VCV000004290.120 - ClinVar

NM_000157.4(GBA1):c.1226A>G (p.Asn409Ser)

Germline

Classification

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.

(53)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic; risk factor

criteria provided, multiple submitters, no conflicts

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: VCV000004290.120

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q22 1: 155235843 (GRCh38) [ NCBI UCSC ] 1: 155205634 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Nov 24, 2024	Oct 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_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

... more HGVS ... less HGVS

Protein change

N409S, N322S, N360S

Other names

N370S

Canonical SPDI

NC_000001.11:155235842:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00060 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00060

1000 Genomes Project 30x 0.00062

The Genome Aggregation Database (gnomAD) 0.00191

Trans-Omics for Precision Medicine (TOPMed) 0.00195

Exome Aggregation Consortium (ExAC) 0.00221

The Genome Aggregation Database (gnomAD), exomes 0.00231

Links

Genetic Testing Registry (GTR): GTR000321628 Genetic Testing Registry (GTR): GTR000325400 Genetic Testing Registry (GTR): GTR000556544 UniProtKB: P04062#VAR_003302 OMIM: 606463.0003 dbSNP: rs76763715 ClinGen: CA116767 VarSome

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
Gene	OMIM	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.
GBA1		-	-	GRCh38 GRCh38 GRCh37	32	408
LOC106627981	-	-	-	GRCh38 GRCh38	-	362

