rs75822236

chr1-155235002-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM5 PP5_Very_Strong BP4

The NM_000157.4(GBA1):c.1604G>A(p.Arg535His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. R535C) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000055 (0 hom., cov: 11)
  • Exomes 𝑓: 0.00012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18 O:1
• Conservation: PhyloP100: 0.830

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155235003-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 242383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 1-155235002-C-T is Pathogenic according to our data. Variant chr1-155235002-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155235002-C-T is described in Lovd as [Pathogenic]. Variant chr1-155235002-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.32971787).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4	c.1604G>A	p.Arg535His	missense_variant	11/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.1604G>A	p.Arg535His	missense_variant	11/11	1	NM_000157.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000553 AC: 5 AN: 90450 Hom.: 0 Cov.: 11

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00123

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000223

Gnomad OTH AF: 0.000931

GnomAD3 exomes AF: 0.000182 AC: 31 AN: 170078 Hom.: 0 AF XY: 0.000155 AC XY: 14 AN XY: 90332

Gnomad AFR exome AF: 0.000112

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00254

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000831

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000439

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000118 AC: 80 AN: 680418 Hom.: 0 Cov.: 9 AF XY: 0.0000993 AC XY: 35 AN XY: 352508

Gnomad4 AFR exome AF: 0.000110

Gnomad4 AMR exome AF: 0.000183

Gnomad4 ASJ exome AF: 0.00244

Gnomad4 EAS exome AF: 0.0000311

Gnomad4 SAS exome AF: 0.0000677

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000340

Gnomad4 OTH exome AF: 0.000206

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000553 AC: 5 AN: 90450 Hom.: 0 Cov.: 11 AF XY: 0.0000243 AC XY: 1 AN XY: 41182

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00123

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000223

Gnomad4 OTH AF: 0.000931

Alfa AF: 0.000384 Hom.: 0

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.0000859 AC: 10

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gaucher disease type I Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 15, 2020	Based on the classification scheme VCGS_Germline_v1.3.4, 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 (OMIM). (I) 0106 - This gene is associated with autosomal recessive disease. (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; 27735925). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (34 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant, also known as R496H in an alternative nomenclature, has been reported in at least 15 patients with Gaucher disease (GD) Type 1. It is often associated with a milder adult-onset GD clinical course, although some patients may experience symptoms during childhood (ClinVar; PMID: 27735925; 23430543). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg535His variant in GBA has been reported in at least 24 individuals with Gaucher Disease (PMID: 17059888, 24756352, 17427031, 20629126, 7655857, 28947706, 23430543, 8432537) and has been identified in 0.2% (22/8934) of Ashkenazi Jewish chromosomes and 0.011% (2/17404) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs75822236). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency taking into consideration that the carrier frequency of GBA variants is increased in the Ashkenazi Jewish population. This variant has also been reported in ClinVar (VariationID: 4311) as pathogenic by EGL Genetic Diagnostics, Knight Diagnostic Laboratories, Counsyl, Integrated Genetics, Fulgent Genetics, and OMIM. In vitro functional studies showing the variant to result in significantly reduced CRIM specific activity provide some evidence that the p.Arg535His variant may slightly impact protein function (PMID: 16293621). 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. However, the presence of this variant in one affected homozygote and in combination with reported pathogenic variants (VariationID: 4302, 4297, 4290, 4288; PMID: 23430543, 28947706, 20629126, 17059888, 8432537) in 9 individuals with Gaucher disease increases the likelihood that the p.Arg535His variant is pathogenic. The phenotype of an individual compound heterozygous for this variant is highly specific for Gaucher disease based on beta-glucosidase levels being below the diagnostic cutoff of 8.7nmol/h/mg protein consistent with disease (PMID: 20629126). One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg535Cys, has been reported in association with disease in ClinVar and the literature, slightly supporting that a change at this position may not be tolerated (Variation ID: 242383; PMID: 27865684, 30637984, 30764785). 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 in affected individual and the presence of another pathogenic variant at the same position. ACMG/AMP Criteria applied: PM3_very-strong, PM5, PM2_supporting, PP4, PS3_supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 19, 2019	NM_001005741.2(GBA):c.1604G>A(R535H, aka R496H) is classified as pathogenic in the context of Gaucher disease and is associated with Type 1 form of disease. Sources cited for classification include the following: PMID 25558695, 8213821, 16293621, 84325327, 12972024, 9240741 and 7916532. Classification of NM_001005741.2(GBA):c.1604G>A(R535H, aka R496H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Hadassah Hebrew University Medical Center	Jun 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 06, 2018	The p.Arg535His (also known as p.Arg496His) variant in GBA has been reported in >20 compound heterozygous individuals (majority of Ashkenazi Jewish origin) with mild forms of Gaucher disease type I (Beutler 1993, Brautbar 2003, Yang 2017). This variant is considered a mild variant, with compound heterozygotes typically presenting as asymptomatic to mild, non-neurological cases (Brautbar 2003, Yang 2017). No homozygotes have been reported, and it is hypothesized that homozygot es may be asymptomatic. This variant was also identified in 0.25% (22/8934) of A shkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org) and in ClinVar (Variation ID# 4311). In vitro functional studies support an impact on p rotein function (Liou 2006, Choy 1996). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Gaucher disease. ACMG/AMP Criteria applied: PM3_Very Strong, PS3_Moderate, PS4_Moderate. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 15, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Feb 02, 2015	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 535 of the GBA protein (p.Arg535His). This variant is present in population databases (rs75822236, gnomAD 0.2%). This missense change has been observed in individual(s) with dementia with Lewy bodies, Gaucher disease, and/or Parkinson's disease (PMID: 8432537, 12972024, 23430543, 23588557, 23699752, 25933391, 27735925). This variant is also known as p.Arg496His or R496H. ClinVar contains an entry for this variant (Variation ID: 4311). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GBA protein function. Experimental studies have shown that this missense change affects GBA function (PMID: 16293621). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2019	Published functional studies demonstrate that this variant had little or no catalytic activity (Liou et al., 2006); This variant is associated with the following publications: (PMID: 33176831, 29471591, 31589614, 32985097, 32042592, 28966932, 29842932, 27735925, 23430543, 12972024, 8432537, 18434642, 26233692, 26857292, 16148263, 22935721, 16293621, 22975760, 23699752, 23588557) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 27, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 10, 2021	- -

