1-155238629-C-T

Position:

chr1-155238629-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000157.4(GBA1):c.476G>A(p.Arg159Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000806 in 1,613,418 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R159W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

GBA1
NM_000157.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.76

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:

GBA1 (HGNC:):

GBA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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 chr1-155238630-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 65570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 1-155238629-C-T is Pathogenic according to our data. Variant chr1-155238629-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBA1	NM_000157.4 linkuse as main transcript	c.476G>A	p.Arg159Gln	missense_variant	5/11	ENST00000368373.8	NP_000148.2	P04062-1A0A068F658

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8 linkuse as main transcript	c.476G>A	p.Arg159Gln	missense_variant	5/11	1	NM_000157.4	ENSP00000357357.3		P04062-1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151758

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

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:

0.00000796

AC:

AN:

251180

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135744

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461660

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151758

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74080

show subpopulations

Gnomad4 AFR

AF:

0.0000243

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

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	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2021	Variant summary: GBA c.476G>A (p.Arg159Gln) results in a conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251180 control chromosomes. c.476G>A has been reported in the literature as p.Arg120Gln in multiple individuals affected with Gaucher Disease (example, Theophilus_1989, Beutler_1993, Koprivica_2000, Felderhoff-Meuser_2004, Rozenberg_2006, Mercimek-Mahmutoglu_2007, Sonder_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in compound heterozygosity with a 12 nucleotide insertion. The most pronounced variant effect results in <1% of normal activity in the patient derived fibroblast homogenate (Felderhoff-Mueser_2004). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 06, 2017	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg159Gln variant in GBA has been reported in at least 6 individuals with Gaucher disease (PMID: 15214004, 17560820, 17059888, 22658918) and has been identified in 0.002891% (1/34592) of Latino chromosomes and 0.0008814% (1/113462) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs79653797). 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: 4291) as pathogenic by OMIM. In vitro functional studies showing that fibroblasts cultured from a patient with Gaucher disease had <1% wild-type activity provide some evidence that the p.Arg159Gln variant may impact protein function (PMID: 15214004). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg159Trp, has been reported in association with Gaucher disease in the literature and ClinVar, supporting that this variant may be pathogenic (VariationID: 65570; PMID: 28727984, 22623374, 17395504, 27865684, 29685539, 30764785, 23936319). Additionally, the presence of this variant in combination with reported pathogenic and likely pathogenic variants and in 4 individuals with Gaucher disease increases the likelihood that the p.Arg159Gln variant is pathogenic (VariationID: 4290, 4333; PMID: 15214004, 17560820, 17059888). 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 reported pathogenic variants, the significantly reduced activity of the protein in fibroblasts derived from a proband, and the presence of a pathogenic variant at the same position. ACMG/AMP Criteria applied: PM3_strong, PM2, PS3_moderate, PM5, PP3 (Richards 2015). -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2024	Functional studies found this variant is associated with significantly reduced enzyme activity compared to wild-type (PMID: 16293621); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.R120Q; This variant is associated with the following publications: (PMID: 34867278, 23588557, 17560820, 16293621, 31589614, 32677286, 35861376, 37750340, 37312046, 35810474, 34779914, 32507414, 15214004, 16546416, 33977031, 32613234, 34820281, 3180993, 10796875, 37198191, 1899336, 17059888) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 22, 2022	- -

Gaucher disease type I

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 15, 2004

- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

May 06, 2020

GBA c.476G>A has been reported in multiple individuals presenting with Gaucher disease. This GBA variant (rs79653797) is rare (<0.1%) in a large population dataset (gnomAD: 2/251180 total alleles; 0.0008%; no homozygotes). This variant is located within a mutational hotpspot, which is in proximity to glucocerebrosidase catalytic sites. An alternate pathogenic missense change (p.Arg159Trp) has been reported at the same amino acid residue. This variant has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is highly evolutionarily conserved across most species assessed. We consider this variant to be likely pathogenic. -

Gaucher disease perinatal lethal

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 15, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;D;.;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D;D;D

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

4.0

H;H;.;.

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.6

D;D;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.98

MutPred

0.90

Loss of methylation at R159 (P = 0.0371);Loss of methylation at R159 (P = 0.0371);.;.;

MVP

0.96

MPC

2.0

ClinPred

1.0

GERP RS

3.5

Varity_R

0.99

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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