NM_000157.4(GBA1):c.1226A>G (p.Asn409Ser)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic; risk factor
Pathogenic (44); Likely pathogenic (4)
Pathogenic (44); Likely pathogenic (4)
49 out of 61 submissions contributed to this classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
61
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000157.4(GBA1):c.1226A>G (p.Asn409Ser)
Variation ID: 4290 Accession: VCV000004290.141
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 155235843 (GRCh38) [ NCBI UCSC ] 1: 155205634 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 5, 2015 Jul 27, 2026 Jun 1, 2026 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000157.4:c.1226A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000148.2:p.Asn409Ser missense NM_001005741.3:c.1226A>G NP_001005741.1:p.Asn409Ser missense NM_001005742.3:c.1226A>G NP_001005742.1:p.Asn409Ser missense NM_001171811.2:c.965A>G NP_001165282.1:p.Asn322Ser missense NM_001171812.2:c.1079A>G NP_001165283.1:p.Asn360Ser missense NC_000001.11:g.155235843T>C NC_000001.10:g.155205634T>C NG_009783.1:g.13855A>G NG_042867.1:g.2305T>C P04062:p.Asn409Ser - Protein change
- N409S, N322S, N360S
- Other names
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N370S
- Canonical SPDI
- NC_000001.11:155235842:T:C
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00060 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00197
Exome Aggregation Consortium (ExAC) 0.00221
Trans-Omics for Precision Medicine (TOPMed) 0.00195
The Genome Aggregation Database (gnomAD), exomes 0.00231
1000 Genomes Project 0.00060
1000 Genomes Project 30x 0.00062
The Genome Aggregation Database (gnomAD) 0.00176
The Genome Aggregation Database (gnomAD) 0.00191
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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| GBA1 | Gene associated with autosomal recessive phenotype | No evidence available |
GRCh38 GRCh38 GRCh37 |
60 | 791 | |
| LOC106627981 | - | - | - |
GRCh38 GRCh38 |
- | 715 |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (18) |
criteria provided, multiple submitters, no conflicts
|
May 11, 2025 | RCV000004515.50 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Aug 27, 2024 | RCV000004516.28 | |
| risk factor (1) |
no assertion criteria provided
|
Aug 1, 2010 | RCV000004517.14 | |
| Pathogenic/Likely pathogenic (13) |
criteria provided, multiple submitters, no conflicts
|
Jun 1, 2026 | RCV000079336.88 | |
| Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Oct 27, 2025 | RCV000396221.23 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Feb 19, 2014 | RCV000414782.10 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Feb 20, 2022 | RCV000515439.13 | |
| risk factor (1) |
criteria provided, single submitter
|
Apr 14, 2020 | RCV001195689.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV001004117.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 4, 2019 | RCV001197918.12 | |
| no classifications from unflagged records (1) |
no classifications from unflagged records
|
Jun 9, 2025 | RCV001270528.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 4, 2022 | RCV002247244.9 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Nov 8, 2023 | RCV004555830.2 | |
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GBA1-related disorder
|
Pathogenic (2) |
criteria provided, single submitter
|
Jun 5, 2025 | RCV003982824.4 |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 27, 2024 | RCV004018556.2 | |
|
GBA1-related disorders
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Pathogenic (1) |
criteria provided, single submitter
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Aug 1, 2025 | RCV006636173.1 |
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autosomal dominant GBA1-related disorders
|
Pathogenic (1) |
criteria provided, single submitter
|
Jan 20, 2026 | RCV006699158.1 |
| click to load more conditions click to collapse | ||||
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
Expand all rows
Collapse all rows
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Pathogenic
(Feb 12, 2015)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease, type I |
Genetic Services Laboratory, University of Chicago
Accession: SCV000247461.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
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risk factor
(Apr 14, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Parkinson disease |
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV001366088.1
First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020 |
Comment:
show
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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 3
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Pathogenic
(Jun 24, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease type I
(Autosomal recessive inheritance)
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000966812.3
First in ClinVar: Aug 26, 2019 Last updated: May 29, 2021 |
Comment:
show
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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 4
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Pathogenic
(Oct 11, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
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Gaucher disease type I
(Autosomal recessive inheritance)
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV005398891.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
show
Based on the classification scheme VCGS_Germline_v1.3.5, 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 (MIM# 230800, 230900, 231000, 231005, 608013). (I) 0106 - This gene is associated with autosomal recessive disease. The different types of Gaucher disease are considered to fall within a spectrum, rather than distinct conditions, and are determined by age of disease onset and the presence and severity of neurologic function. Specific counselling about individual case prognosis is hindered by a significant overlap in the clinical features of individuals with various genotypes (OMIM, PMID: 20301446). (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). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition (v4) (3207 heterozygotes, 8 homozygotes). (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4) (2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated glycosyl hydrolase family 30 TIM-barrel domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant, also known as N370S due to alternate nomenclature, is a well-established pathogenic variant associated Gaucher disease Type 1. It is has been reported as a mild allele, where homozygous carriers my remain asymptomatic (ClinVar; PMID: 31010158, 20301446). Association studies have also shown that this variant, in the heterozygous state, may confer increased risk for Parkinson Disease (PMID: 25249066; 26868973, 31010158) (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
|
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Pathogenic
(Apr 29, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000800925.5
First in ClinVar: Aug 04, 2018 Last updated: Jan 11, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 22
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Pathogenic
(Jul 10, 2015)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease type I |
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Study: CSER-NextGen
Accession: SCV000538031.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017 |
Comment:
show
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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
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Pathogenic
(Jan 18, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697577.1
First in ClinVar: Oct 14, 2017 Last updated: Oct 14, 2017 |
Comment:
show
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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
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Pathogenic
(Jun 20, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease, type I |
Hadassah Hebrew University Medical Center
Accession: SCV001437672.1
First in ClinVar: Oct 10, 2020 Last updated: Oct 10, 2020 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
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Pathogenic
(Oct 15, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease type I |
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001441565.1
First in ClinVar: Nov 06, 2020 Last updated: Nov 06, 2020 |
Comment:
show
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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
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Pathogenic
(May 03, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Parkinson disease, late-onset |
Fulgent Genetics, Fulgent Genetics
Accession: SCV001652786.1
First in ClinVar: May 29, 2021 Last updated: May 29, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Platform type: Hybrid Capture Next-generation Sequencing
|
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Pathogenic
(Jan 22, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease
(Autosomal recessive inheritance)
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001423049.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 05, 2022 |
Comment:
show
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). (less)
Observation: 1
Collection method: curation
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: curation
Allele origin: germline
Affected status: unknown
|
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Pathogenic
(May 04, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Lewy body dementia |
Mendelics
Accession: SCV002516447.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
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Pathogenic
(Feb 20, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Lewy body dementia
Parkinson disease, late-onset Gaucher disease type I Gaucher disease type II Gaucher disease type III Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome Gaucher disease perinatal lethal |
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611266.2
First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
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Likely pathogenic
(Nov 08, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Lewy body dementia
Parkinson disease, late-onset
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. |
Clinical Genomics Laboratory, Washington University in St. Louis
Accession: SCV005045123.1
First in ClinVar: May 26, 2024 Last updated: May 26, 2024 |
Comment:
show
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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
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Pathogenic
(Feb 01, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease type I |
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051785.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
Observation: 1
Collection method: curation
Allele origin: germline
Affected status: no
Observation 1
Collection method: curation
Allele origin: germline
Affected status: no
|
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Likely pathogenic
(Mar 25, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease type I |
Dasa
Accession: SCV002318968.2
First in ClinVar: Apr 02, 2022 Last updated: Apr 13, 2025 |
Comment:
show
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 (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
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Pathogenic
(Aug 17, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease |
Department of Pathology and Laboratory Medicine, Sinai Health System
Accession: SCV005918182.1
First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025 |
Observation: 1
Collection method: research
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: research
Allele origin: germline
Affected status: unknown
|
|
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Likely pathogenic
(Feb 16, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Laboratory of Genetics, Children's Clinical University Hospital Latvia
Accession: SCV006308082.1
First in ClinVar: Aug 23, 2025 Last updated: Aug 23, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Mar 03, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Revvity Omics, Revvity
Accession: SCV002024202.4
First in ClinVar: Nov 29, 2021 Last updated: Sep 06, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Oct 27, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease |
Natera, Inc.