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.
Dementia, Lewy body, susceptibility to	risk factor (1)	no assertion criteria provided	Aug 1, 2010	RCV000004517.14
Gaucher disease type I	Pathogenic/Likely pathogenic (17)	criteria provided, multiple submitters, no conflicts	Oct 11, 2024	RCV000004515.46
Parkinson disease, late-onset	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Aug 27, 2024	RCV000004516.26
not provided	Pathogenic (12)	criteria provided, multiple submitters, no conflicts	Jan 25, 2024	RCV000079336.69
Gaucher disease	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jan 22, 2020	RCV000396221.19
Akinesia Rigidity	Likely pathogenic (1)	criteria provided, single submitter	Feb 19, 2014	RCV000414782.10
Gaucher disease perinatal lethal Gaucher disease type I Gaucher disease type II Gaucher disease type III Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome Lewy body dementia Parkinson disease, late-onset	Pathogenic (2)	criteria provided, single submitter	Feb 20, 2022	RCV000515439.12
Gaucher disease type I Gaucher disease type II Gaucher disease type III Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome	Pathogenic (1)	criteria provided, single submitter	-	RCV001004117.9
Gaucher disease perinatal lethal	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 4, 2019	RCV001197918.12
Parkinson disease	risk factor (1)	criteria provided, single submitter	Apr 14, 2020	RCV001195689.12
Abnormal bleeding Thrombocytopenia	Uncertain significance (1)	no assertion criteria provided	May 1, 2020	RCV001270528.9
Lewy body dementia	Pathogenic (1)	criteria provided, single submitter	May 4, 2022	RCV002247244.9
Lewy body dementia Parkinson disease, late-onset	Likely pathogenic (1)	criteria provided, single submitter	Nov 8, 2023	RCV004555830.2
GBA1-related disorder	Pathogenic (1)	no assertion criteria provided	Feb 21, 2024	RCV003982824.3
not specified	Pathogenic (1)	criteria provided, single submitter	Dec 30, 2020	RCV004018556.1
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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.	More information 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.
Pathogenic (Feb 12, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease, type I Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000247461.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015
Likely pathogenic (Feb 19, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Akinesia Rigidity Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492778.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017
Pathogenic (Jul 10, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type I Affected status: no Allele origin: germline	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: 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 … (more) 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)
Pathogenic (Jan 18, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Gaucher disease Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000697577.1 First in ClinVar: Oct 14, 2017 Last updated: Oct 14, 2017	Publications: PubMed (2) PubMed: 8294487‚ 25249066 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 … (more) 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)
Pathogenic (May 18, 2017)	criteria provided, single submitter (EGL Classification Definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000224863.5 First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GBA http://www.ncbi.nlm.nih.gov/book… http://www.ncbi.nlm.nih.gov/books/NBK1269/ Number of individuals with the variant: 105 Sex: mixed
risk factor (Apr 14, 2020)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Parkinson disease Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV001366088.1 First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (13) PubMed: 26096741‚ 25653295‚ 17395504‚ 8294487‚ 19846850‚ 26905200‚ 25456120‚ 22592100‚ 26868973‚ 22451204‚ 10796875‚ 24756352‚ 29527153 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 … (more) 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) Number of individuals with the variant: 3
Pathogenic (Oct 18, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Gaucher disease type I Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001194072.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (8) PubMed: 22220748‚ 19260119‚ 18979180‚ 16293621‚ 3353383‚ 10796875‚ 19217815‚ 15146461 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 … (more) 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)
Pathogenic (Jun 20, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease, type I Affected status: yes Allele origin: germline	Hadassah Hebrew University Medical Center Accession: SCV001437672.1 First in ClinVar: Oct 10, 2020 Last updated: Oct 10, 2020	Publications: PubMed (1) PubMed: 33223529
Pathogenic (Jan 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease perinatal lethal Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368701.2 First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS1,PM3,PP3,PP5.
Pathogenic (May 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Parkinson disease, late-onset Affected status: yes Allele origin: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV001652786.1 First in ClinVar: May 29, 2021 Last updated: May 29, 2021
Pathogenic (Jun 24, 2020)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Gaucher disease type I (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000966812.3 First in ClinVar: Aug 26, 2019 Last updated: May 29, 2021	Publications: PubMed (13) PubMed: 26096741‚ 25653295‚ 17395504‚ 8294487‚ 19846850‚ 25456120‚ 10796875‚ 29527153‚ 24756352‚ 26905200‚ 22592100‚ 26868973‚ 22451204 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 … (more) 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) Number of individuals with the variant: 4
Pathogenic (Sep 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001905653.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Clinical Features: Renal hypoplasia (present) , Renal agenesis (present) , Ventricular septal defect (present) , Polydactyly (present)
Pathogenic (Mar 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002501646.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (79): PubMed: 3353383 28834018 25249066 22592100 20837833 27393345 21228398 22623374 27094865 22995991 30302829 30528841 30609409 21742527 17875915 9556036 21472771 33473340 22192918 20816920 30146349 18979180 25333069 29487000 25653295 22220748 28779532 27312774 26096741 8294487 24434810 27271787 22975760 29625627 16293621 19217815 22160715 19830760 30216542 24195576 25168325 24022302 23676350 24020503 27153395 21700325 15146461 21745757 30606667 23588557 18987351 19945510 33281709 20980259 32714263 31996268 32658388 30364808 30487145 29431110 29140481 20643691 29842932 23642305 19846850 28966932 19260119 22961873 20980263 25456120 14578207 27735925 23277556 21653695 29029963 32042592 22388998 8160756 31188768 Number of individuals with the variant: 8 Secondary finding: no
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Lewy body dementia Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002516447.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Feb 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	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 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611266.2 First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher Disease Affected status: yes Allele origin: germline	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: 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 … (more) 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)
