NM_000157.4(GBA1):c.1297G>T (p.Val433Leu) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 8, 2024
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:: RCV001382044.16

Allele description

NM_000157.4(GBA1):c.1297G>T (p.Val433Leu)

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.1297G>T (p.Val433Leu)

Other names:

V394L

HGVS:

NC_000001.11:g.155235772C>A
NG_009783.1:g.13926G>T
NG_042867.1:g.2234C>A
NM_000157.4:c.1297G>TMANE SELECT
NM_001005741.3:c.1297G>T
NM_001005742.3:c.1297G>T
NM_001171811.2:c.1036G>T
NM_001171812.2:c.1150G>T
NP_000148.2:p.Val433Leu
NP_001005741.1:p.Val433Leu
NP_001005742.1:p.Val433Leu
NP_001165282.1:p.Val346Leu
NP_001165283.1:p.Val384Leu
NC_000001.10:g.155205563C>A
NM_000157.3:c.1297G>T
NM_001005741.2:c.1297G>T
NM_001005741.3:c.1297G>T
NM_001005742.2:c.1297G>T
P04062:p.Val433Leu
c.1297G>T (p.Val433Leu)

Protein change:

V346L; VAL394LEU

Links:

UniProtKB: P04062#VAR_003310; OMIM: 606463.0005; dbSNP: rs80356769

NCBI 1000 Genomes Browser:

rs80356769

Molecular consequence:

NM_000157.4:c.1297G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001005741.3:c.1297G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001005742.3:c.1297G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001171811.2:c.1036G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001171812.2:c.1150G>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001580650	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 10714667, 24685312, 25653295, 27271787, 8294487, 14578207, 21257328, 28492532
SCV002024186	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 10, 2022)	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

SCV001580650

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 8, 2024)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV002024186

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 10, 2022)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Myoclonus from selective dentate nucleus degeneration in type 3 Gaucher disease.

Verghese J, Goldberg RF, Desnick RJ, Grace ME, Goldman JE, Lee SC, Dickson DW, Rapin I.

Arch Neurol. 2000 Mar;57(3):389-95.

PubMed [citation]

PMID:: 10714667

Patients with type 1 Gaucher disease in South Florida, USA: demographics, genotypes, disease severity and treatment outcomes.

Orenstein M, Barbouth D, Bodamer OA, Weinreb NJ.

Orphanet J Rare Dis. 2014 Mar 31;9:45. doi: 10.1186/1750-1172-9-45.

PubMed [citation]

PMID:: 24685312
PMCID:: PMC4230272

See all PubMed Citations (9)

Details of each submission

From Invitae, SCV001580650.4

#	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 valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 433 of the GBA protein (p.Val433Leu). This variant is present in population databases (rs80356769, gnomAD 0.07%). This missense change has been observed in individual(s) with Gaucher disease and Parkinson's disease (PMID: 10714667, 24685312, 25653295, 27271787). This variant is also known as p.Val394Leu or V394L. ClinVar contains an entry for this variant (Variation ID: 4292). 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) performed at Invitae indicates that this missense variant is not expected to disrupt GBA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GBA function (PMID: 8294487, 14578207, 21257328). 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 Revvity Omics, Revvity, SCV002024186.3

#	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

Last Updated: Sep 16, 2024

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