rs76763715

chr1-155235843-T-Cchr1-155235843-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 12P and 5B. PM1 PM5 PP5_Very_Strong BP4 BS2

The NM_000157.4(GBA1):c.1226A>G(p.Asn409Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.002 in 1,613,914 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic,risk factor (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N409K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0019 (3 hom., cov: 30)
  • Exomes 𝑓: 0.0020 (5 hom.)
• Consequence: GBA1 NM_000157.4 missense, splice_region
• Scores: Splicing: ADA: 0.5713
• Clinical Significance: Pathogenic/Likely pathogenic; risk factor criteria provided, multiple submitters, no conflicts P:43 U:1 O:6
• Conservation: PhyloP100: 4.36

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 7 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000157.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155235842-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 594893.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP5: Variant 1-155235843-T-C is Pathogenic according to our data. Variant chr1-155235843-T-C is described in ClinVar as [Likely_pathogenic, risk_factor]. Clinvar id is 4290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155235843-T-C is described in Lovd as [Pathogenic]. Variant chr1-155235843-T-C is described in Lovd as [Likely_benign]. Variant chr1-155235843-T-C is described in Lovd as [Benign]. Variant chr1-155235843-T-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.01917398).. Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4	c.1226A>G	p.Asn409Ser	missense_variant, splice_region_variant	9/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.1226A>G	p.Asn409Ser	missense_variant, splice_region_variant	9/11	1	NM_000157.4	P1

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 281 AN: 151930 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00231 AC: 581 AN: 251444 Hom.: 4 AF XY: 0.00230 AC XY: 313 AN XY: 135900

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.0269

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00208

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00201 AC: 2941 AN: 1461866 Hom.: 5 Cov.: 32 AF XY: 0.00199 AC XY: 1445 AN XY: 727230

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.0282

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000880

Gnomad4 NFE exome AF: 0.00172

Gnomad4 OTH exome AF: 0.00306

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152048 Hom.: 3 Cov.: 30 AF XY: 0.00165 AC XY: 123 AN XY: 74322

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00182

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00291 Hom.: 1

Bravo AF: 0.00195

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00221 AC: 268

EpiCase AF: 0.00267

EpiControl AF: 0.00332

ClinVar

Significance: Pathogenic/Likely pathogenic; risk factor

Submissions summary: Pathogenic:43 Uncertain:1 Other:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gaucher disease type I Pathogenic:15

Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Mar 24, 2015	The GBA variant (c.1226A>G) was identified in many patients in the literature and is a well-known pathogenic variant with phenotypic variability (Tsuji et al. 1988, PMID: 3353383; Fairley et al. 2008, PMID: 18979180; Hruska et al. 2008, PMID: 18338393). The variant is more commonly known as “N370S” reflecting an older nomenclature. Approximately one quarter of all reported type 1 Gaucher disease cases in the International Collaborative Gaucher Group (ICGG) Gaucher Registry are homozygotes for this allele (Fairley et al. 2008, PMID: 18979180). Alleles with this mutation have been shown to have lower activity compared to the wildtype (Grace et al. 1994, PMID: 23510062; Montfort et al. 2004, PMID: 15146461). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	Jan 26, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 25, 2022	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 15826241; 16293621; 15605411) - PS3_moderate. The c.1226A>G;p.(Asn409Ser) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 4290; PMID: 26096741; PMID: 28779532; PMID: 25249066; PMID: 23676350) -PS4. The variant is located in a mutational hot spot - PM1. Missense variant in GBA that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. In summary, the currently available evidence indicates that the variant is likely pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 18, 2019	NM_001005741.2(GBA):c.1226A>G(N409S, aka N370S) 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 22220748, 19260119, 18979180, 16293621, 3353383, 10796875, 19217815, 15146461. Classification of NM_001005741.2(GBA):c.1226A>G(N409S, aka N370S) 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	Genetic Services Laboratory, University of Chicago	Feb 12, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 24, 2020	The p.Asn409Ser variant in GBA (previously known as p.Asn370Ser) is a well-established pathogenic variant for Gaucher disease (GD) type 1. It accounts for >50% of all pathogenic alleles identified in Caucasian patients with GD type 1 and has been associated with a milder course of disease without primary neurological disease (Koprivika 2000 PMID: 10796875, Erdos 2007 PMID: 17395504, Grabowski 2015 PMID: 26096741). It has also been reported by other clinical laboratories in ClinVar (Variation ID 4290). This variant has been detected in 2.7% (276/10150) of Ashkenazi Jewish chromosomes, including 2 homozygotes, and 2% (255/126662) of European chromosomes, including 2 homozygotes, by the Genome Aggregation Database (gnomAD, http://exac.broadinstitute.org). In summary, this variant is pathogenic for GD type I in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_Strong, PP1_Strong. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Mar 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Hadassah Hebrew University Medical Center	Jun 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 25, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 20, 2023	Criteria applied: PM3_VSTR,PS3_SUP,PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jul 10, 2015	The c.1226A>G (p.Asn409Ser) variant is a known missense variant in a gene where missense is a common mechanism of disease. This variant is very common in the Ashkenazi Jewish population (carrier frequency 41%, Tsuji et al. 1988), and this patient has indeed reported an Ashkenazi Jewish ancestry. In addition, several functional studies have shown this variant to have reduced catalytic activity (by 81-95%) (Babajani et al. 2012). It is found at a very low frequency in control population databases (1000 Genomes, ExAc, and Exome Sequencing Project [ESP]) and has been predicted deleterious by various computational algorithms. It has been reported pathogenic by reputable patient databases (ClinVar, Human Genetic Mutation Database [HGMD] and Emory Genetic Laboratory). In summary, the c.1226A>G (p.Asn409Ser) meets our criteria for a recessive pathogenic variant for Gaucher disease. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 05, 2021	The GBA c.1226A>G (p.Asn409Ser) missense variant, also described in the literature as p.Asn370Ser or N370S, is a well-established pathogenic variant associated with Gaucher disease, type 1, with an increased prevalence in the affected Ashkenazi Jewish population. The variant accounts for approximately 77% of GBA variant alleles in the ICGG Gaucher registry cohort (Koprivica et al. 2000; Fairley et al. 2008; Grabowski et al. 2015; Pastores et al. 2018). Individuals who are homozygous for the p.Asn409Ser variant tend to have milder disease than those who are compound heterozygous, but the phenotype is variable and some may present with a moderate to severe disease phenotype (Fairly et al. 2008; Taddei et al. 2009). Additionally, two large meta-analyses (Mao et al. 2013; Gan-Or et al. 2015) and a multi-center case control study (Sidransky et al. 2009) have reported an increased risk of developing Parkinson disease in heterozygous carriers of the p.Asn409Ser variant. The p.Asn409Ser variant is reported at a frequency of 0.029120 in the Ashkenazi Jewish population of the Genome Aggregation Database (version 3.1.1), including three homozygous individuals in the Total population. This allele frequency is high but consistent with the carrier frequency in this population and variable phenotypic manifestations in homozygous individuals (Pastores et al. 2018). In vitro functional studies have demonstrated reduced enzymatic activity for p.Asn409Ser compared to wild-type protein (Montfort et al. 2004; Malini et al. 2014). Based on the evidence, the p.Asn409Ser variant is classified as pathogenic for Gaucher disease. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 15, 2020	GBA c.1226A>G has been reported as the most common disease-causing variant in Gaucher disease, particularly among Ashkenazi Jewish patients. Numerous functional studies have demonstrated that this variant causes reduced enzyme activity compared to wild-type protein. This GBA variant (rs76763715) reaches polymorphic frequency (>1%) within the Ashkenazi Jewish subpopulation in a large population dataset (gnomAD: 279/10368 alleles; 2.7%, 2 homozygotes). This variant has been reported in ClinVar. We consider this variant to be pathogenic. -

