rs439898

chr1-155238630-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 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:8 O:1
• Conservation: PhyloP100: 4.35

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 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
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• 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 id is 65570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4	c.475C>T	p.Arg159Trp	missense_variant	5/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.475C>T	p.Arg159Trp	missense_variant	5/11	1	NM_000157.4	P1

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

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

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000497

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

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000480 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gaucher disease Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 02, 2020	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 -
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	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 25, 2023	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. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 14, 2020	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). -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 15, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 18, 2021	PS3, PS4_moderate, PM2, PP3, PP4 -

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
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;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
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

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

Other links and lift over

dbSNP: rs439898; hg19: chr1-155208421;