Accession: SCV007532975.1
First in ClinVar: Apr 04, 2026 Last updated: Apr 04, 2026 |
Comment:
show
The c.1226A>G variant in GBA1 is a missense variant predicted to cause substitution of asparagine to serine at amino acid 409. This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 29920646). Additionally, this variant has been observed to segregate in affected family members (PMID: 29920646). Given the available evidence, this variant is classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jan 20, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
autosomal dominant GBA1-related disorders
(Autosomal dominant inheritance)
|
Variantyx, Inc.
Accession: SCV007600430.1
First in ClinVar: Jun 06, 2026 Last updated: Jun 06, 2026 |
Comment:
show
This is a nonsynonymous variant in the GBA1 gene (OMIM: 606463). Pathogenic variants in this gene have been associated with autosomal dominant GBA1-related disorders (rick factor). The frequency of this variant in affected individuals is significantly increased compared to controls (PMID: 23676350, 25249066, 28779532, 26096741) (PS4). Functional studies have shown that this variant alters GBA protein function (PMID: 22592100, 8294487, 22160715) (PS3), and multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.673) (PP3). This variant has a 0.1728% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the current evidence, this variant is classified as pathogenic for autosomal dominant GBA1-related disorders (risk factor). (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(May 11, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease type I |
3billion
Accession: SCV007609830.1
First in ClinVar: Jun 20, 2026 Last updated: Jun 20, 2026 |
Comment:
show
The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.200%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 25456120, 26905200). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.67 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (> 0.75, sensitivity 0.96 and precision 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004290). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 26096741). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Platform type: exome sequencing
|
|
|
Pathogenic
(Jun 01, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000692646.43
First in ClinVar: Feb 15, 2018 Last updated: Jul 27, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 43
|
|
|
Pathogenic
(Jan 26, 2015)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease, type I |
Courtagen Diagnostics Laboratory, Courtagen Life Sciences
Accession: SCV000236536.2
First in ClinVar: Jul 05, 2015 Last updated: Jul 12, 2015 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jun 14, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher Disease |
Illumina Laboratory Services, Illumina
Accession: SCV000348574.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jun 14, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Susceptibility to Parkinson's Disease |
Illumina Laboratory Services, Illumina
Accession: SCV000348575.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely pathogenic
(Feb 19, 2014)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Akinesia
Rigidity |
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492778.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
|
|
|
Pathogenic
(Dec 03, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease type I |
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746370.1
First in ClinVar: Jun 24, 2017 Last updated: Jun 24, 2017 |
Observation: 1
Collection method: clinical testing
Allele origin: inherited
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: inherited
Affected status: yes
Age: 10-19 weeks gestation
Geographic origin: Iran
|
|
|
Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease type I
Gaucher disease type II Gaucher disease type III Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome |
Baylor Genetics
Accession: SCV001162848.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Oct 18, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease type I |
Myriad Genetics, Inc.
Accession: SCV001194072.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
show
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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Jan 01, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease perinatal lethal |
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368701.2
First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020 |
Comment:
show
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS1,PM3,PP3,PP5. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
|
|
|
Pathogenic
(Mar 04, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease perinatal lethal |
Baylor Genetics
Accession: SCV001523473.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
show
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
|
|
|
Pathogenic
(Sep 15, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided
(Autosomal recessive inheritance)
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001905653.1
First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Renal hypoplasia (present) , Renal agenesis (present) , Ventricular septal defect (present) , Polydactyly (present)
|
|
|
Pathogenic
(Jan 10, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV000321702.6
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
Comment:
show
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) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Oct 05, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease type I |
Illumina Laboratory Services, Illumina
Accession: SCV002034836.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
Comment:
show
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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Mar 08, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease type I |
CENTOGENE GmbH and LLC - Guiding Precision Medicine
Accession: SCV002059258.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Mar 23, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501646.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 8
Secondary finding: no
Platform type: NGS
|
|
|
Pathogenic
(Sep 29, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Parkinson disease, late-onset
(Autosomal dominant inheritance)
|
Institute of Human Genetics Munich, TUM University Hospital
Accession: SCV002764719.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Parkinsonian disorder (present)
|
|
|
Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher Disease |
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046061.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
show
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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Nov 25, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease type I |
Baylor Genetics
Accession: SCV003836166.2
First in ClinVar: Mar 11, 2023 Last updated: Dec 24, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Jun 27, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not specified |
Ambry Genetics
Accession: SCV002755618.3
First in ClinVar: Dec 03, 2022 Last updated: Jan 13, 2025 |
Comment:
show
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 pathogenic variant found in autosomal recessive Gaucher disease and is associated with type 1 (non-neuronopathic) disease (Tsuji, 1988). One study including 798 homozygotes and 1278 compound heterozygotes determined this variant can cause a range of phenotypes, from mild adult-onset to pediatric onset with severe complications. However, this variant was not observed to be associated with central nervous system involvement (Fairley, 2008). This variant, with or without a second GBA variant, has also been associated with an increased risk of developing late onset Parkinson disease in multiple, large case-control studies (Sidransky, 2009; Gan-Or, 2015; Smith, 2022; Pitz, 2024). 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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Nov 27, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001471102.8
First in ClinVar: Jan 26, 2021 Last updated: Mar 11, 2025 |
Comment:
show
The GBA c.1226A>G; p.Asn409Ser variant (rs76763715, ClinVar Variation ID: 4290), 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). 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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Mar 30, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease |
Molecular Genetics, Royal Melbourne Hospital
Accession: SCV005900331.1
First in ClinVar: Mar 29, 2025 Last updated: Mar 29, 2025 |
Comment:
show
This sequence change in GBA is predicted to replace asparagine with serine at codon 409, p.(Asn409Ser) (also known as Asn370Ser or N370S). The asparagine residue is moderately conserved (100 vertebrates, UCSC), and is located in the glycosyl hydrolase family 30 TIM-barrel domain. There is a small physicochemical difference between asparagine and serine. The highest population minor allele frequency in gnomAD v2.1 is 2.7% (279/10,368 alleles, 2 homozygotes) in the Ashkenazi Jewish population, while the highest continental population minor allele frequency in gnomAD v2.1 is 0.2% (264/129,124 alleles, 2 homozygotes) in the European (non-Finnish) population. This variant is the most common allele reported in individuals with Gaucher disease, identified in both homozygous and compound heterozygous states (PMID: 11025794). Carriers of the variant have been found to have an increased risk of Parkinson's disease and Lewy body dementia (PMID: 18332251, 19286695, 20947659, 23588557, 33209983). At least one patient with this variant displayed deficient glucocerebrosidase (glucosylceramidase) enzyme activity in fibroblasts, which is highly specific for Gaucher disease (PMID: 8294487, 15826241). Reduced enzyme activity and abnormal protein function has also been demonstrated in heterologous expression systems indicating that this variant impacts protein function (PMID: 8294487, 22160715). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/6 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3_Supporting, PP4. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