not provided Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 23, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 18, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 2023	The GBA c.1226A>G; p.Asn409Ser variant (rs76763715), also known as N370S, is a common pathogenic variant reported in the homozygous and compound heterozygous state in individuals with type I Gaucher disease (Fairley 2008, Grace 1994, Tsuji 1988). While this variant is found in the Ashkenazi Jewish population with an overall allele frequency of 2.7% (279/10368 alleles) in the Genome Aggregation Database, it is commonly associated with disease in individuals of Ashkenazi Jewish descent (Tsuji 1988). The asparagine at codon 409 is moderately conserved, and functional studies demonstrate this variant has reduced enzymatic activity (Grace 1994, Tsuji 1988). Based on available information, this variant is considered to be pathogenic. References: Fairley C et al. Phenotypic heterogeneity of N370S homozygotes with type I Gaucher disease: an analysis of 798 patients from the ICGG Gaucher Registry. J Inherit Metab Dis. 2008;31(6):738-744. PMID: 18979180. Grace ME et al. Analysis of human acid beta-glucosidase by site-directed mutagenesis and heterologous expression. J Biol Chem. 1994;269(3):2283-2291. PMID: 8294487. Tsuji S et al. Genetic heterogeneity in type 1 Gaucher disease: multiple genotypes in Ashkenazic and non-Ashkenazic individuals. Proc Natl Acad Sci U S A. 1988;85(7):2349-2352. PMID: 3353383. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 409 of the GBA protein (p.Asn409Ser). This variant is present in population databases (rs76763715, gnomAD 2.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with Gaucher disease or Parkinson disease (PMID: 23676350, 25249066, 26096741, 28779532). This variant is also known as p.Asn370Ser or N370S. ClinVar contains an entry for this variant (Variation ID: 4290). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects GBA function (PMID: 8294487, 22160715, 22592100). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	GBA1: PM3:Very Strong, PS3, PM1, PP1:Moderate, PM2:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2020	Published functional studies demonstrate that the defective protein shows reduced activity compared to wildtype (Grace et al., 1994; Malini et al., 2014); Observed in 279/10,368 (2.7%) alleles from individuals of Ashkenazi Jewish background, including multiple unrelated homozygous individuals, in large population cohorts, which is consistent with the high carrier frequency of this pathogenic variant among Ashkenazi Jewish individuals (Lek et al. 2016; Diaz et al., 2000); This variant is associated with the following publications: (PMID: 31996268, 32042592, 8294487, 30146349, 28779532, 30216542, 30364808, 28966932, 21745757, 19260119, 22388998, 21472771, 20837833, 23642305, 21700325, 19830760, 22961873, 22220748, 24022302, 24434810, 22975760, 22995991, 20643691, 22623374, 23588557, 16293621, 20980259, 20980263, 21653695, 18979180, 25333069, 21742527, 19217815, 22592100, 23676350, 20816920, 19945510, 18987351, 25653295, 25168325, 24020503, 22160715, 23277556, 22192918, 25249066, 21228398, 15146461, 12022475, 10777718, 27393345, 27094865, 27312774, 26096741, 27271787, 27153395, 19846850, 25456120, 28834018, 29625627, 24195576, 29431110, 29140481, 14578207, 8160756, 30302829, 30528841, 30609409, 30487145, 29842932, 27735925, 29029963, 28218669, 29487000, 30606667, 31188768, 9556036, 33281709, 32658388) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 11, 2023	- -