Pathogenic (Oct 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002024202.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Aug 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Parkinson disease, late-onset Affected status: yes Allele origin: germline	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV005395957.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024
Pathogenic (Jan 26, 2015)	criteria provided, single submitter (Courtagen Life Sciences Classifications) Method: clinical testing	Gaucher disease, type I Affected status: unknown Allele origin: germline	Courtagen Diagnostics Laboratory, Courtagen Life Sciences Accession: SCV000236536.2 First in ClinVar: Jul 05, 2015 Last updated: Jul 12, 2015
Pathogenic (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Gaucher Disease Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000348574.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Pathogenic (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Susceptibility to Parkinson's Disease Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000348575.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (9) PubMed: 25653295‚ 25249066‚ 23676350‚ 22192918‚ 20947659‚ 19846850‚ 18987351‚ 18434642‚ 22968580
Pathogenic (Dec 03, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type I Affected status: yes Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000746370.1 First in ClinVar: Jun 24, 2017 Last updated: Jun 24, 2017	Age: 10-19 weeks gestation Geographic origin: Iran
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type I Gaucher disease type II Gaucher disease type III Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001162848.1 First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020
Pathogenic (Oct 15, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type I Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV001441565.1 First in ClinVar: Nov 06, 2020 Last updated: Nov 06, 2020	Publications: PubMed (7) PubMed: 12482401‚ 20672374‚ 21431620‚ 24022302‚ 25456120‚ 26905200‚ 27872820 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 … (more) 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)
Pathogenic (Mar 04, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease perinatal lethal Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001523473.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Jan 10, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321702.6 First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016	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 … (more) 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)
Pathogenic (Oct 05, 2021)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Gaucher disease type I Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV002034836.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021	Publications: PubMed (10) PubMed: 10796875‚ 15146461‚ 18979180‚ 19260119‚ 19846850‚ 20301446‚ 23676350‚ 24022302‚ 25653295‚ 26096741 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 … (more) 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)
Pathogenic (Mar 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type I Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002059258.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022
Pathogenic (Jan 22, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Gaucher disease (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	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	Publications: PubMed (6) PubMed: 17427031‚ 14757438‚ 21472771‚ 16293621‚ 20980259‚ 28923368 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/70ea0f99-df79-45a1-b766-b23ceb052e02 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 … (more) 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)
Likely pathogenic (Mar 25, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type I Affected status: yes Allele origin: germline	DASA Accession: SCV002318968.1 First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022	Publications: PubMed (7) PubMed: 15826241‚ 16293621‚ 15605411‚ 26096741‚ 28779532‚ 25249066‚ 23676350 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. … (more) 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) Number of individuals with the variant: 1 Sex: female Geographic origin: Brazil
Pathogenic (Sep 29, 2020)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Parkinson disease, late-onset (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV002764719.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Number of individuals with the variant: 1 Clinical Features: Parkinsonian disorder (present)
Pathogenic (Nov 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type I (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004175942.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Comment: Criteria applied: PM3_VSTR,PS3_SUP,PP3 Clinical Features: Decreased beta-glucocerebrosidase level (present) Sex: male
Pathogenic (Nov 25, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type I Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003836166.2 First in ClinVar: Mar 11, 2023 Last updated: Dec 24, 2023
Pathogenic (Jan 25, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000936391.5 First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024	Publications: PubMed (7) PubMed: 23676350‚ 25249066‚ 26096741‚ 28779532‚ 8294487‚ 22160715‚ 22592100 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). … (more) 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)
Pathogenic (Sep 27, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001471102.7 First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024	Comment: The GBA c.1226A>G; p.Asn409Ser variant (rs76763715), also known as N370S, is a common pathogenic variant reported in the homozygous and compound heterozygous state in individuals … (more) The GBA c.1226A>G; p.Asn409Ser variant (rs76763715), also known as N370S, is a common pathogenic variant reported in the homozygous and compound heterozygous state in individuals with type I Gaucher disease (Fairley 2008, Grace 1994, Tsuji 1988). While this variant is found in the Ashkenazi Jewish population with an overall allele frequency of 2.7% (279/10368 alleles) in the Genome Aggregation Database, it is commonly associated with disease in individuals of Ashkenazi Jewish descent (Tsuji 1988). The asparagine at codon 409 is moderately conserved, and functional studies demonstrate this variant has reduced enzymatic activity (Grace 1994, Tsuji 1988). Based on available information, this variant is considered to be pathogenic. References: Fairley C et al. Phenotypic heterogeneity of N370S homozygotes with type I Gaucher disease: an analysis of 798 patients from the ICGG Gaucher Registry. J Inherit Metab Dis. 2008;31(6):738-744. PMID: 18979180. Grace ME et al. Analysis of human acid beta-glucosidase by site-directed mutagenesis and heterologous expression. J Biol Chem. 1994;269(3):2283-2291. PMID: 8294487. Tsuji S et al. Genetic heterogeneity in type 1 Gaucher disease: multiple genotypes in Ashkenazic and non-Ashkenazic individuals. Proc Natl Acad Sci U S A. 1988;85(7):2349-2352. PMID: 3353383. (less)