|
|
|
Pathogenic
(May 18, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Eurofins Ntd Llc (ga)
Accession: SCV000224863.6
First in ClinVar: Jun 28, 2015 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 105
Zygosity: 16 Homozygotes, 89 Single Heterozygotes
Sex: mixed
|
|
|
Pathogenic
(Nov 20, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Gaucher disease type I
(Autosomal recessive inheritance)
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004175942.2
First in ClinVar: Dec 17, 2023 Last updated: Apr 13, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Clinical Features:
Decreased beta-glucocerebrosidase level (present)
Sex: male
|
|
|
Pathogenic
(Aug 27, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Parkinson disease, late-onset |
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV005395957.2
First in ClinVar: Nov 17, 2024 Last updated: Apr 28, 2025 |
Comment:
show
This missense variant is situated the functional domain Glyco_Hydro_30 and involves a conserved nucleotide. It was found in a heterozygous state. In silico prediction scores for this alteration are discordant. This variant is reported in population databases (v4.1.0), with an allele count of 3223. This variant is reported multiple times in ClinVar as pathogenic (VCV000004290.118). Pathogenic missense variants in this gene have been reported in individuals with Gaucher disease and Parkinsons disease (PMID: 23676350, 25249066, 26096741, 28779532). According to the available evidence, this variant is considered to be pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Jun 05, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
GBA1-related disorder
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV007126246.1
First in ClinVar: Dec 20, 2025 Last updated: Dec 20, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Jan 26, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000936391.7
First in ClinVar: Aug 14, 2019 Last updated: Mar 07, 2026 |
Comment:
show
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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Aug 01, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
GBA1-related disorders
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV007521185.1
First in ClinVar: Mar 28, 2026 Last updated: Mar 28, 2026 |
Comment:
show
This variant is also known in literature as p.Asn370Ser (PMID: 23588557). The c.1226A>G (p.Asn409Ser) variant affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein. This variant has been previously reported as a homozygous and compound heterozygous change in patients with Gaucher disease and correlates with a non-neuropathic phenotype (PMID: 3353383, 26096741, 25558695). The variant has also been reported as a heterozygous change in individuals with Parkinson disease (PMID: 21745757, 25249066). Functional studies demonstrate that this variant leads to reduced glucosylceramidase activity (PMID: 22592100, 8294487, 22160715). The c.1226A>G (p.Asn409Ser) variant is present in the latest version of the gnomAD population database at an allele frequency of 0.2% (3223/1613914), including 8 homozygous individuals. The frequency data for variants in the GBA1 gene in population databases may be unreliable due to the presence of pseudogenes and paralogs (PMID: 20301446). Based on the available evidence, c.1226A>G (p.Asn409Ser) is classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Mar 24, 2015)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Gaucher disease, type I |
Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000238464.1 First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
Comment:
show
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). (less)
Observation: 1
Collection method: research
Allele origin: germline
Affected status: no
Observation 1
Collection method: research
Allele origin: germline
Affected status: no
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Study: VKGL Data-share Consensus
Accession: SCV001951306.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001971110.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Feb 21, 2024)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
GBA1-related condition
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004796704.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
show
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). (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Aug 01, 2010)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
GAUCHER DISEASE, TYPE I |
OMIM
Accession: SCV000024689.5
First in ClinVar: Apr 04, 2013 Last updated: Sep 14, 2020 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Comment on evidence:
Gaucher Disease The asn370-to-ser (N370S) substitution in exon 9 of the GBA gene has been reported as resulting from a 5841A-G transition (Latham et al., … (more)
Gaucher Disease The asn370-to-ser (N370S) substitution in exon 9 of the GBA gene has been reported as resulting from a 5841A-G transition (Latham et al., 1990) and from a 1226A-G transition (Tsuji et al., 1988), depending upon the reference sequence cited. It is the most common Gaucher disease allele in the Ashkenazi Jewish population and is only associated with the nonneuronopathic type I form of Gaucher disease (230800) (Zimran et al., 1989). Tsuji et al. (1988) identified the N370S substitution in an Ashkenazi Jewish patient with type I Gaucher disease. Transient expression studies following oligonucleotide-directed mutagenesis of the normal cDNA confirmed that the mutation results in loss of glucocerebrosidase activity. Allele-specific hybridization with oligonucleotide probes demonstrated that this mutation occurs exclusively with the type I phenotype. None of 6 type II (230900) patients, 11 type III (231000) patients, or 12 normal controls had this allele. In contrast, 15 of 24 type I patients had 1 allele with this mutation, and 3 others were homozygous for the mutation. Furthermore, some of the Ashkenazi Jewish type I patients had only 1 allele with this mutation, suggesting allelic heterogeneity even in this population. One patient with type I disease was compound heterozygous for N370S and L444P (606463.0001). Zimran et al. (1989) found that the N370S substitution was associated with a mild clinical phenotype compared to L444P. Eight of 22 patients homozygous for N370S were entirely symptom-free. In symptomatic patients, the clinical features of the N370S homozygotes were usually related to splenomegaly and thrombocytopenia. Kolodny et al. (1989, 1990) studied an unusual Ashkenazi Jewish family with affected members in 3 successive generations. Both N370S and L444P segregated in the family; 4 affected individuals were homozygous for N370S mutation, while 3 others were compound heterozygotes for the 2 mutations. Clinical severity was more marked in compound heterozygotes than in homozygotes. Firon et al. (1990) found the N370S mutation in type I patients only. Zimran et al. (1990) identified a 3931G-A polymorphism in intron 6 of the GBA gene, termed PvuII. Analysis of 54 unrelated Jewish Gaucher patients showed strong linkage disequilibrium between the negative polymorphism genotype and the common Jewish N370S mutation. Among 593 unrelated normal Ashkenazi Jewish individuals, Zimran et al. (1991) identified 37 heterozygotes and 2 homozygotes for the N370S mutation, yielding an allele frequency of 0.035. Among 1,528 Ashkenazi Jewish individuals, Beutler et al. (1993) identified 87 heterozygotes and 4 homozygotes for N370S, yielding a frequency of 0.0311; pooling with data reported by Zimran et al. (1991) yielded a frequency of 0.032 for the N370S allele. Mistry et al. (1992) used the amplification refractory mutation system (ARMS) for direct detection of GBA mutations in Gaucher disease. PCR primers were designed to discriminate between mutant and wildtype alleles and to allow separation from products of the related pseudogene. The N370S mutation and a 2-bp insertion (84insGG; 606463.0014) were found exclusively in 5 patients of Ashkenazi Jewish descent. Van Weely et al. (1993) studied the properties of control and N370S mutant GBA in vitro and in vivo. The results indicated that the intralysosomal pH in the intact cell has a critical influence on the activation state of N370S GBA and its ability to hydrolyze substrate. This phenomenon may partly explain the clinical heterogeneity in patients with Gaucher disease caused by the N370S mutation. Walley et al. (1993) found that the N370S mutation accounted for 26% of Gaucher disease alleles among non-Jewish patients in the United Kingdom (total alleles = 54). They found a correlation between the presence of at least 1 N370S allele and mild disease. The L444P mutation accounted for 35% of the alleles and the remaining 39% were rare or undefined. The N370S mutation and the 84insGG mutation reportedly account for approximately 70% and 10%, respectively, of mutations in the Jewish population. Ida et al. (1995) found neither mutation in 32 unrelated Japanese Gaucher patients, of whom 20 were type I, 6 were type II, and 6 were type III. Cormand et al. (1998) found that N370S and L444P accounted for 66.1% of Gaucher disease alleles in Spain. Linkage disequilibrium was detected between these 2 mutations and an intragenic polymorphism, indicating that expansion of founder alleles occurred in both cases. Analysis of several microsatellite markers close to the GBA gene allowed them to establish a putative haplotype of the ancestral N370S chromosome. Koprivica et al. (2000) found that homozygosity or heterozygosity for N370S resulted in type I Gaucher disease. Dimitriou et al. (2010) determined that the frequency of the N370S allele is 0.0046 in the Greek population. Parkinson Disease and Lewy Body Dementia Mata et al. (2008) identified heterozygosity for the N370S mutation in 11 (1.5%) of 721 patients with Parkinson disease (PD; 168600), 1 (1.8%) of 57 patients with Lewy body dementia (DLB; 127750), and 2 (0.4%) of 554 control individuals. All individuals were of European origin. Mata et al. (2008) estimated that the population-attributable risk for GBA mutations in Lewy body disorders was only about 3% in patients of European ancestry. Neumann et al. (2009) identified a heterozygous N370S mutation in 8 (1.01%) of 790 British patients with PD and in 1 (0.39%) of 257 controls. (less)
