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

Germline classification:: risk factor (1 submission)
Last evaluated:: Apr 14, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001195689.12

Allele description [Variation Report for NM_000157.4(GBA1):c.1226A>G (p.Asn409Ser)]

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

Genes:

LOC106627981:GBA recombination region [Gene]
GBA1:glucosylceramidase beta 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q22

Genomic location:

Preferred name:

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

Other names:

N370S

HGVS:

NC_000001.11:g.155235843T>C
NG_009783.1:g.13855A>G
NG_042867.1:g.2305T>C
NM_000157.4:c.1226A>GMANE SELECT
NM_001005741.3:c.1226A>G
NM_001005742.3:c.1226A>G
NM_001171811.2:c.965A>G
NM_001171812.2:c.1079A>G
NP_000148.2:p.Asn409Ser
NP_001005741.1:p.Asn409Ser
NP_001005741.1:p.Asn409Ser
NP_001005742.1:p.Asn409Ser
NP_001165282.1:p.Asn322Ser
NP_001165283.1:p.Asn360Ser
NC_000001.10:g.155205634T>C
NM_000157.3:c.1226A>G
NM_000157.4:c.1226A>G
NM_001005741.2(GBA):c.1226A>G
NM_001005741.2:c.1226A>G
NM_001005741.3:c.1226A>G
NM_001005742.2:c.1226A>G
NM_001171811.1:c.965A>G
P04062:p.Asn409Ser
c.1226A>G (p.Asn409Ser)

Protein change:

N322S; ASN370SER

Links:

UniProtKB: P04062#VAR_003302; OMIM: 606463.0003; dbSNP: rs76763715

NCBI 1000 Genomes Browser:

rs76763715

Molecular consequence:

NM_000157.4:c.1226A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001005741.3:c.1226A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001005742.3:c.1226A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001171811.2:c.965A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001171812.2:c.1079A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Parkinson disease (PD)
Identifiers:: MONDO: MONDO:0005180; MeSH: D010300; MedGen: C0030567; OMIM: PS168600

Recent activity

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beta-1,4-galactosyltransferase 5 isoform X1 [Pelodiscus sinensis]
beta-1,4-galactosyltransferase 5 isoform X1 [Pelodiscus sinensis]
gi|1394740210|ref|XP_006129522.3|

Protein
MULTISPECIES: IS1182 family transposase [Bacteroidaceae]
MULTISPECIES: IS1182 family transposase [Bacteroidaceae]
gi|500646614|ref|WP_011964905.1|

Protein
MULTISPECIES: nuclear transport factor 2 family protein [Mycobacterium]
MULTISPECIES: nuclear transport factor 2 family protein [Mycobacterium]
gi|489496750|ref|WP_003401666.1|

Protein
PREDICTED: B-box zinc finger protein 20-like [Erythranthe guttata]
PREDICTED: B-box zinc finger protein 20-like [Erythranthe guttata]
gi|848875864|ref|XP_012838399.1|

Protein
UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit...
UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit isoform X3 [Meriones unguiculatus]
gi|2599595422|ref|XP_060231024.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001366088	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	risk factor (Apr 14, 2020)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 26096741, 25653295, 17395504, 8294487, 19846850, 26905200, 25456120, 22592100, 26868973, 22451204, 10796875, 24756352, 29527153, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001366088

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

risk factor
(Apr 14, 2020)

germline

clinical testing

PubMed (14)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	3	3	not provided	not provided	not provided	clinical testing

Citations

PubMed

Gaucher disease types 1 and 3: Phenotypic characterization of large populations from the ICGG Gaucher Registry.

Grabowski GA, Zimran A, Ida H.

Am J Hematol. 2015 Jul;90 Suppl 1:S12-8. doi: 10.1002/ajh.24063. Review.

PubMed [citation]

PMID:: 26096741

Differential effects of severe vs mild GBA mutations on Parkinson disease.

Gan-Or Z, Amshalom I, Kilarski LL, Bar-Shira A, Gana-Weisz M, Mirelman A, Marder K, Bressman S, Giladi N, Orr-Urtreger A.

Neurology. 2015 Mar 3;84(9):880-7. doi: 10.1212/WNL.0000000000001315. Epub 2015 Feb 4.

PubMed [citation]

PMID:: 25653295
PMCID:: PMC4351661

See all PubMed Citations (14)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV001366088.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (14)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		3	not provided	3	not provided

Last Updated: Nov 10, 2024

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