Gaucher disease Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 19, 2016	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2022

The p.R535H pathogenic mutation (also known as c.1604G>A and p.R496H), located in coding exon 11 of the GBA gene, results from a G to A substitution at nucleotide position 1604. The arginine at codon 535 is replaced by histidine, an amino acid with highly similar properties. In one study of 2,012 individuals screened for various autosomal recessive conditions, it was the third most common GBA alteration detected with a carrier frequency of 1 in 335 (Scott SA et al. Hum. Mutat. 2010; 31(11):1240-50). In addition, this variant has been detected on several alleles from individuals with Gaucher disease; however, specific phenotype information and/or additional mutation and phase information was not provided (Beutler E et al. Genomics 1993;15(1):203-5; Siebert M et al. JIMD Rep 2013 ; 9():7-16; Alfonso P et al. J. Hum. Genet. 2007; 52(5):391-6). This variant has also been detected in two individuals with Parkinson disease and Lewy body dementia (Chahine LM et al. JAMA Neurol 2013; 70(7):852-8; Nalls MA et al. JAMA Neurol 2013 ; 70(6):727-35). In another study which characterized basic kinetic, stability, and activator response properties of this alteration in an in vitro environment, authors concluded that this alteration has little, if any, in vitro catalytic activity (Liou B et al. J. Biol. Chem. 2006; 281(7):4242-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Parkinson disease, late-onset Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 03, 2021

- -

Gaucher disease type II;C0268251:Gaucher disease type III;C0752347:Lewy body dementia;C1842704:Gaucher disease perinatal lethal;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I;C3160718:Parkinson disease, late-onset Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 29, 2021

- -

Gaucher disease type II;C0268251:Gaucher disease type III;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Benign	21
Dann	Benign	0.94
DEOGEN2	Uncertain	0.58	D;D;.;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.84
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.46	N;N;.;.
MutationTaster	Benign	0.077	A;A;A;A;A
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Uncertain	0.57
Sift	Benign	0.052	T;T;T;D
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.49	P;P;.;.
Vest4		0.68
MVP		0.79
MPC		0.99
ClinPred		0.018	T
GERP RS		1.2
Varity_R		0.13
gMVP		0.67

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: rs75822236; hg19: chr1-155204793;