|
|
|
risk factor
(Aug 01, 2010)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
PARKINSON DISEASE, LATE-ONSET SUSCEPTIBILITY TO |
OMIM
Accession: SCV000024690.5
First in ClinVar: Apr 04, 2013 Last updated: Sep 14, 2020 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Comment on evidence:
Gaucher Disease The asn370-to-ser (N370S) substitution in exon 9 of the GBA gene has been reported as resulting from a 5841A-G transition (Latham et al., … (more)
Gaucher Disease The asn370-to-ser (N370S) substitution in exon 9 of the GBA gene has been reported as resulting from a 5841A-G transition (Latham et al., 1990) and from a 1226A-G transition (Tsuji et al., 1988), depending upon the reference sequence cited. It is the most common Gaucher disease allele in the Ashkenazi Jewish population and is only associated with the nonneuronopathic type I form of Gaucher disease (230800) (Zimran et al., 1989). Tsuji et al. (1988) identified the N370S substitution in an Ashkenazi Jewish patient with type I Gaucher disease. Transient expression studies following oligonucleotide-directed mutagenesis of the normal cDNA confirmed that the mutation results in loss of glucocerebrosidase activity. Allele-specific hybridization with oligonucleotide probes demonstrated that this mutation occurs exclusively with the type I phenotype. None of 6 type II (230900) patients, 11 type III (231000) patients, or 12 normal controls had this allele. In contrast, 15 of 24 type I patients had 1 allele with this mutation, and 3 others were homozygous for the mutation. Furthermore, some of the Ashkenazi Jewish type I patients had only 1 allele with this mutation, suggesting allelic heterogeneity even in this population. One patient with type I disease was compound heterozygous for N370S and L444P (606463.0001). Zimran et al. (1989) found that the N370S substitution was associated with a mild clinical phenotype compared to L444P. Eight of 22 patients homozygous for N370S were entirely symptom-free. In symptomatic patients, the clinical features of the N370S homozygotes were usually related to splenomegaly and thrombocytopenia. Kolodny et al. (1989, 1990) studied an unusual Ashkenazi Jewish family with affected members in 3 successive generations. Both N370S and L444P segregated in the family; 4 affected individuals were homozygous for N370S mutation, while 3 others were compound heterozygotes for the 2 mutations. Clinical severity was more marked in compound heterozygotes than in homozygotes. Firon et al. (1990) found the N370S mutation in type I patients only. Zimran et al. (1990) identified a 3931G-A polymorphism in intron 6 of the GBA gene, termed PvuII. Analysis of 54 unrelated Jewish Gaucher patients showed strong linkage disequilibrium between the negative polymorphism genotype and the common Jewish N370S mutation. Among 593 unrelated normal Ashkenazi Jewish individuals, Zimran et al. (1991) identified 37 heterozygotes and 2 homozygotes for the N370S mutation, yielding an allele frequency of 0.035. Among 1,528 Ashkenazi Jewish individuals, Beutler et al. (1993) identified 87 heterozygotes and 4 homozygotes for N370S, yielding a frequency of 0.0311; pooling with data reported by Zimran et al. (1991) yielded a frequency of 0.032 for the N370S allele. Mistry et al. (1992) used the amplification refractory mutation system (ARMS) for direct detection of GBA mutations in Gaucher disease. PCR primers were designed to discriminate between mutant and wildtype alleles and to allow separation from products of the related pseudogene. The N370S mutation and a 2-bp insertion (84insGG; 606463.0014) were found exclusively in 5 patients of Ashkenazi Jewish descent. Van Weely et al. (1993) studied the properties of control and N370S mutant GBA in vitro and in vivo. The results indicated that the intralysosomal pH in the intact cell has a critical influence on the activation state of N370S GBA and its ability to hydrolyze substrate. This phenomenon may partly explain the clinical heterogeneity in patients with Gaucher disease caused by the N370S mutation. Walley et al. (1993) found that the N370S mutation accounted for 26% of Gaucher disease alleles among non-Jewish patients in the United Kingdom (total alleles = 54). They found a correlation between the presence of at least 1 N370S allele and mild disease. The L444P mutation accounted for 35% of the alleles and the remaining 39% were rare or undefined. The N370S mutation and the 84insGG mutation reportedly account for approximately 70% and 10%, respectively, of mutations in the Jewish population. Ida et al. (1995) found neither mutation in 32 unrelated Japanese Gaucher patients, of whom 20 were type I, 6 were type II, and 6 were type III. Cormand et al. (1998) found that N370S and L444P accounted for 66.1% of Gaucher disease alleles in Spain. Linkage disequilibrium was detected between these 2 mutations and an intragenic polymorphism, indicating that expansion of founder alleles occurred in both cases. Analysis of several microsatellite markers close to the GBA gene allowed them to establish a putative haplotype of the ancestral N370S chromosome. Koprivica et al. (2000) found that homozygosity or heterozygosity for N370S resulted in type I Gaucher disease. Dimitriou et al. (2010) determined that the frequency of the N370S allele is 0.0046 in the Greek population. Parkinson Disease and Lewy Body Dementia Mata et al. (2008) identified heterozygosity for the N370S mutation in 11 (1.5%) of 721 patients with Parkinson disease (PD; 168600), 1 (1.8%) of 57 patients with Lewy body dementia (DLB; 127750), and 2 (0.4%) of 554 control individuals. All individuals were of European origin. Mata et al. (2008) estimated that the population-attributable risk for GBA mutations in Lewy body disorders was only about 3% in patients of European ancestry. Neumann et al. (2009) identified a heterozygous N370S mutation in 8 (1.01%) of 790 British patients with PD and in 1 (0.39%) of 257 controls. (less)
|
|
|
risk factor
(Aug 01, 2010)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
DEMENTIA, LEWY BODY, SUSCEPTIBILITY TO |
OMIM
Accession: SCV000024691.5
First in ClinVar: Apr 04, 2013 Last updated: Sep 14, 2020 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Comment on evidence:
Gaucher Disease The asn370-to-ser (N370S) substitution in exon 9 of the GBA gene has been reported as resulting from a 5841A-G transition (Latham et al., … (more)
Gaucher Disease The asn370-to-ser (N370S) substitution in exon 9 of the GBA gene has been reported as resulting from a 5841A-G transition (Latham et al., 1990) and from a 1226A-G transition (Tsuji et al., 1988), depending upon the reference sequence cited. It is the most common Gaucher disease allele in the Ashkenazi Jewish population and is only associated with the nonneuronopathic type I form of Gaucher disease (230800) (Zimran et al., 1989). Tsuji et al. (1988) identified the N370S substitution in an Ashkenazi Jewish patient with type I Gaucher disease. Transient expression studies following oligonucleotide-directed mutagenesis of the normal cDNA confirmed that the mutation results in loss of glucocerebrosidase activity. Allele-specific hybridization with oligonucleotide probes demonstrated that this mutation occurs exclusively with the type I phenotype. None of 6 type II (230900) patients, 11 type III (231000) patients, or 12 normal controls had this allele. In contrast, 15 of 24 type I patients had 1 allele with this mutation, and 3 others were homozygous for the mutation. Furthermore, some of the Ashkenazi Jewish type I patients had only 1 allele with this mutation, suggesting allelic heterogeneity even in this population. One patient with type I disease was compound heterozygous for N370S and L444P (606463.0001). Zimran et al. (1989) found that the N370S substitution was associated with a mild clinical phenotype compared to L444P. Eight of 22 patients homozygous for N370S were entirely symptom-free. In symptomatic patients, the clinical features of the N370S homozygotes were usually related to splenomegaly and thrombocytopenia. Kolodny et al. (1989, 1990) studied an unusual Ashkenazi Jewish family with affected members in 3 successive generations. Both N370S and L444P segregated in the family; 4 affected individuals were homozygous for N370S mutation, while 3 others were compound heterozygotes for the 2 mutations. Clinical severity was more marked in compound heterozygotes than in homozygotes. Firon et al. (1990) found the N370S mutation in type I patients only. Zimran et al. (1990) identified a 3931G-A polymorphism in intron 6 of the GBA gene, termed PvuII. Analysis of 54 unrelated Jewish Gaucher patients showed strong linkage disequilibrium between the negative polymorphism genotype and the common Jewish N370S mutation. Among 593 unrelated normal Ashkenazi Jewish individuals, Zimran et al. (1991) identified 37 heterozygotes and 2 homozygotes for the N370S mutation, yielding an allele frequency of 0.035. Among 1,528 Ashkenazi Jewish individuals, Beutler et al. (1993) identified 87 heterozygotes and 4 homozygotes for N370S, yielding a frequency of 0.0311; pooling with data reported by Zimran et al. (1991) yielded a frequency of 0.032 for the N370S allele. Mistry et al. (1992) used the amplification refractory mutation system (ARMS) for direct detection of GBA mutations in Gaucher disease. PCR primers were designed to discriminate between mutant and wildtype alleles and to allow separation from products of the related pseudogene. The N370S mutation and a 2-bp insertion (84insGG; 606463.0014) were found exclusively in 5 patients of Ashkenazi Jewish descent. Van Weely et al. (1993) studied the properties of control and N370S mutant GBA in vitro and in vivo. The results indicated that