NM_000157.4(GBA1):c.667T>C (p.Trp223Arg) AND not specified

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 17, 2021
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:: RCV004019535.1

Allele description [Variation Report for NM_000157.4(GBA1):c.667T>C (p.Trp223Arg)]

NM_000157.4(GBA1):c.667T>C (p.Trp223Arg)

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.667T>C (p.Trp223Arg)

HGVS:

NC_000001.11:g.155238228A>G
NG_009783.1:g.11470T>C
NG_042867.1:g.4690A>G
NM_000157.4:c.667T>CMANE SELECT
NM_001005741.2(GBA):c.667T>C
NM_001005741.3:c.667T>C
NM_001005742.3:c.667T>C
NM_001171811.2:c.406T>C
NM_001171812.2:c.520T>C
NP_000148.2:p.Trp223Arg
NP_001005741.1:p.Trp223Arg
NP_001005741.1:p.Trp223Arg
NP_001005742.1:p.Trp223Arg
NP_001165282.1:p.Trp136Arg
NP_001165283.1:p.Trp174Arg
NC_000001.10:g.155208019A>G
NM_000157.4:c.667T>C
NM_001005741.2(GBA):c.667T>C
NM_001005741.2:c.667T>C
NM_001005741.3:c.667T>C
NM_001005742.2:c.667T>C
P04062:p.Trp223Arg

Protein change:

W136R

Links:

UniProtKB: P04062#VAR_003273; dbSNP: rs61748906

NCBI 1000 Genomes Browser:

rs61748906

Molecular consequence:

NM_000157.4:c.667T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001005741.3:c.667T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001005742.3:c.667T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001171811.2:c.406T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001171812.2:c.520T>C - 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
SCV003570750	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 17, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10679038, 10757640, 17059888, 24801745, 26220978, 32547927 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003570750

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 17, 2021)

germline

clinical testing

PubMed (6)
[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

Novel point mutation (W184R) in neonatal type 2 Gaucher disease.

Choy FY, Wong K, Vallance HD, Baldwin V.

Pediatr Dev Pathol. 2000 Mar-Apr;3(2):180-3.

PubMed [citation]

PMID:: 10679038

Gaucher disease: expression and characterization of mild and severe acid beta-glucosidase mutations in Portuguese type 1 patients.

Amaral O, Marcão A, Sá Miranda M, Desnick RJ, Grace ME.

Eur J Hum Genet. 2000 Feb;8(2):95-102.

PubMed [citation]

PMID:: 10757640

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV003570750.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The c.667T>C (p.W223R) alteration is located in exon 7 (coding exon 6) of the GBA gene. This alteration results from a T to C substitution at nucleotide position 667, causing the tryptophan (W) at amino acid position 223 to be replaced by an arginine (R). Based on data from gnomAD, the C allele has an overall frequency of <0.01% (2/251106) total alleles studied. The highest observed frequency was <0.01% (2/113588) of European (non-Finnish) alleles. This alteration, also referred to as p.W184R in the literature, has been reported in the compound heterozygous state with a second mutation in multiple patients with Gaucher disease (Amaral, 2000; Choy, 2000; Rozenberg, 2006; Panicker, 2014; Dimitriou, 2020). This amino acid position is highly conserved in available vertebrate species. Expression studies in Sf9 cells showed very low activity and an essentially inactive protein (Amaral, 2000). Human induced pluripotent stem cells from fibroblasts of an affected patient with this alteration and a second alteration showed low levels of beta-glucocerebrosidase activity and widespread lysosomal depletion and dysfunction (Panicker, 2014; Awad, 2015). This alteration is predicted to be deleterious by in silico analysis. 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 30, 2024

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