NM_000157.4:c.475C>T

Variant names:

• chr1-155238630-G-A
• rs439898
• NM_000157.4:c.475C>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000157.4(GBA1):​c.475C>T​(p.Arg159Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000461 in 151,886 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. R159Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000025 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 4.35
• Publications: 55 publications found

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 Gene-Disease associations (from GenCC):

• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Gaucher disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
• Gaucher disease perinatal lethal

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• late-onset Parkinson disease

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Gaucher disease type I

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• Gaucher disease type II

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• Gaucher disease type III

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000157.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155238629-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.1739 (below the threshold of 3.09). Trascript score misZ: 2.2879 (below the threshold of 3.09). GenCC associations: The gene is linked to late-onset Parkinson disease, Gaucher disease perinatal lethal, Gaucher disease, Gaucher disease type I, Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome, Gaucher disease type II, Parkinson disease, Gaucher disease type III.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 1-155238630-G-A is Pathogenic according to our data. Variant chr1-155238630-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 65570.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	c.475C>T	p.Arg159Trp	missense_variant	Exon 5 of 11	ENST00000368373.8	NP_000148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8	c.475C>T	p.Arg159Trp	missense_variant	Exon 5 of 11	1	NM_000157.4	ENSP00000357357.3

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151886 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251176 AF XY: 0.00000737

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000246 AC: 36 AN: 1461626 Hom.: 0 Cov.: 33 AF XY: 0.0000289 AC XY: 21 AN XY: 727122

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000598 AC: 2 AN: 33470

American (AMR) AF: 0.0000447 AC: 2 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86242

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111820

Other (OTH) AF: 0.0000497 AC: 3 AN: 60372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151886 Hom.: 0 Cov.: 29 AF XY: 0.0000270 AC XY: 2 AN XY: 74182

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000242 AC: 1 AN: 41282

American (AMR) AF: 0.00 AC: 0 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000141084), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000480 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Jun 18, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4_moderate, PM2, PP3, PP4 -

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 159 of the GBA protein (p.Arg159Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with dementia with Lewy bodies, Gaucher disease, and/or Parkinson's disease (PMID: 17395504, 17427031, 22623374, 23430543, 23588557, 24126159, 24313877). This variant is also known as p.Arg120Trp. ClinVar contains an entry for this variant (Variation ID: 65570). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GBA protein function with a positive predictive value of 80%. This variant disrupts the p.Arg159 amino acid residue in GBA. Other variant(s) that disrupt this residue have been observed in individuals with GBA-related conditions (PMID: 17059888), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Jan 15, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 22, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GBA1: PM3:Very Strong, PM2, PS3:Supporting -

Gaucher disease Pathogenic:4 Other:1

Jan 14, 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.Arg159Trp variant in GBA has been reported in at least 8 individuals with Gaucher disease (PMID: 28727984, 22623374, 17395504, 27865684, 29685539, 30764785). Data from large population studies is insufficient to assess the frequency of this variant. This variant has also been reported in ClinVar (VariationID: 65570) as pathogenic by EGL Genetic Diagnostics. In vitro functional studies demonstrating reduced protein levels and activity in cells of Gaucher disease patient's provide some evidence that the p.Arg159Trp variant may slightly impact protein function (PMID: 22623374, 27865684). However, these types of assays may not accurately represent biological function. Animal models in Drosophila melanogaster have shown that this variant causes Gaucher disease (PMID: 23936319). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additionally, the presence of this variant in combination with reported pathogenic variants and in 6 individuals with Gaucher disease increases the likelihood that the p.Arg159Trp variant is pathogenic (VariationID: 4288, 93459, 4290, 4297; PMID: 28727984, 22623374, 17395504, 30764785). One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg159Gln, has been reported in association with Gaucher disease in the literature and ClinVar, supporting that this variant may be pathogenic (PMID: 22658918, 15214004, 17560820, 17059888; VariationID: 4291). 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 in vitro and in animal models, and computational evidence. ACMG/AMP Criteria applied: PM3_strong, PS3, PP3 (Richards 2015). -

May 06, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 02, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Gaucher disease. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been reported (PMID: 24022302, 31010158). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan (exon 5). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3; 4 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2; highest allele count: 2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Glyco_hydro_30C domain (NCBI, PDB, DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in both homozygotes and compound heterozygotes with Gaucher disease (Clinvar; PMID: 17395504, 10796875, 10649495, 28727984). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant NM_000157.3: c.1448T>C; p.(Leu483Pro) in a recessive disease (SEALS report ref 20R142425B). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jan 25, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GBA c.475C>T (p.Arg159Trp) results in a non-conservative amino acid change located in the TIM-barrel domain (IPR033453) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 150660 control chromosomes (gnomAD, v3.1). c.475C>T has been reported in the literature in individuals affected with Gaucher Disease, including multiple cases in which it has been reported in trans with a pathogenic variant (c.1226A>G, p.Asn409Ser) in the same gene (e.g. D'Amore_2021, Silva Garcia_2021). The c.475C>T variant has also been reported in the heterozygous state in individuals affected with Parkinson disease (e.g. Mitsui_2009). These data indicate that the variant is very likely to be associated with disease. Additionally, this variant affects the same amino acid residue where a different missence change (c.476G>A, p.Arg159Gln) has been determined to be pathogenic. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	.;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.7	H;H;.;.
PhyloP100		4.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.8	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.040	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.96
MutPred		0.83		Gain of catalytic residue at M162 (P = 0.0078);Gain of catalytic residue at M162 (P = 0.0078);.;.;
MVP		0.97
MPC		1.8
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.96
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs439898; hg19: chr1-155208421;