the intralysosomal pH in the intact cell has a critical influence on the activation state of N370S GBA and its ability to hydrolyze substrate. This phenomenon may partly explain the clinical heterogeneity in patients with Gaucher disease caused by the N370S mutation. Walley et al. (1993) found that the N370S mutation accounted for 26% of Gaucher disease alleles among non-Jewish patients in the United Kingdom (total alleles = 54). They found a correlation between the presence of at least 1 N370S allele and mild disease. The L444P mutation accounted for 35% of the alleles and the remaining 39% were rare or undefined. The N370S mutation and the 84insGG mutation reportedly account for approximately 70% and 10%, respectively, of mutations in the Jewish population. Ida et al. (1995) found neither mutation in 32 unrelated Japanese Gaucher patients, of whom 20 were type I, 6 were type II, and 6 were type III. Cormand et al. (1998) found that N370S and L444P accounted for 66.1% of Gaucher disease alleles in Spain. Linkage disequilibrium was detected between these 2 mutations and an intragenic polymorphism, indicating that expansion of founder alleles occurred in both cases. Analysis of several microsatellite markers close to the GBA gene allowed them to establish a putative haplotype of the ancestral N370S chromosome. Koprivica et al. (2000) found that homozygosity or heterozygosity for N370S resulted in type I Gaucher disease. Dimitriou et al. (2010) determined that the frequency of the N370S allele is 0.0046 in the Greek population. Parkinson Disease and Lewy Body Dementia Mata et al. (2008) identified heterozygosity for the N370S mutation in 11 (1.5%) of 721 patients with Parkinson disease (PD; 168600), 1 (1.8%) of 57 patients with Lewy body dementia (DLB; 127750), and 2 (0.4%) of 554 control individuals. All individuals were of European origin. Mata et al. (2008) estimated that the population-attributable risk for GBA mutations in Lewy body disorders was only about 3% in patients of European ancestry. Neumann et al. (2009) identified a heterozygous N370S mutation in 8 (1.01%) of 790 British patients with PD and in 1 (0.39%) of 257 controls. (less)
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740270.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
not provided
(-)
N
Not contributing to aggregate classification
|
no classification provided
|
Gaucher disease |
GenomeConnect, ClinGen
Accession: SCV000607211.2
First in ClinVar: Oct 14, 2017 Last updated: Apr 13, 2025 |
Comment:
show
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. (less)
Observation: 1
Collection method: phenotyping only
Allele origin: maternal
Affected status: unknown
Observation 1
Collection method: phenotyping only
Allele origin: maternal
Affected status: unknown
Clinical Features:
Oral-pharyngeal dysphagia (present) , Abnormality of the skull (present) , Hypermetropia (present) , Seizures (present) , Abnormality of movement (present) , Generalized hypotonia (present) , Hypertonia (present) , Encephalopathy (present) , EEG abnormality (present) , Abnormality of coordination (present) , Cognitive impairment (present) , Cerebral palsy (present) , Abnormality of the curvature of the vertebral column (present) , Abnormality of the musculature of the pelvis (present) , Abnormality of the musculature of the thorax (present) , Abnormality of the musculature of the limbs (present) , Abnormality of muscle physiology (present) , Feeding difficulties (present)
Indication for testing: Diagnostic
Test name: Exome Sequencing
Age: 0-9 years
Sex: male
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-02-14
Testing laboratory interpretation: Pathogenic
|
|
|
not provided
(-)
N
Not contributing to aggregate classification
|
no classification provided
|
Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome
Gaucher disease type III Gaucher disease type I Gaucher disease type II Gaucher disease perinatal lethal Parkinson disease, late-onset Lewy body dementia |
GenomeConnect, ClinGen
Accession: SCV000986753.2
First in ClinVar: Aug 31, 2019 Last updated: Apr 13, 2025 |
Comment:
show
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. (less)
Observation 1
Collection method: phenotyping only
Allele origin: unknown
Affected status: no
Clinical Features:
Abnormality of the optic nerve (present) , Ptosis (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Abnormality of movement (present) , Abnormality of muscle physiology (present)
Age: 0-9 years
Sex: male
Platform type: Gene Panel Sequencing|Triplet Repeat
Testing laboratory: MNG Laboratories (Medical Neurogenetics, LLC.)
Date variant was reported to submitter: 2017-04-12
Testing laboratory interpretation: Pathogenic
|
|
|
not provided
(-)
N
Not contributing to aggregate classification
|
no classification provided
|
Gaucher disease |
GeneReviews
Accession: SCV002586408.1
First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(May 01, 2020)
N
Not contributing to aggregate classification
|
Flagged submission
flagged submission
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Thrombocytopenia
Abnormal bleeding |
Birmingham Platelet Group; University of Birmingham
Accession: SCV001450827.1
First in ClinVar: Dec 19, 2020 Last updated: Dec 19, 2020 |
Observation: 1
Collection method: research
Allele origin: germline
Affected status: yes
Observation 1
Collection method: research
Allele origin: germline
Affected status: yes
|
|
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Citation text
Kolodny, E., Firon, N., Natowicz, M., Horowitz, M. Gaucher disease in three successive generations of an Ashkenazi Jewish family: analysis of intrafamilial clinical variability by molecular diagnosis. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A202-only, 1989.
Citation text
Kolodny, E., Firon, N., Natowicz, M., Horowitz, M. Gaucher disease in three successive generations of an Ashkenazi Jewish family: analysis of intrafamilial clinical variability by molecular diagnosis. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A202-only, 1989.
Citation text
Kolodny, E., Firon, N., Natowicz, M., Horowitz, M. Gaucher disease in three successive generations of an Ashkenazi Jewish family: analysis of intrafamilial clinical variability by molecular diagnosis. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A202-only, 1989.
Comment:
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.
Comment:
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.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.5, 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 (MIM# 230800, 230900, 231000, 231005, 608013). (I) 0106 - This gene is associated with autosomal recessive disease. The different types of Gaucher disease are considered to fall within a spectrum, rather than distinct conditions, and are determined by age of disease onset and the presence and severity of neurologic function. Specific counselling about individual case prognosis is hindered by a significant overlap in the clinical features of individuals with various genotypes (OMIM, PMID: 20301446). (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). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition (v4) (3207 heterozygotes, 8 homozygotes). (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4) (2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated glycosyl hydrolase family 30 TIM-barrel domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant, also known as N370S due to alternate nomenclature, is a well-established pathogenic variant associated Gaucher disease Type 1. It is has been reported as a mild allele, where homozygous carriers my remain asymptomatic (ClinVar; PMID: 31010158, 20301446). Association studies have also shown that this variant, in the heterozygous state, may confer increased risk for Parkinson Disease (PMID: 25249066; 26868973, 31010158) (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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).
Comment:
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.
Comment:
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
Comment:
The c.1226A>G variant in GBA1 is a missense variant predicted to cause substitution of asparagine to serine at amino acid 409. This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 29920646). Additionally, this variant has been observed to segregate in affected family members (PMID: 29920646). Given the available evidence, this variant is classified as Pathogenic.
Comment:
This is a nonsynonymous variant in the GBA1 gene (OMIM: 606463). Pathogenic variants in this gene have been associated with autosomal dominant GBA1-related disorders (rick factor). The frequency of this variant in affected individuals is significantly increased compared to controls (PMID: 23676350, 25249066, 28779532, 26096741) (PS4). Functional studies have shown that this variant alters GBA protein function (PMID: 22592100, 8294487, 22160715) (PS3), and multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.673) (PP3). This variant has a 0.1728% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the current evidence, this variant is classified as pathogenic for autosomal dominant GBA1-related disorders (risk factor).
Comment:
The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.200%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 25456120, 26905200). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.67 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (> 0.75, sensitivity 0.96 and precision 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004290). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 26096741). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
GBA1: PM3:Strong, PP1:Strong, PS3, PM1, PM2:Supporting
Comment:
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.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS1,PM3,PP3,PP5.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
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)
Comment:
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.
Comment:
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.
