ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.1226A>G (p.Asn409Ser) (rs76763715)

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Total submissions: 35
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000079336 SCV000224863 pathogenic not provided 2017-05-18 criteria provided, single submitter clinical testing
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000004515 SCV000236536 pathogenic Gaucher disease type I 2015-01-26 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000004515 SCV000247461 pathogenic Gaucher disease type I 2015-02-12 criteria provided, single submitter clinical testing
GeneDx RCV000079336 SCV000321702 pathogenic not provided 2020-01-10 criteria provided, single submitter clinical testing 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)
Illumina Clinical Services Laboratory,Illumina RCV000396221 SCV000348574 pathogenic Gaucher disease 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000305321 SCV000348575 pathogenic Susceptibility to Parkinson disease 2016-06-14 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414782 SCV000492778 likely pathogenic Rigidity; Akinesia 2014-02-19 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000004515 SCV000538031 pathogenic Gaucher disease type I 2015-07-10 criteria provided, single submitter clinical testing 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.
Fulgent Genetics,Fulgent Genetics RCV000515439 SCV000611266 pathogenic Lewy body dementia; Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease, perinatal lethal; Gaucher disease type 3C; Parkinson disease, late-onset 2017-05-18 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000079336 SCV000692646 pathogenic not provided 2021-06-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000396221 SCV000697577 pathogenic Gaucher disease 2016-01-18 criteria provided, single submitter clinical testing 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.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000004515 SCV000746370 pathogenic Gaucher disease type I 2017-12-03 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000079336 SCV000800925 pathogenic not provided 2019-07-15 criteria provided, single submitter clinical testing
Invitae RCV000079336 SCV000936391 pathogenic not provided 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 409 of the GBA protein (p.Asn409Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. The frequency data for this variant in the population databases (rs76763715, ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant is a well known variant in individuals affected with Gaucher disease (PMID: 26096741). This variant has also been seen in patients with Parkinson's disease (PMID: 28779532, 25249066, 23676350). This variant is also known as p.Asn370Ser or N370S in the literature. ClinVar contains an entry for this variant (Variation ID: 4290). Experimental studies have shown that this missense change impairs enzyme activity of the GBA protein (PMID: 22592100, 8294487, 22160715). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000004515 SCV000966812 pathogenic Gaucher disease type I 2020-06-24 criteria provided, single submitter clinical testing 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.
Baylor Genetics RCV001004117 SCV001162848 pathogenic Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease type 3C criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000004515 SCV001194072 pathogenic Gaucher disease type I 2019-10-18 criteria provided, single submitter clinical testing 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001195689 SCV001366088 risk factor Parkinson disease 2020-04-14 criteria provided, single submitter clinical testing 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.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197918 SCV001368701 pathogenic Gaucher disease, perinatal lethal 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS1,PM3,PP3,PP5.
Hadassah Hebrew University Medical Center RCV000004515 SCV001437672 pathogenic Gaucher disease type I 2019-06-20 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000004515 SCV001441565 pathogenic Gaucher disease type I 2020-10-15 criteria provided, single submitter clinical testing 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001284998 SCV001471102 pathogenic none provided 2020-08-04 criteria provided, single submitter clinical testing 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. 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. 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.
Baylor Genetics RCV001197918 SCV001523473 pathogenic Gaucher disease, perinatal lethal 2019-03-04 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics,Fulgent Genetics RCV001449606 SCV001652786 pathogenic Hereditary late onset Parkinson disease 2021-05-03 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000079336 SCV001905653 pathogenic not provided 2021-09-15 criteria provided, single submitter clinical testing
OMIM RCV000004515 SCV000024689 pathogenic Gaucher disease type I 2010-08-01 no assertion criteria provided literature only
OMIM RCV000004516 SCV000024690 risk factor Parkinson disease, late-onset 2010-08-01 no assertion criteria provided literature only
OMIM RCV000004517 SCV000024691 risk factor Dementia, Lewy body, susceptibility to 2010-08-01 no assertion criteria provided literature only
Division of Human Genetics,Children's Hospital of Philadelphia RCV000004515 SCV000238464 pathogenic Gaucher disease type I 2015-03-24 no assertion criteria provided research 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).
GenomeConnect, ClinGen RCV000396221 SCV000607211 not provided Gaucher disease no assertion provided phenotyping only 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.
GenomeConnect, ClinGen RCV000515439 SCV000986753 not provided Lewy body dementia; Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease, perinatal lethal; Gaucher disease type 3C; Parkinson disease, late-onset no assertion provided phenotyping only 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.
Broad Institute Rare Disease Group, Broad Institute RCV000396221 SCV001423049 pathogenic Gaucher disease 2020-01-22 no assertion criteria provided curation 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).
Birmingham Platelet Group; University of Birmingham RCV001270528 SCV001450827 uncertain significance Abnormal bleeding; Thrombocytopenia 2020-05-01 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000079336 SCV001740270 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000079336 SCV001951306 pathogenic not provided no assertion criteria provided clinical testing

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