Gaucher disease Pathogenic:4 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 18, 2016	Variant summary: c.1226A>G affects a conserved nucleotide, resulting in amino acid change from Asn to Ser. 2/3 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant was found in 272/123472 control chromosomes at a frequency of 0.0022029, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.005). This variant has been reported in multiple GD pts as well as in pts with Parkinson disease. Functional study showed variant with 13.3% of WT activity (Grace_1994). In addition, multiple clinical laboratories classified this variant as pathogenic. Taken together, this variant was classified as a Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Asn409Ser variant in GBA has been reported in about 80% of all individuals with Gaucher disease with an increased prevalence in the affected Ashkenazi Jewish population, and has segregated with disease in 7 affected relatives from 3 families (PMID: 14757438, 17427031, 20301446). The variant has been identified in 2.691% (279/10368) of Ashkenazi Jewish chromosomes, including 2 homozygotes. Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role due to the variable phenotypic presentation of this variant. This variant has also been reported in ClinVar (VariationID: 4290) as a VUS by Praxis fuer Humangenetik Tuebingen, as likely pathogenic by University Medical Centre Ljubljana, as Pathogenic by Genetic Services Laboratory, GeneDx, Illumina Clinical Services, Counsyl, Knight Diagnostic Laboratories, EGL Genetic Diagnostics, Fulgent Genetics, Integrated Genetics, Shahid Beheshti University of Medical Sciences, Mayo Clinic Genetic Testing Laboratories, Children's Hospital of Philadelphia, and OMIM. In vitro functional studies showing reduced enzymatic activity, increased a-synuclein concentration, restoration of enzymatic activity through molecular chaperones, and a shifted optimal pH for enzymatic activity provide some evidence that the p.Asn409Ser variant may impact protein function (PMID: 14757438, 21472771, 28923368, 20980259). However, these types of assays may not accurately represent biological function. Additionally, animal models in mice demonstrating enzyme properties comparable to those in human Gaucher patients have shown that this variant causes Gaucher disease (PMID: 16293621). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The phenotype of an individual homozygous or compound heterozygous for this variant is highly specific for Gaucher disease based on hepatomegaly, splenomegaly, and low residual enzyme activity consistent with disease (PMID: 14757438). The p.Asn409Ser variant is located in a region of GBA that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 20980259, 16293621, 14757438, 28923368). Additionally, the presence of this variant in at least 26 homozygotes and in combination with reported pathogenic variants in at least 65 individuals with Gaucher disease increases the likelihood that the p.Asn409Ser variant is pathogenic (VariationID: 4288, 93459; PMID: 17427031, 14757438). The p.Asn409Ser variant is pathogenic based off of our findings, multiple reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM3_very-strong, PS3, PM1, PP1_moderate, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant is also known in literature as p.Asn370Ser (PMID: 23588557), and is the most common cause of Gaucher disease (PMID: 3353383, 26096741, 12022475). It has also been reported in patients with Parkinson disease or Lewy body dementia (LBD) spectrum of disorders (PMID: 21745757, 25249066). Functional studies indicate that this variant reduces enzyme activity of the GBA protein (PMID: 22592100, 8294487, 22160715). The frequency data for variants in the GBA gene in population databases may be unreliable due to the presence of pseudogenes and paralogs (PMID: 20301446). In silico analyses support a deleterious effect of the c.1226A>G (p.Asn409Ser) variant on protein function. Based on the available evidence, the c.1226A>G (p.Asn409Ser) variant is classified as Pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Parkinson disease, late-onset Pathogenic:3 Other:1

risk factor, no assertion criteria provided	literature only	OMIM	Aug 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 29, 2020	- -

Gaucher disease perinatal lethal Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS1,PM3,PP3,PP5. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 04, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

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 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 20, 2022	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as pathogenic and reported on 04/12/2017 by GTR ID MNG Laboratories. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

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

-

- -

GBA1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2024

The GBA1 c.1226A>G variant is predicted to result in the amino acid substitution p.Asn409Ser. This variant has been documented to be causative for Gaucher disease in numerous studies, occurring in the homozygous or compound heterozygous state. In vitro functional studies indicated that this variant results in loss of enzyme activity (see for example, Tsuji et al. 1988. PubMed ID: 3353383; Sidransky et al. 2009. PubMed ID: 19846850). This variant is reported in 2.72% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including four homozygous individuals. This variant is classified as pathogenic for Gaucher disease. Of note, several studies have also identified this variant as a risk factor for Parkinson’s disease (Sidransky et al. 2009. PubMed ID: 19846850). -