Comment:
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 pathogenic variant found in autosomal recessive Gaucher disease and is associated with type 1 (non-neuronopathic) disease (Tsuji, 1988). One study including 798 homozygotes and 1278 compound heterozygotes determined this variant can cause a range of phenotypes, from mild adult-onset to pediatric onset with severe complications. However, this variant was not observed to be associated with central nervous system involvement (Fairley, 2008). This variant, with or without a second GBA variant, has also been associated with an increased risk of developing late onset Parkinson disease in multiple, large case-control studies (Sidransky, 2009; Gan-Or, 2015; Smith, 2022; Pitz, 2024). 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.
Comment:
The GBA c.1226A>G; p.Asn409Ser variant (rs76763715, ClinVar Variation ID: 4290), 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). 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.
Comment:
This sequence change in GBA is predicted to replace asparagine with serine at codon 409, p.(Asn409Ser) (also known as Asn370Ser or N370S). The asparagine residue is moderately conserved (100 vertebrates, UCSC), and is located in the glycosyl hydrolase family 30 TIM-barrel domain. There is a small physicochemical difference between asparagine and serine. The highest population minor allele frequency in gnomAD v2.1 is 2.7% (279/10,368 alleles, 2 homozygotes) in the Ashkenazi Jewish population, while the highest continental population minor allele frequency in gnomAD v2.1 is 0.2% (264/129,124 alleles, 2 homozygotes) in the European (non-Finnish) population. This variant is the most common allele reported in individuals with Gaucher disease, identified in both homozygous and compound heterozygous states (PMID: 11025794). Carriers of the variant have been found to have an increased risk of Parkinson's disease and Lewy body dementia (PMID: 18332251, 19286695, 20947659, 23588557, 33209983). At least one patient with this variant displayed deficient glucocerebrosidase (glucosylceramidase) enzyme activity in fibroblasts, which is highly specific for Gaucher disease (PMID: 8294487, 15826241). Reduced enzyme activity and abnormal protein function has also been demonstrated in heterologous expression systems indicating that this variant impacts protein function (PMID: 8294487, 22160715). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/6 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3_Supporting, PP4.
Comment:
Criteria applied: PM3_VSTR,PS3_SUP,PP3
Comment:
This missense variant is situated the functional domain Glyco_Hydro_30 and involves a conserved nucleotide. It was found in a heterozygous state. In silico prediction scores for this alteration are discordant. This variant is reported in population databases (v4.1.0), with an allele count of 3223. This variant is reported multiple times in ClinVar as pathogenic (VCV000004290.118). Pathogenic missense variants in this gene have been reported in individuals with Gaucher disease and Parkinsons disease (PMID: 23676350, 25249066, 26096741, 28779532). According to the available evidence, this variant is considered to be pathogenic.
Comment:
PS3, PM3_Strong
Comment:
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.
Comment:
This variant is also known in literature as p.Asn370Ser (PMID: 23588557). The c.1226A>G (p.Asn409Ser) variant affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein. This variant has been previously reported as a homozygous and compound heterozygous change in patients with Gaucher disease and correlates with a non-neuropathic phenotype (PMID: 3353383, 26096741, 25558695). The variant has also been reported as a heterozygous change in individuals with Parkinson disease (PMID: 21745757, 25249066). Functional studies demonstrate that this variant leads to reduced glucosylceramidase activity (PMID: 22592100, 8294487, 22160715). The c.1226A>G (p.Asn409Ser) variant is present in the latest version of the gnomAD population database at an allele frequency of 0.2% (3223/1613914), including 8 homozygous individuals. The frequency data for variants in the GBA1 gene in population databases may be unreliable due to the presence of pseudogenes and paralogs (PMID: 20301446). Based on the available evidence, c.1226A>G (p.Asn409Ser) is classified as Pathogenic.
Comment:
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).
Comment:
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).
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Analysis of rare Parkinson's disease variants in millions of people. | Pitz V | NPJ Parkinson's disease | 2024 | PMID: 38191580 |
| Gaucher Disease. | Adam MP | - | 2023 | PMID: 20301446 |
| GBA Variants and Parkinson Disease: Mechanisms and Treatments. | Smith L | Cells | 2022 | PMID: 35455941 |
| Parental exome analysis identifies shared carrier status for a second recessive disorder in couples with an affected child. | Mor-Shaked H | European journal of human genetics : EJHG | 2021 | PMID: 33223529 |
| Genetic characterization of the Albanian Gaucher disease patient population. | Cullufi P | JIMD reports | 2020 | PMID: 33473340 |
| Novel Variants in LRRK2 and GBA Identified in Latino Parkinson Disease Cohort Enriched for Caribbean Origin. | Nuytemans K | Frontiers in neurology | 2020 | PMID: 33281709 |
| The SPID-GBA study: Sex distribution, Penetrance, Incidence, and Dementia in GBA-PD. | Straniero L | Neurology. Genetics | 2020 | PMID: 33209983 |
| Association Between Glucocerebrosidase Mutations and Parkinson's Disease in Ireland. | Olszewska DA | Frontiers in neurology | 2020 | PMID: 32714263 |
| GBA-Related Parkinson's Disease: Dissection of Genotype-Phenotype Correlates in a Large Italian Cohort. | Petrucci S | Movement disorders : official journal of the Movement Disorder Society | 2020 | PMID: 32658388 |
| The N370S/R496H genotype in type 1 Gaucher disease - Natural history and implications for pre symptomatic diagnosis and counseling. | Zeid N | Molecular genetics and metabolism reports | 2020 | PMID: 32042592 |
| Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies. | Orme T | Acta neuropathologica communications | 2020 | PMID: 31996268 |
| GBA, Gaucher Disease, and Parkinson's Disease: From Genetic to Clinic to New Therapeutic Approaches. | Riboldi GM | Cells | 2019 | PMID: 31010158 |
| Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project. | Ceyhan-Birsoy O | American journal of human genetics | 2019 | PMID: 30609409 |
| Generation of two iPSC lines derived from two unrelated patients with Gaucher disease. | Nagel M | Stem cell research | 2019 | PMID: 30606667 |
| Genetic analysis of neurodegenerative diseases in a pathology cohort. | Blauwendraat C | Neurobiology of aging | 2019 | PMID: 30528841 |
| Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson's disease. | Ruskey JA | European journal of medical genetics | 2019 | PMID: 29842932 |
| Gaucher Disease Involving Virchow's Lymph Node: a Case Report. | Zinovkin DA | Folia medica | 2018 | PMID: 31188768 |
| High-frequency actionable pathogenic exome variants in an average-risk cohort. | Rego S | Cold Spring Harbor molecular case studies | 2018 | PMID: 30487145 |
| Corticobasal syndrome in a man with Gaucher disease type 1: Expansion of the understanding of the neurological spectrum. | Potnis KC | Molecular genetics and metabolism reports | 2018 | PMID: 30364808 |
| Coding variation in GBA explains the majority of the SYT11-GBA Parkinson's disease GWAS locus. | Blauwendraat C | Movement disorders : official journal of the Movement Disorder Society | 2018 | PMID: 30302829 |
| A novel Parkinson's disease risk variant, p. W378R, in the Gaucher's disease GBA gene. | Lubomski M | Movement disorders : official journal of the Movement Disorder Society | 2018 | PMID: 30216542 |
| Mutation analysis of Parkinson's disease genes in a Russian data set. | Emelyanov AK | Neurobiology of aging | 2018 | PMID: 30146349 |
| The GBA p.Trp378Gly mutation is a probable French-Canadian founder mutation causing Gaucher disease and synucleinopathies. | Ruskey JA | Clinical genetics | 2018 | PMID: 29920646 |
| A pilot screening of high-risk Gaucher disease children using dried blood spot methods in Shandong province of China. | Lei K | Orphanet journal of rare diseases | 2018 | PMID: 29625627 |
| Integrated Genetic Analysis of Racial Differences of Common GBA Variants in Parkinson's Disease: A Meta-Analysis. | Zhang Y | Frontiers in molecular neuroscience | 2018 | PMID: 29527153 |
