ClinVar Genomic variation as it relates to human health
NM_000157.4(GBA1):c.667T>C (p.Trp223Arg)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000157.4(GBA1):c.667T>C (p.Trp223Arg)
Variation ID: 93457 Accession: VCV000093457.50
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 155238228 (GRCh38) [ NCBI UCSC ] 1: 155208019 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 2, 2016 Oct 20, 2024 Dec 7, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000157.4:c.667T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000148.2:p.Trp223Arg missense NM_001005741.3:c.667T>C NP_001005741.1:p.Trp223Arg missense NM_001005742.2:c.667T>C NM_001005742.3:c.667T>C NP_001005742.1:p.Trp223Arg missense NM_001171811.2:c.406T>C NP_001165282.1:p.Trp136Arg missense NM_001171812.2:c.520T>C NP_001165283.1:p.Trp174Arg missense NC_000001.11:g.155238228A>G NC_000001.10:g.155208019A>G NG_009783.1:g.11470T>C NG_042867.1:g.4690A>G P04062:p.Trp223Arg - Protein change
- W223R, W136R, W174R
- Other names
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- Canonical SPDI
- NC_000001.11:155238227:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD) 0.00003
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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GBA1 | - | - |
GRCh38 GRCh38 GRCh37 |
32 | 410 | |
LOC106627981 | - | - | - |
GRCh38 GRCh38 |
- | 364 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 7, 2023 | RCV000079351.42 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 6, 2019 | RCV000243066.14 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 13, 2020 | RCV000588402.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 17, 2021 | RCV004019535.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Dec 19, 2012)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000232103.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: mixed
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Pathogenic
(Dec 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV005080113.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Functional studies found that W223R is associated with significantly reduced enzyme activity (PMID: 10757640); In silico analysis supports that this missense variant has a deleterious … (more)
Functional studies found that W223R is associated with significantly reduced enzyme activity (PMID: 10757640); 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: 9516376, 25435509, 8889578, 11112377, 18078074, 10679038, 27864021, 16396828, 29198828, 26220978, 16418594, 18070135, 24904648, 30606667, 32658388, 34586679, 17059888, 33301762, 10757640) (less)
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Pathogenic
(Jun 30, 2017)
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criteria provided, single submitter
Method: clinical testing
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Gaucher disease
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697591.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Jun 06, 2019)
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criteria provided, single submitter
Method: clinical testing
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Gaucher disease type I
Gaucher disease type II Gaucher disease type III (Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000305642.2
First in ClinVar: Oct 02, 2016 Last updated: Jul 14, 2019 |
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Pathogenic
(Jan 13, 2020)
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criteria provided, single submitter
Method: curation
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Gaucher disease
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422957.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 05, 2022 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Sep 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003570750.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Apr 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000608495.31
First in ClinVar: Oct 30, 2017 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Sep 27, 2017)
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no assertion criteria provided
Method: clinical testing
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Gaucher disease
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002086474.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Uncertain significance
(Jun 24, 2022)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003808660.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Gaucher disease: Biochemical and molecular findings in 141 patients diagnosed in Greece. | Dimitriou E | Molecular genetics and metabolism reports | 2020 | PMID: 32547927 |
Trio approach reveals higher risk of PD in carriers of severe vs. mild GBA mutations. | Arkadir D | Blood cells, molecules & diseases | 2018 | PMID: 27864021 |
The role of cardiac magnetic resonance in assessing the cardiac involvement in Gaucher type 1 patients: morphological and functional evaluations. | Roghi A | Journal of cardiovascular medicine (Hagerstown, Md.) | 2017 | PMID: 27136700 |
Altered TFEB-mediated lysosomal biogenesis in Gaucher disease iPSC-derived neuronal cells. | Awad O | Human molecular genetics | 2015 | PMID: 26220978 |
Gaucher iPSC-derived macrophages produce elevated levels of inflammatory mediators and serve as a new platform for therapeutic development. | Panicker LM | Stem cells (Dayton, Ohio) | 2014 | PMID: 24801745 |
Detection of 12 new mutations in Gaucher disease Brazilian patients. | Rozenberg R | Blood cells, molecules & diseases | 2006 | PMID: 17059888 |
Gaucher disease: expression and characterization of mild and severe acid beta-glucosidase mutations in Portuguese type 1 patients. | Amaral O | European journal of human genetics : EJHG | 2000 | PMID: 10757640 |
Novel point mutation (W184R) in neonatal type 2 Gaucher disease. | Choy FY | Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society | 2000 | PMID: 10679038 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GBA | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8e060888-a478-42e4-8c76-15221933538e | - | - | - | - |
Text-mined citations for rs61748906 ...
HelpRecord last updated Nov 30, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.