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

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 8, 2023
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:: RCV004555830.2

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]

Condition(s)

Name:: Lewy body dementia (DLB)
Synonyms:: Diffuse Lewy body disease; Autosomal dominant diffuse Lewy body disease; Lewy Body Disease
Identifiers:: MONDO: MONDO:0007488; MedGen: C0752347; OMIM: 127750

Name:: Parkinson disease, late-onset (PD)
Synonyms:: Parkinson's disease; PARKINSON DISEASE, LATE-ONSET, SUSCEPTIBILITY TO; Susceptibility to Parkinson's Disease; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008199; MedGen: C3160718; OMIM: 168600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005045123	Clinical Genomics Laboratory, Washington University in St. Louis	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 8, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005045123

Clinical Genomics Laboratory, Washington University in St. Louis

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 8, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Clinical Genomics Laboratory, Washington University in St. Louis, SCV005045123.1

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

Description

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.

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

Last Updated: Nov 24, 2024

ClinVar

Relating variation to medicine