Pathogenic (Dec 30, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002755618.2 First in ClinVar: Dec 03, 2022 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 3353383‚ 15146461‚ 18979180 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 … (more) The c.1226A>G (p.N409S) alteration is located in exon 10 (coding exon 9) of the GBA gene. This alteration results from an A to G substitution at nucleotide position 1226, causing the asparagine (N) at amino acid position 409 to be replaced by a serine (S). Based on data from gnomAD, the G allele has an overall frequency of 0.22% (632/282786) total alleles studied. The highest observed frequency was 2.69% (279/10368) of Ashkenazi Jewish alleles. This is the most common mutation found in Gaucher disease and is associated with type 1 (non-neuronopathic) disease (Tsuji, 1988). One study including 798 homozygotes and 1278 compound heterozygotes determined this mutation can cause a range of phenotypes, from mild adult-onset to pediatric onset with severe complications. However, this mutation was not observed to be associated with central nervous system involvement (Fairley, 2008). This amino acid position is not well conserved in available vertebrate species. A functional study found that Sf9 cells containing this mutation expressed significantly less protein when compared to wild-type (Montfort, 2004). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
Likely pathogenic (Nov 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	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. Affected status: yes Allele origin: germline	Clinical Genomics Laboratory, Washington University in St. Louis Accession: SCV005045123.1 First in ClinVar: May 26, 2024 Last updated: May 26, 2024	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‚Äôs disease and dementia with … (more) 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‚Äôs 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‚Äôs 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)
Pathogenic (May 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000800925.4 First in ClinVar: Aug 04, 2018 Last updated: Jun 09, 2024	Publications: Bookshelf: NBK1269 Bookshelf: NBK1269 Number of individuals with the variant: 15
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Gaucher disease type I Affected status: no Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005051785.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (Jan 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000692646.30 First in ClinVar: Feb 15, 2018 Last updated: Oct 20, 2024	Comment: GBA1: PM3:Very Strong, PS3, PM1, PP1:Moderate, PM2:Supporting Number of individuals with the variant: 29
Pathogenic (Oct 11, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type I (Autosomal recessive inheritance) Affected status: no Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005398891.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (7) PubMed: 1864608‚ 10079102‚ 15146461‚ 20301446‚ 25249066‚ 26868973‚ 31010158 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 … (more) 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)
Pathogenic (Mar 24, 2015)	no assertion criteria provided Method: research	Gaucher disease, type I Affected status: no Allele origin: germline	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	Publications: PubMed (5) PubMed: 3353383‚ 18979180‚ 18338393‚ 8294487‚ 15146461 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, … (more) 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)
risk factor (Aug 01, 2010)	no assertion criteria provided Method: literature only	PARKINSON DISEASE, LATE-ONSET SUSCEPTIBILITY TO Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024690.5 First in ClinVar: Apr 04, 2013 Last updated: Sep 14, 2020	Publications: PubMed (17) PubMed: 1899336‚ 3353383‚ 2569551‚ 2117855‚ 2309702‚ 1971142‚ 1897529‚ 8516282‚ 1348297‚ 8450045‚ 8487270‚ 7789963‚ 9554746‚ 10796875‚ 20662857‚ 18332251‚ 19286695 Kolodny, E., Firon, N., Natowicz, (more...) 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 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)	no assertion criteria provided Method: literature only	DEMENTIA, LEWY BODY, SUSCEPTIBILITY TO Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024691.5 First in ClinVar: Apr 04, 2013 Last updated: Sep 14, 2020	Publications: PubMed (17) PubMed: 1899336‚ 3353383‚ 2569551‚ 2117855‚ 2309702‚ 1971142‚ 1897529‚ 8516282‚ 1348297‚ 8450045‚ 8487270‚ 7789963‚ 9554746‚ 10796875‚ 20662857‚ 18332251‚ 19286695 Kolodny, E., Firon, N., Natowicz, (more...) 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 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 (Aug 01, 2010)	no assertion criteria provided Method: literature only	GAUCHER DISEASE, TYPE I Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024689.5 First in ClinVar: Apr 04, 2013 Last updated: Sep 14, 2020	Publications: PubMed (17) PubMed: 1899336‚ 3353383‚ 2569551‚ 2117855‚ 2309702‚ 1971142‚ 1897529‚ 8516282‚ 1348297‚ 8450045‚ 8487270‚ 7789963‚ 9554746‚ 10796875‚ 20662857‚ 18332251‚ 19286695 Kolodny, E., Firon, N., Natowicz, (more...) 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 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 (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	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
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001971110.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Feb 21, 2024)	no assertion criteria provided Method: clinical testing	GBA1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004796704.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	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 … (more) 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)
Uncertain significance (May 01, 2020)	no assertion criteria provided Method: research	Thrombocytopenia Abnormal bleeding Affected status: yes Allele origin: germline	Birmingham Platelet Group; University of Birmingham Accession: SCV001450827.1 First in ClinVar: Dec 19, 2020 Last updated: Dec 19, 2020
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001951306.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
not provided (-)	no classification provided Method: literature only	Gaucher disease Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV002586408.1 First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022	Publications: Bookshelf: NBK1269 Bookshelf: NBK1269
not provided (-)	no classification provided Method: phenotyping only	Gaucher disease Affected status: unknown Allele origin: maternal	GenomeConnect, ClinGen Accession: SCV000607211.1 First in ClinVar: Oct 14, 2017 Last updated: Oct 14, 2017	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 … (more) 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) Clinical Features: Oral-pharyngeal dysphagia (present) , Abnormality of the skull (present) , Hypermetropia (present) , Seizures (present) , Abnormality of movement (present) , Generalized hypotonia (present) , … (more) 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) (less) Indication for testing: Diagnostic 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 (-)	no classification provided Method: phenotyping only	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 Affected status: no Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV000986753.1 First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019	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 … (more) 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) Clinical Features: Abnormality of the optic nerve (present) , Ptosis (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Abnormality of movement (present) , Abnormality … (more) Abnormality of the optic nerve (present) , Ptosis (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Abnormality of movement (present) , Abnormality of muscle physiology (present) (less) Age: 0-9 years Sex: male Testing laboratory: MNG Laboratories (Medical Neurogenetics, LLC.) Date variant was reported to submitter: 2017-04-12 Testing laboratory interpretation: Pathogenic
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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 (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:

