rs2230288

chr1-155236376-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 2P and 18B. PM1 BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000157.4(GBA1):c.1093G>A(p.Glu365Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,614,092 control chromosomes in the GnomAD database, including 196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,risk factor (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (23 hom., cov: 32)
  • Exomes 𝑓: 0.013 (173 hom.)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Benign/Likely benign; risk factor criteria provided, multiple submitters, no conflicts U:1 B:15 O:5
• Conservation: PhyloP100: 0.321

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 Benign. Variant got -16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000157.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.110501975).
• BP6: Variant 1-155236376-C-T is Benign according to our data. Variant chr1-155236376-C-T is described in ClinVar as [Likely_benign, risk_factor]. Clinvar id is 199044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155236376-C-T is described in Lovd as [Likely_benign]. Variant chr1-155236376-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0101 (1540/152250) while in subpopulation NFE AF= 0.0128 (868/67984). AF 95% confidence interval is 0.0121. There are 23 homozygotes in gnomad4. There are 843 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4	c.1093G>A	p.Glu365Lys	missense_variant	8/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.1093G>A	p.Glu365Lys	missense_variant	8/11	1	NM_000157.4	P1

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1541 AN: 152132 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0482

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.0105 AC: 2630 AN: 251434 Hom.: 34 AF XY: 0.0102 AC XY: 1387 AN XY: 135894

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00585

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00232

Gnomad FIN exome AF: 0.0438

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0125 AC: 18333 AN: 1461842 Hom.: 173 Cov.: 33 AF XY: 0.0121 AC XY: 8795 AN XY: 727234

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.00244

Gnomad4 ASJ exome AF: 0.00520

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00212

Gnomad4 FIN exome AF: 0.0435

Gnomad4 NFE exome AF: 0.0134

Gnomad4 OTH exome AF: 0.00980

GnomAD4 genome AF: 0.0101 AC: 1540 AN: 152250 Hom.: 23 Cov.: 32 AF XY: 0.0113 AC XY: 843 AN XY: 74442

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0482

Gnomad4 NFE AF: 0.0128

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.0119 Hom.: 6

Bravo AF: 0.00634

TwinsUK AF: 0.0156 AC: 58

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0121 AC: 104

ExAC AF: 0.00980 AC: 1190

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00894

EpiControl AF: 0.00996

ClinVar

Significance: Benign/Likely benign; risk factor

Submissions summary: Uncertain:1 Benign:15 Other:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2018	This variant is associated with the following publications: (PMID: 21700325, 11903352, 15146461, 22623374, 16293621, 21742527, 21831682, 22227325, 18987351, 22001711, 27094865, 27571329, 27312774, 26000814, 28030538, 26296077, 27153395, 1864608, 28834018, 28830825, 29140481, 30302829, 30146349, 29842932, 29487000, 30777654, 24022302, 23225227, 31996268, 32618053, 32658388) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 19, 2024	The heterozygous c.1093G>A (p.Glu365Lys) missense variant in the GBA1 gene (MIM:606463) is classified as a variant of uncertain significance. Pathogenic variants in the GBA1 gene have been associated with autosomal recessive Gaucher disease. This variant has been reported previously in the literature as a modifier variant or very mild variant (PMID 24022302; PMID 21831682). This variant has also been reported at a higher frequency in patients with Parkinson's disease as compared to controls with an odds ratio of 1.65-5.5 (PMID 29842932; PMID 32618053; PMID 27571329; PMID 26296077; PMID 27094865; PMID 28830825; PMID 32853481). Expression studies from several groups showed an average enzyme activity between 39% and 54% of wild type constructs (PMID 24022302; PMID 21831682). This level of activity reduction is not sufficient to cause Gaucher disease when in trans to another pathogenic GBA mutation. The overall minor allele frequency for this variant (rs2230288) is approximately 1.073% with a frequency up to 4.325% in Finnish sub-populations. This amino acid is moderately conserved across species and an in silico meta-predictor is inconclusive as to whether this amino acid change impacts protein function. Taken together, the evidence is not sufficient to determine whether this variant is a hypomorphic allele or is associated with increased risk for Parkinson's disease. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 23, 2022	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	GBA1: BS1, BS2 -