| Glucocerebrosidase gene variants are accumulated in idiopathic REM sleep behavior disorder. | Gámez-Valero A | Parkinsonism & related disorders | 2018 | PMID: 29487000 |
| The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants. | Reuter MS | CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne | 2018 | PMID: 29431110 |
| Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease. | Robak LA | Brain : a journal of neurology | 2017 | PMID: 29140481 |
| Genetic risk factors in Finnish patients with Parkinson's disease. | Ylönen S | Parkinsonism & related disorders | 2017 | PMID: 29029963 |
| Frequency of GBA variants in autopsy-proven multiple system atrophy. | Sklerov M | Movement disorders clinical practice | 2017 | PMID: 28966932 |
| Insights into the structural biology of Gaucher disease. | Smith L | Experimental neurology | 2017 | PMID: 28923368 |
| GBA mutations in Parkinson disease: earlier death but similar neuropathological features. | Adler CH | European journal of neurology | 2017 | PMID: 28834018 |
| N370S-GBA1 mutation causes lysosomal cholesterol accumulation in Parkinson's disease. | García-Sanz P | Movement disorders : official journal of the Movement Disorder Society | 2017 | PMID: 28779532 |
| Early manifestations of type 1 Gaucher disease in presymptomatic children diagnosed after parental carrier screening. | Yang AC | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27735925 |
| Nine-year experience in Gaucher disease diagnosis at the Spanish reference center Fundación Jiménez Díaz. | Ortiz-Cabrera NV | Molecular genetics and metabolism reports | 2016 | PMID: 27872820 |
| Genome-wide assessment of Parkinson's disease in a Southern Spanish population. | Bandrés-Ciga S | Neurobiology of aging | 2016 | PMID: 27393345 |
| Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies. | Geiger JT | Neurobiology of disease | 2016 | PMID: 27312774 |
| Is one diagnosis the whole story? patients with double diagnoses. | Kurolap A | American journal of medical genetics. Part A | 2016 | PMID: 27271787 |
| Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
| Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson's Disease. | Benitez BA | Molecular neurodegeneration | 2016 | PMID: 27094865 |
| ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons. | Fernandes HJ | Stem cell reports | 2016 | PMID: 26905200 |
| Mutations of glucocerebrosidase gene and susceptibility to Parkinson's disease: An updated meta-analysis in a European population. | Zhao F | Neuroscience | 2016 | PMID: 26868973 |
| Gaucher disease types 1 and 3: Phenotypic characterization of large populations from the ICGG Gaucher Registry. | Grabowski GA | American journal of hematology | 2015 | PMID: 26096741 |
| Differential effects of severe vs mild GBA mutations on Parkinson disease. | Gan-Or Z | Neurology | 2015 | PMID: 25653295 |
| An update of Gaucher mutations distribution in the Ashkenazi Jewish population: prevalence and country of origin of the mutation R496H. | Bronstein S | The Israel Medical Association journal : IMAJ | 2014 | PMID: 25558695 |
| iPSC-derived dopamine neurons reveal differences between monozygotic twins discordant for Parkinson's disease. | Woodard CM | Cell reports | 2014 | PMID: 25456120 |
| Disease variants in genomes of 44 centenarians. | Freudenberg-Hua Y | Molecular genetics & genomic medicine | 2014 | PMID: 25333069 |
| Glucocerebrosidase mutations in primary parkinsonism. | Asselta R | Parkinsonism & related disorders | 2014 | PMID: 25249066 |
| Cognitive impairment in carriers of glucocerebrosidase gene mutation in Parkinson disease patients. | Malec-Litwinowicz M | Neurologia i neurochirurgia polska | 2014 | PMID: 25168325 |
| Comparison of Parkinson risk in Ashkenazi Jewish patients with Gaucher disease and GBA heterozygotes. | Alcalay RN | JAMA neurology | 2014 | PMID: 24756352 |
| Two novel mutations in glucocerebrosidase, C23W and IVS7-1 G>A, identified in Type 1 Gaucher patients heterozygous for N370S. | Jack A | Gene | 2014 | PMID: 24434810 |
| Recurrent pulmonary aspergillosis and mycobacterial infection in an unsplenectomized patient with type 1 Gaucher disease. | Machaczka M | Upsala journal of medical sciences | 2014 | PMID: 24195576 |
| Functional analysis of 11 novel GBA alleles. | Malini E | European journal of human genetics : EJHG | 2014 | PMID: 24022302 |
| Unfolded protein response in Gaucher disease: from human to Drosophila. | Maor G | Orphanet journal of rare diseases | 2013 | PMID: 24020503 |
| Mutations in GBA and risk of Parkinson's disease: a meta-analysis based on 25 case-control studies. | Mao X | Neurological research | 2013 | PMID: 23676350 |
| Transgenic mice expressing human glucocerebrosidase variants: utility for the study of Gaucher disease. | Sanders A | Blood cells, molecules & diseases | 2013 | PMID: 23642305 |
| A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies. | Nalls MA | JAMA neurology | 2013 | PMID: 23588557 |
| Histone deacetylase inhibitors increase glucocerebrosidase activity in Gaucher disease by modulation of molecular chaperones. | Yang C | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 23277556 |
| An informatics approach to analyzing the incidentalome. | Berg JS | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22995991 |
| An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. | Lazarin GA | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22975760 |
| Greater risk of parkinsonism associated with non-N370S GBA1 mutations. | Barrett MJ | Journal of inherited metabolic disease | 2013 | PMID: 22968580 |
| Age-specific Parkinson disease risk in GBA mutation carriers: information for genetic counseling. | Rana HQ | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22935721 |
| Characterization of the N370S mutant of glucocerebrosidase by hydrogen/deuterium exchange mass spectrometry. | Tang L | Chembiochem : a European journal of chemical biology | 2012 | PMID: 22961873 |
| Gaucher disease paradigm: from ERAD to comorbidity. | Bendikov-Bar I | Human mutation | 2012 | PMID: 22623374 |
| Pharmacological chaperones facilitate the post-ER transport of recombinant N370S mutant β-glucocerebrosidase in plant cells: evidence that N370S is a folding mutant. | Babajani G | Molecular genetics and metabolism | 2012 | PMID: 22592100 |
| Meta-analysis of Parkinson's disease: identification of a novel locus, RIT2. | Pankratz N | Annals of neurology | 2012 | PMID: 22451204 |
| Genome-wide association study of N370S homozygous Gaucher disease reveals the candidacy of CLN8 gene as a genetic modifier contributing to extreme phenotypic variation. | Zhang CK | American journal of hematology | 2012 | PMID: 22388998 |
| Gaucher disease: a pyrosequencing frequency analysis of the N370S and L444P mutations in the Spanish population. | García-Rodríguez B | Clinical genetics | 2012 | PMID: 22220748 |
| Glucocerebrosidase N370S and L444P mutations as risk factors for Parkinson's disease in Brazilian patients. | Guimarães Bde C | Parkinsonism & related disorders | 2012 | PMID: 22192918 |
| Histone deacetylase inhibitors prevent the degradation and restore the activity of glucocerebrosidase in Gaucher disease. | Lu J | Proceedings of the National Academy of Sciences of the United States of America | 2011 | PMID: 22160715 |
| β-Glucocerebrosidase gene mutations in two cohorts of Greek patients with sporadic Parkinson's disease. | Moraitou M | Molecular genetics and metabolism | 2011 | PMID: 21745757 |
| Aggregation of α-synuclein in brain samples from subjects with glucocerebrosidase mutations. | Choi JH | Molecular genetics and metabolism | 2011 | PMID: 21742527 |
| Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. | Mazzulli JR | Cell | 2011 | PMID: 21700325 |
| Alpha-synuclein interacts with Glucocerebrosidase providing a molecular link between Parkinson and Gaucher diseases. | Yap TL | The Journal of biological chemistry | 2011 | PMID: 21653695 |
| Acid β-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter α-synuclein processing. | Cullen V | Annals of neurology | 2011 | PMID: 21472771 |
| Gaucher disease: when molecular testing and clinical presentation disagree -the novel c.1226A>G(p.N370S)--RecNcil allele. | Balwani M | Journal of inherited metabolic disease | 2011 | PMID: 21431620 |
| Carrier testing for severe childhood recessive diseases by next-generation sequencing. | Bell CJ | Science translational medicine | 2011 | PMID: 21228398 |
| X-ray and biochemical analysis of N370S mutant human acid β-glucosidase. | Wei RR | The Journal of biological chemistry | 2011 | PMID: 20980263 |