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:

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:

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:

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:

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:

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:

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:

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:

The GBA c.1226A>G; p.Asn409Ser variant (rs76763715), also known as N370S, is a common pathogenic variant reported in the homozygous and compound heterozygous state in individuals with type I Gaucher disease (Fairley 2008, Grace 1994, Tsuji 1988). While this variant is found in the Ashkenazi Jewish population with an overall allele frequency of 2.7% (279/10368 alleles) in the Genome Aggregation Database, it is commonly associated with disease in individuals of Ashkenazi Jewish descent (Tsuji 1988). The asparagine at codon 409 is moderately conserved, and functional studies demonstrate this variant has reduced enzymatic activity (Grace 1994, Tsuji 1988). Based on available information, this variant is considered to be pathogenic. References: Fairley C et al. Phenotypic heterogeneity of N370S homozygotes with type I Gaucher disease: an analysis of 798 patients from the ICGG Gaucher Registry. J Inherit Metab Dis. 2008;31(6):738-744. PMID: 18979180. Grace ME et al. Analysis of human acid beta-glucosidase by site-directed mutagenesis and heterologous expression. J Biol Chem. 1994;269(3):2283-2291. PMID: 8294487. Tsuji S et al. Genetic heterogeneity in type 1 Gaucher disease: multiple genotypes in Ashkenazic and non-Ashkenazic individuals. Proc Natl Acad Sci U S A. 1988;85(7):2349-2352. PMID: 3353383.

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 mutation found in Gaucher disease and is associated with type 1 (non-neuronopathic) disease (Tsuji, 1988). One study including 798 homozygotes and 1278 compound heterozygotes determined this mutation can cause a range of phenotypes, from mild adult-onset to pediatric onset with severe complications. However, this mutation was not observed to be associated with central nervous system involvement (Fairley, 2008). This amino acid position is not well conserved in available vertebrate species. A functional study found that Sf9 cells containing this mutation expressed significantly less protein when compared to wild-type (Montfort, 2004). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.

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‚Äôs 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‚Äôs 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:

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 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:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Gaucher Disease.	Adam MP	-	2023	PMID: 20301446
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
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
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
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
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
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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Text-mined citations for rs76763715 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000157.4(GBA1):c.1226A>G (p.Asn409Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs76763715 ...