NM_000157.4(GBA1):c.1226A>G (p.Asn409Ser) AND not specified

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 30, 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:: RCV004018556.1

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)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002755618	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 30, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 3353383, 15146461, 18979180 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002755618

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Dec 30, 2020)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Genetic heterogeneity in type 1 Gaucher disease: multiple genotypes in Ashkenazic and non-Ashkenazic individuals.

Tsuji S, Martin BM, Barranger JA, Stubblefield BK, LaMarca ME, Ginns EI.

Proc Natl Acad Sci U S A. 1988 Apr;85(7):2349-52. Erratum in: Proc Natl Acad Sci U S A 1988 Aug;85(15):5708.

PubMed [citation]

PMID:: 3353383
PMCID:: PMC279989

Functional analysis of 13 GBA mutant alleles identified in Gaucher disease patients: Pathogenic changes and "modifier" polymorphisms.

Montfort M, Chabás A, Vilageliu L, Grinberg D.

Hum Mutat. 2004 Jun;23(6):567-75. Erratum in: Hum Mutat. 2005 Sep;26(3):276.

PubMed [citation]

PMID:: 15146461

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002755618.2

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

Description

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.

#	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		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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