), and multiple publications noted that the diagnosis of Gaucher disease was confirmed biochemically, demonstrating <5% of normal glucocerebrosidase activity in patients samples (e.g. Choy 1997, Huang_2020). These data indicate that the variant is very likely to be associated with disease. The variant was also reported as a complex allele, together with several pathogenic variants in cis, in multiple compound heterozygous individuals affected with Gaucher Disease, and in heterozygotes affected with early onset Parkinson disease (e.g. Du_2018, Kang_2018, Olkhovych_2017 [NO_PMID], Sheth_2019, D Amore_2021, Ren_2023), where the complex alleles encompassing several variants are believed to be the result of recombination events with the highly homologous pseudogene (see e.g. Hruska_2008). The following publications have been ascertained in the context of this evaluation (PMID: 18338393, 10206680, 19433657, 34649574, 30461613, 32165122, 29934114, 33176831, 25356393, 30764785, 36845659, 22429443). ClinVar contains an entry for this variant (Variation ID: 928835). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Benign

DANN

Benign

0.64

DEOGEN2

Pathogenic

0.97

D;D;.;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.75

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.49

.;T;T;T

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.80

D;D;D;D

MetaSVM

Uncertain

0.51

MutationAssessor

Benign

1.2

L;L;.;.

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.8

D;D;D;D

REVEL

Uncertain

0.62

Sift

Uncertain

0.010

D;D;T;D

Sift4G

Benign

0.20

T;T;T;T

Polyphen

0.0080

B;B;.;.

Vest4

0.79

MutPred

0.68

Gain of disorder (P = 0.0058);Gain of disorder (P = 0.0058);.;.;

MVP

0.73

MPC

1.0

ClinPred

0.17

GERP RS

2.5

Varity_R

0.53

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