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 25, 2020	Variant summary: GBA c.1093G>A (p.Glu365Lys) results in a 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 0.01 in 252724 control chromosomes, predominantly at a frequency of 0.012 within the Non-Finnish European subpopulation in the gnomAD database, including 11 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in GBA causing Gaucher Disease phenotype (0.005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1093G>A has been reported in the literature in individuals affected with Gaucher Disease. This variant did not co-segregate with disease in at-least one family with a clinical diagnosis of Gaucher's disease. Specifically, while two affected siblings were compound heterozygous for G202R and L444P, the healthy father carried this variant in compound heterozygous state with G202R, further supporting non-pathogenic role (Zhao_2003). This variant has been reported in many GD patients, all within a complex allele with another variant in cis (such as D140H+E326K, N188S+E326K, and L444P+E326K), and the variant alone has not been reported in any GD patients. This variant has also been reported in many PD patients, and has been suggested to be modestly increase risk for PD with borderline odds ratios (OR) by multiple studies in Europeans, including a GWAS study (Nichols_2009, Lesage_2011, Pankratz_2012, Durhan_2013, Ran_2016, Mata_2016). Meanwhile, there are other conflicting case-control studies that do not show this variant as a significant risk allele for PD (Bras_2009, Alcalay_2015, Han_2016). Multiple functional studies show that the variant alone could lead to 30-60% of wild-type enzymatic activity and the complex alleles show much lower activities than the each of the single variant alone, suggesting an additive effect. However, in at-least one reported instance, the specific activity of the complex allele E326K+L444P was not different from that of L444P alone in a study where a genotype of E326K+L444P and E233X in trans was reported in a patient with a severe neonatal type 2 course (Grace_1999). This points to L444P being more penetrant relative to E326K in this patient. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. While one clinical diagnostic laboratory has classified this variant as benign and two have classified it as uncertain significance. Another lab classified it as risk factor before 2014, all without evidence for independent evaluation. Taken together, in context of Gaucher disease, this variant alone is likely not disease-causing; however, it can possibly increase the functional defect of another GBA variant in cis. In context of Parkinsons disease, this variant may be a mild risk allele. Since this variant does not confer a considerable or clinically significant risk for Parkinsons disease and does not cause Gaucher disease, it is classified as likely benign in line with its role as functional polymorphism. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 02, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 0.97% in ExAC, 4.3% in Finnish, 12 hom -

Gaucher disease Benign:2 Other:1

Benign, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Glu365Lys variant in GBA has been reported in at least 14 individuals with Gaucher disease (PMID: 15967693, 23225227, 29980418, 11903352) and has been identified in 4.325% (1086/25110) of European (Finnish) chromosomes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs2230288). This variant has also been reported in ClinVar (VariationID: 199044) as likely benign by Integrated Genetics, as a VUS by Mayo Clinic Genetic Testing Laboratories and Praxis fuer Humangenetik Tuebingen, and as benign by Laboratory for Molecular Medicine, EGL Genetic Diagnostics, and University Medical Centre Ljubljana. The p.Glu365Lys variant did not segregate with Gaucher disease in 2 affected relatives of an individual with the variant, suggesting that this variant is not pathogenic for Gaucher disease (PMID: 12791040). In vitro functional studies demonstrating that the variant alone reduces enzyme activity only to the lower level of the normal range, about 42% of wild-type, provide some evidence that the p.Glu365Lys variant may not impact protein function when not part of a complex allele. Additional functional studies have shown that the variant leads to further reduction of enzyme activity when in cis with other pathogenic variants, suggesting that the variant may increase disease severity when in cis with a pathogenic variant (PMID: 15967693, 23225227, 22227325). 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. This variant was found in cis with another pathogenic variant in every Gaucher disease patient found to carry the variant, suggesting that it may not cause disease (VariationID: 4288, 4290, 4314; PMID: 15967693, 23225227, 29980418, 11903352). In summary, this variant meets criteria to be classified as benign for Gaucher disease in an autosomal recessive manner--but is expected to increase disease severity as part of a complex allele--based on the high frequency of the variant in the general population, nonsegregation of the variant with disease, the presence of the variant in cis with pathogenic variants in affected individuals, and in vitro functional studies. ACMG/AMP Criteria applied: BS1, BS4, BP2, BS3_supporting (Richards 2015). -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 23, 2020	- -

Gaucher disease perinatal lethal Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

Parkinson disease, late-onset Other:1

risk factor, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 03, 2021

- -

Hyperlipidemia;C0020538:Hypertensive disorder;C0037822:Abnormality of speech or vocalization;C0242422:Parkinsonian disorder;C0497327:Dementia;C1836296:Lower limb muscle weakness Other:1

risk factor, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jun 19, 2014

- -

Parkinsonian disorder Other:1

risk factor, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Feb 17, 2014

- -

Rigidity;C0040822:Tremor;C0151564:Cogwheel rigidity;C0242422:Parkinsonian disorder Other:1

risk factor, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Dec 12, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;D;.;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.15	N
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.0	L;L;.;.
MutationTaster	Benign	0.00018	A;A;A;A;A
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Uncertain	0.59
Sift	Benign	0.78	T;T;T;T
Sift4G	Benign	0.87	T;T;T;T
Polyphen		0.015	B;B;.;.
Vest4		0.22
MPC		0.86
ClinPred		0.0093	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
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

Other links and lift over

dbSNP: rs2230288; hg19: chr1-155206167;