NM_000157.4(GBA1):c.1246G>A (p.Gly416Ser) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Dec 28, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000723428.12

Allele description [Variation Report for NM_000157.4(GBA1):c.1246G>A (p.Gly416Ser)]

NM_000157.4(GBA1):c.1246G>A (p.Gly416Ser)

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.1246G>A (p.Gly416Ser)

Other names:

G377S

HGVS:

NC_000001.11:g.155235823C>T
NG_009783.1:g.13875G>A
NG_042867.1:g.2285C>T
NM_000157.3(GBA):c.1246G>A
NM_000157.4:c.1246G>AMANE SELECT
NM_001005741.3:c.1246G>A
NM_001005742.3:c.1246G>A
NM_001171811.2:c.985G>A
NM_001171812.2:c.1099G>A
NP_000148.2:p.Gly416Ser
NP_001005741.1:p.Gly416Ser
NP_001005742.1:p.Gly416Ser
NP_001165282.1:p.Gly329Ser
NP_001165283.1:p.Gly367Ser
NC_000001.10:g.155205614C>T
NM_000157.3(GBA):c.1246G>A
NM_000157.3:c.1246G>A
NM_001005741.2:c.1246G>A
NM_001005741.3:c.1246G>A
P04062:p.Gly416Ser

Protein change:

G329S; GLY377SER

Links:

UniProtKB: P04062#VAR_003303; OMIM: 606463.0040; dbSNP: rs121908311

NCBI 1000 Genomes Browser:

rs121908311

Molecular consequence:

NM_000157.4:c.1246G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001005741.3:c.1246G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001005742.3:c.1246G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001171811.2:c.985G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001171812.2:c.1099G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000700355	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Apr 3, 2017)	germline	clinical testing	Citation Link,
SCV002018392	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 24, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002125693	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 28, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 8081401, 17395504, 20432762, 23430543, 27632223, 29140481, 25287185, 28492532
SCV002578604	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 5, 2022)	germline	clinical testing	Citation Link

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
not provided	germline	unknown	3	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

Use of denaturing gradient gel electrophoresis to identify mutant sequences in the beta-glucocerebrosidase gene.

Laubscher KH, Glew RH, Lee RE, Okinaka RT.

Hum Mutat. 1994;3(4):411-5. No abstract available.

PubMed [citation]

PMID:: 8081401

See all PubMed Citations (9)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000700355.2

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

#	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	not provided	not provided

From Revvity Omics, Revvity, SCV002018392.3

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

#	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

From Invitae, SCV002125693.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 416 of the GBA protein (p.Gly416Ser). This variant is present in population databases (rs121908311, gnomAD 0.003%). This missense change has been observed in individual(s) with Gaucher disease and/or Parkinson's disease (PMID: 8081401, 17395504, 20432762, 23430543, 25287185, 27632223, 29140481). It is commonly reported in individuals of Brazilian ancestry (PMID: 25287185). This variant is also known as p.Gly377Ser or G377S. ClinVar contains an entry for this variant (Variation ID: 4327). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GBA protein function. For these reasons, this variant has been 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

From GeneDx, SCV002578604.2

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8081401, 25946768, 16981045, 17395504, 23430543, 25732996, 29140481, 27717005, 20432762, 21742527, 33176831, 31467847, 27632223, 25287185, 10757640, 12595585, 22429443)

#	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: Mar 30, 2024

ClinVar

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