Variant rs147138516 details in Genebe, Genetics Data Aggregator

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:

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBA1	NM_000157.4 linkuse as main transcript	c.535G>C	p.Asp179His	missense_variant	5/11	ENST00000368373.8	NP_000148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8 linkuse as main transcript	c.535G>C	p.Asp179His	missense_variant	5/11	1	NM_000157.4	ENSP00000357357	P1	P04062-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

151754

Hom.:

Cov.:

show subpopulations

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:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000135

AC:

AN:

250934

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135674

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000291

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000125

AC:

182

AN:

1461636

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000159

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000158

AC:

AN:

151754

Hom.:

Cov.:

AF XY:

0.000189

AC XY:

AN XY:

74104

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:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 23, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2023	Identified in siblings with low beta-glucocerebrosidase activity and discordant phenotypes; these siblings were also compound heterozygous for another variant in GBA. One sibling had neuronopathic Gaucher and the other was nearly asymptomatic at the age of 60. The authors attribute the difference in GBA activity and phenotype to a heterozygous variant in SCARB2, a beta-glucocerebrosidase transporter, identified only in the severely affected sibling. More evidence is needed to evaluate the pathogenicity of D179H (PMID: 21796727, 22623374); Identified in the heterozygous state in patients with Lewy body dementia and with Parkinson disease with dementia; however, D179H was also identified in the heterozygous state in control individuals used in some of these studies (PMID: 32618053, 27717005, 23588557, 29948939, 31809948); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.D140H; This variant is associated with the following publications: (PMID: 18160322, 30777654, 31809948, 1864608, 23588557, 27717005, 29948939, 27397011, 22623374, 34308104, 32618053, 32191290, 36598340, 21796727) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 10, 2023

Variant summary: GBA c.535G>C (p.Asp179His) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 260904 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in GBA causing Gaucher Disease (0.00016 vs 0.005), allowing no conclusion about variant significance. The variant was reported in the literature in a haplotype with c.1093G>A (p.Glu365Lys) in compound heterozygosity with c.586A>C (p.Lys196Gln) in two brothers diagnosed with Type I Gaucher disease (GD) and subsequently reported in another study with an overlapping cohort (Example, Eyal_1991, Park_2003). These data indicate that the variant may be associated with Gaucher Disease. In functional studies, the c.535G>C variant alone was shown to result in a mild reduction of enzyme activity (approximately 50-74% residual activity), while the presence of the complex allele c.535G>C + c.1093G>A resulted in significantly decreased activity compared to either individual allele (20-25% residual activity; Grace_1999, Ron_2005). The c.535G>C variant and c.535G>C + c.1093G>A complex allele have also been reported as single alleles or as non-informative genotypes (second allele not specified) in patients with Parkinson's Disease (PD) and dementia, and it has been suggested that monoallelic variants in GBA may be risk factors for PD, but a pathogenic contribution of this variant towards these associations have not been conclusively determined (Example, Lesage_2011, Meeus_2012, Tsuang_2012, Nalls_2013, Crosiers_2016, Liu_2016, Mata_2016, Blauwendraat_2017, Moors_2019, Geut_2019, den Heijer_2020, Oliveira_2021). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Gaucher disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

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

Jan 14, 2020

The p.Asp179His variant in GBA has been reported in at least 3 individuals with Gaucher disease (PMID: 22350617, 22623374, 10079102) and has been identified in 0.027% (35/128762) of European (non-Finnish) chromosomes, including 1 homozygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs147138516). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (VariationID: 242811) as likely pathogenic by Integrated Genetics and as a VUS by Praxis fuer Humangenetik Tuebingen. In vitro functional studies provide some evidence that the p.Asp179His variant may not impact protein function (PMID: 21831682, 10079102). 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 combination with a reported pathogenic variant and in an individual with Gaucher disease increases the likelihood that the p.Asp179His variant is pathogenic (VariationID: 4297; PMID: 22350617). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BS3_supporting, PM3_supporting (Richards 2015). -

Gaucher disease perinatal lethal

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jul 17, 2023

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. 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. The different types of Gaucher disease are considered to fall within a spectrum, rather than distinct conditions, and are determined by age of disease onset and the presence and severity of neurologic function. Specific counseling about individual case prognosis is hindered by a significant overlap in the clinical features of individuals with various genotypes (OMIM, PMID: 20301446). (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 aspartic acid to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2 and v3) <0.01 for a recessive condition (56 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated glycosol hydrolase family 20 TIM-barrel domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS by several clinical laboratories in ClinVar, and has been observed as part of a complex allele with p.(Glu365Lys) in one family with Gaucher disease where it was observed to be compound heterozygous (PMID: 1864608). This complex allele has also been described as a risk allele for parkinsons disease (PMID: 36598340). (I) 0903 - This variant has limited evidence for segregation with disease. This variant as part of a complex allele with p.(Glu365Lys) was observed as compound heterozygous in two brothers with Gaucher disease. Other unaffected families members were either only heterozygous for one of the alleles or were not a carrier of either (PMID: 1864608). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been shown to only reduce b-glucosidase activity to 50% by itself, but in a complex allele with p.(Glu365Lys) it reduced enzyme activity to only 20% of normal activity (PMID: 10079102). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.066

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.93

D;D;.;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.35

LIST_S2

Uncertain

0.95

.;D;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Uncertain

0.46

T;T;T;T

MetaSVM

Pathogenic

0.90

MutationAssessor

Uncertain

2.0

M;M;.;.

MutationTaster

Benign

0.63

N;N;N;N;N

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.4

N;N;N;N

REVEL

Pathogenic

0.75

Sift

Benign

0.049

D;D;T;D

Sift4G

Benign

0.083

T;T;T;T

Polyphen

0.25

B;B;.;.

Vest4

0.33

MVP

0.87

MPC

0.91

ClinPred

0.12

GERP RS

2.6

Varity_R

0.33

gMVP

0.84

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.

rs147138516

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