| Large-scale screening of the Gaucher's disease-related glucocerebrosidase gene in Europeans with Parkinson's disease. | Lesage S | Human molecular genetics | 2011 | PMID: 20947659 |
| Molecular basis of reduced glucosylceramidase activity in the most common Gaucher disease mutant, N370S. | Offman MN | The Journal of biological chemistry | 2010 | PMID: 20980259 |
| Type 1 Gaucher disease: significant disease manifestations in "asymptomatic" homozygotes. | Balwani M | Archives of internal medicine | 2010 | PMID: 20837833 |
| Mutational analysis of GIGYF2, ATP13A2 and GBA genes in Brazilian patients with early-onset Parkinson's disease. | Dos Santos AV | Neuroscience letters | 2010 | PMID: 20816920 |
| Experience with carrier screening and prenatal diagnosis for 16 Ashkenazi Jewish genetic diseases. | Scott SA | Human mutation | 2010 | PMID: 20672374 |
| Gaucher disease: frequency of the N370S mutation in the Greek population. | Dimitriou E | Clinical genetics | 2010 | PMID: 20662857 |
| Interaction between parkin and mutant glucocerebrosidase variants: a possible link between Parkinson disease and Gaucher disease. | Ron I | Human molecular genetics | 2010 | PMID: 20643691 |
| Glucocerebrosidase mutations are not a common risk factor for Parkinson disease in North Africa. | Nishioka K | Neuroscience letters | 2010 | PMID: 19945510 |
| Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. | Sidransky E | The New England journal of medicine | 2009 | PMID: 19846850 |
| Chaperone activity of bicyclic nojirimycin analogues for Gaucher mutations in comparison with N-(n-nonyl)deoxynojirimycin. | Luan Z | Chembiochem : a European journal of chemical biology | 2009 | PMID: 19830760 |
| Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. | Neumann J | Brain : a journal of neurology | 2009 | PMID: 19286695 |
| The underrecognized progressive nature of N370S Gaucher disease and assessment of cancer risk in 403 patients. | Taddei TH | American journal of hematology | 2009 | PMID: 19260119 |
| Participation of asparagine 370 and glutamine 235 in the catalysis by acid beta-glucosidase: the enzyme deficient in Gaucher disease. | Liou B | Molecular genetics and metabolism | 2009 | PMID: 19217815 |
| Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset. | Nichols WC | Neurology | 2009 | PMID: 18987351 |
| Phenotypic heterogeneity of N370S homozygotes with type I Gaucher disease: an analysis of 798 patients from the ICGG Gaucher Registry. | Fairley C | Journal of inherited metabolic disease | 2008 | PMID: 18979180 |
| Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. | Gan-Or Z | Neurology | 2008 | PMID: 18434642 |
| Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). | Hruska KS | Human mutation | 2008 | PMID: 18338393 |
| Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. | Mata IF | Archives of neurology | 2008 | PMID: 18332251 |
| Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease. | Clark LN | Neurology | 2007 | PMID: 17875915 |
| Mutation analysis and genotype/phenotype relationships of Gaucher disease patients in Spain. | Alfonso P | Journal of human genetics | 2007 | PMID: 17427031 |
| Genetic and clinical features of patients with Gaucher disease in Hungary. | Erdos M | Blood cells, molecules & diseases | 2007 | PMID: 17395504 |
| Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations. | Liou B | The Journal of biological chemistry | 2006 | PMID: 16293621 |
| The N370S (Asn370-->Ser) mutation affects the capacity of glucosylceramidase to interact with anionic phospholipid-containing membranes and saposin C. | Salvioli R | The Biochemical journal | 2005 | PMID: 15826241 |
| Identification and functional characterization of five novel mutant alleles in 58 Italian patients with Gaucher disease type 1. | Miocić S | Human mutation | 2005 | PMID: 15605411 |
| Functional analysis of 13 GBA mutant alleles identified in Gaucher disease patients: Pathogenic changes and "modifier" polymorphisms. | Montfort M | Human mutation | 2004 | PMID: 15146461 |
| Expression and functional characterization of mutated glucocerebrosidase alleles causing Gaucher disease in Spanish patients. | Alfonso P | Blood cells, molecules & diseases | 2004 | PMID: 14757438 |
| Viable mouse models of acid beta-glucosidase deficiency: the defect in Gaucher disease. | Xu YH | The American journal of pathology | 2003 | PMID: 14578207 |
| High prevalence of the 55-bp deletion (c.1263del55) in exon 9 of the glucocerebrosidase gene causing misdiagnosis (for homozygous N370S (c.1226A > G) mutation) in Spanish Gaucher disease patients. | Torralba MA | Blood cells, molecules & diseases | 2002 | PMID: 12482401 |
| The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease. | Charrow J | Archives of internal medicine | 2000 | PMID: 11025794 |
| Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease. | Koprivica V | American journal of human genetics | 2000 | PMID: 10796875 |
| Non-pseudogene-derived complex acid beta-glucosidase mutations causing mild type 1 and severe type 2 gaucher disease. | Grace ME | The Journal of clinical investigation | 1999 | PMID: 10079102 |
| Reliable co-segregation analysis for prenatal diagnosis and heterozygote detection in Gaucher disease. | Cormand B | Prenatal diagnosis | 1998 | PMID: 9556036 |
| Molecular analysis and clinical findings in the Spanish Gaucher disease population: putative haplotype of the N370S ancestral chromosome. | Cormand B | Human mutation | 1998 | PMID: 9554746 |
| Characteristics of gene mutations among 32 unrelated Japanese Gaucher disease patients: absence of the common Jewish 84GG and 1226G mutations. | Ida H | Human genetics | 1995 | PMID: 7789963 |
| Analysis of human acid beta-glucosidase by site-directed mutagenesis and heterologous expression. | Grace ME | The Journal of biological chemistry | 1994 | PMID: 8294487 |
| RecTL: a complex allele of the glucocerebrosidase gene associated with a mild clinical course of Gaucher disease. | Zimran A | American journal of medical genetics | 1994 | PMID: 8160756 |
| Gaucher disease as a paradigm of current issues regarding single gene mutations of humans. | Beutler E | Proceedings of the National Academy of Sciences of the United States of America | 1993 | PMID: 8516282 |
| Gaucher's disease in the United Kingdom: screening non-Jewish patients for the two common mutations. | Walley AJ | Journal of medical genetics | 1993 | PMID: 8487270 |
| Role of pH in determining the cell-type-specific residual activity of glucocerebrosidase in type 1 Gaucher disease. | van Weely S | The Journal of clinical investigation | 1993 | PMID: 8450045 |
| Genetic diagnosis of Gaucher's disease. | Mistry PK | Lancet (London, England) | 1992 | PMID: 1348297 |
| Heterogeneity of mutations in the acid beta-glucosidase gene of Gaucher disease patients. | Latham TE | DNA and cell biology | 1991 | PMID: 1899336 |
| High frequency of the Gaucher disease mutation at nucleotide 1226 among Ashkenazi Jews. | Zimran A | American journal of human genetics | 1991 | PMID: 1897529 |
| Three unique base pair changes in a family with Gaucher disease. | Eyal N | Human genetics | 1991 | PMID: 1864608 |
| Genotype assignment in Gaucher disease by selective amplification of the active glucocerebrosidase gene. | Firon N | American journal of human genetics | 1990 | PMID: 2309702 |
| Mutation analysis of an Ashkenazi Jewish family with Gaucher disease in three successive generations. | Kolodny EH | American journal of medical genetics | 1990 | PMID: 2117855 |
| Linkage of the PvuII polymorphism with the common Jewish mutation for Gaucher disease. | Zimran A | American journal of human genetics | 1990 | PMID: 1971142 |
| Prediction of severity of Gaucher's disease by identification of mutations at DNA level. | Zimran A | Lancet (London, England) | 1989 | PMID: 2569551 |
| Genetic heterogeneity in type 1 Gaucher disease: multiple genotypes in Ashkenazic and non-Ashkenazic individuals. | Tsuji S | Proceedings of the National Academy of Sciences of the United States of America | 1988 | PMID: 3353383 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GBA | - | - | - | - |
| http://www.ncbi.nlm.nih.gov/books/NBK1269/ | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/70ea0f99-df79-45a1-b766-b23ceb052e02 | - | - | - | - |
| Kolodny, E., Firon, N., Natowicz, M., Horowitz, M. Gaucher disease in three successive generations of an Ashkenazi Jewish family: analysis of intrafamilial clinical variability by molecular diagnosis. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A202-only, 1989. | - | - | - | - |
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