Lewy body dementia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Rigidity;C0085623:Akinesia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Feb 19, 2014

- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2020

The c.1226A>G (p.N409S) alteration is located in exon 10 (coding exon 9) of the GBA gene. This alteration results from an A to G substitution at nucleotide position 1226, causing the asparagine (N) at amino acid position 409 to be replaced by a serine (S). Based on data from gnomAD, the G allele has an overall frequency of 0.22% (632/282786) total alleles studied. The highest observed frequency was 2.69% (279/10368) of Ashkenazi Jewish alleles. This is the most common mutation found in Gaucher disease and is associated with type 1 (non-neuronopathic) disease (Tsuji, 1988). One study including 798 homozygotes and 1278 compound heterozygotes determined this mutation can cause a range of phenotypes, from mild adult-onset to pediatric onset with severe complications. However, this mutation was not observed to be associated with central nervous system involvement (Fairley, 2008). This amino acid position is not well conserved in available vertebrate species. A functional study found that Sf9 cells containing this mutation expressed significantly less protein when compared to wild-type (Montfort, 2004). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Lewy body dementia;C3160718:Parkinson disease, late-onset Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Nov 08, 2023

The GBA c.1226A>G (p.Asn409Ser) variant, historically described as p.Asn370Ser, is associated in the heterozygous state with increased risk for late-onset Parkinson’s disease and dementia with Lewy bodies with an odds ratio reported to be around 3.08-3.96 (Mata IF et al., PMID: 18332251; Neumann J et al., PMID: 19286695; Sidransky E et al., PMID: 19846850; Zhao F et al., 26868973). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 2.7% in Ashkenazi Jewish population. Functional studies show reduced enzyme activity and increased levels of alpha-synuclein protein, indicating that this variant impacts protein function (Fernandes HJR et al., PMID: 26905200; Woodard CM et al., PMID: 25456120). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to GBA function. This variant has been reported in the ClinVar database as a pathogenic variant by six submitters, likely pathogenic by one submitter and a risk factor by one submitter for late-onset Parkinson’s disease. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic. -

Thrombocytopenia;C1458140:Abnormal bleeding Uncertain:1

Uncertain significance, no assertion criteria provided

research

Birmingham Platelet Group; University of Birmingham

May 01, 2020

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Parkinson disease Other:1

risk factor, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 14, 2020

GBA c.1226A>G (p.Asn409Ser historically reported as p.Asn370Ser) is a well-established pathogenic variant for autosomal recessive Gaucher disease type I. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of Ashkenazi Jewish ancestry (2.7%, Genome Aggregation Database (gnomAD); rs76763715) and has been reported by clinical laboratories in ClinVar (Variation ID: 4290). Several studies have also reported an odds ratio of 3.08-3.96 for developing Parkinson disease in heterozygous carriers of this variant (OR=3.96 [95% CI 2.6-6.02] Sidransky 2009 PMID: 19846850, OR=3.08 [95% CI 2.32-4.09] Pankratz 2012 PMID: 22451204, OR=3.16 [95% CI 1.76-5.70] Zhao 2016 PMID: 26868973, OR=3.84 [95% CI 1.86-7.91] Zhang 2018 PMID: 29527153). In vitro functional studies suggest this variant results in reduced enzyme activity and increased levels of a-synuclein protein (Woodard 2014 PMID: 25456120, Fernandes 2016 PMID: 26905200). In summary, this variant is an established risk allele for Parkinson disease. -

Dementia, Lewy body, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 01, 2010

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;.;.
Eigen	Benign	0.086
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.019	T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.013	D;D;D;D
Sift4G	Uncertain	0.033	D;D;D;D
Polyphen		0.61	P;P;.;.
Vest4		0.64
MVP		0.93
MPC		1.0
ClinPred		0.031	T
GERP RS		3.5
Varity_R		0.59
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.57
dbscSNV1_RF	Benign	0.39
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs76763715; hg19: chr1-155205634;