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

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 13, 2020
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:: RCV000588402.14

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)

Name:: Gaucher disease
Synonyms:: Acute cerebral Gaucher disease; Cerebroside lipidosis syndrome; Gaucher splenomegaly; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018150; MedGen: C0017205

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hypothetical protein CEUSTIGMA_g1022.t1 [Chlamydomonas eustigma]
hypothetical protein CEUSTIGMA_g1022.t1 [Chlamydomonas eustigma]
gi|1238997711|dbj|GAX73571.1||gnl|W GY|GAX73571

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Component Of for Nucleotide (Select 15638900) (10)
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Taxonomy Links for Protein (Select 767984460) (1)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000697591	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 30, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17059888, 10757640, 26220978, 10679038 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001422957	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 13, 2020)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 10679038, 27136700, 24801745, 17059888, 27864021, 25741868 Citation Link,
SCV002086474	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 27, 2017)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000697591

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jun 30, 2017)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV001422957

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 13, 2020)

germline

curation

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV002086474

Natera, Inc.

no assertion criteria provided

Pathogenic
(Sep 27, 2017)

germline

clinical testing

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, curation

Citations

PubMed

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

Altered TFEB-mediated lysosomal biogenesis in Gaucher disease iPSC-derived neuronal cells.

Awad O, Sarkar C, Panicker LM, Miller D, Zeng X, Sgambato JA, Lipinski MM, Feldman RA.

Hum Mol Genet. 2015 Oct 15;24(20):5775-88. doi: 10.1093/hmg/ddv297. Epub 2015 Jul 28.

PubMed [citation]

PMID:: 26220978

See all PubMed Citations (8)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697591.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: The GBA c.667T>C (p.Trp223Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide and it is located in the Glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This was confirmed by functional studies showing abrogated Beta-glucosidase catalytic activity (0.0004 total units of specific activity per cross-reacting immunologic material (CRIM SA) (vs. 1 in control) (Amaral_2000, Awad_2015). This variant was found in 3/112128 control chromosomes at a frequency of 0.0000268, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). This variant was reported in multiple patients with Gaucher disease (Choy_1999, Rozenberg_2006) in which pseudogene interference was ruled out. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant 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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422957.2

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

Description

The p.Trp223Arg variant in GBA has been reported in at least 8 individuals with Gaucher disease (PMID: 17059888, 24801745, 27136700, 10679038, 27864021) and has been Identified in 0.002% (2/111560) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs61748906). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 93457) as benign by Prevention Genetics, likely pathogenic by Praxis fuer Humangenetik Tuebingen, and pathogenic by Integrated Genetics and EGL Genetic Diagnostics. In vitro functional studies demonstrating very low glucocerebrosidase activity in mutant hiPSC macrophages provide some evidence that the p.Trp223Arg variant may impact protein function (PMID: 24801745). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with reported pathogenic variants and in 8 individuals with Gaucher disease increases the likelihood that the p.Trp223Arg variant is pathogenic (VariationID: 4288, 4290, 4293; PMID: 17059888, 24801745, 27136700, 10679038, 27864021). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the presence of the variant in combination with other pathogenic variants in affected individuals, functional studies, and the low frequency of the variant in the general population. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PS3_moderate, PP3 (Richards 2015).

#	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 Natera, Inc., SCV002086474.1

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

Last Updated: Oct 13, 2024

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