ClinVar Genomic variation as it relates to human health
NM_000157.4(GBA1):c.476G>A (p.Arg159Gln)
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.476G>A (p.Arg159Gln)
Variation ID: 4291 Accession: VCV000004291.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 155238629 (GRCh38) [ NCBI UCSC ] 1: 155208420 (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 Apr 4, 2013 Feb 4, 2024 Jun 22, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000157.4:c.476G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000148.2:p.Arg159Gln missense NM_000157.3:c.476G>A NM_001005741.3:c.476G>A NP_001005741.1:p.Arg159Gln missense NM_001005742.3:c.476G>A NP_001005742.1:p.Arg159Gln missense NM_001171811.2:c.215G>A NP_001165282.1:p.Arg72Gln missense NM_001171812.2:c.329G>A NP_001165283.1:p.Arg110Gln missense NC_000001.11:g.155238629C>T NC_000001.10:g.155208420C>T NG_009783.1:g.11069G>A NG_042867.1:g.5091C>T P04062:p.Arg159Gln - Protein change
- R159Q, R110Q, R72Q
- Other names
- R119Q
- Canonical SPDI
- NC_000001.11:155238628:C:T
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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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
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
Help
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 |
29 | 386 | |
LOC106627981 | - | - | - |
GRCh38 GRCh38 |
- | 344 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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
Help
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 (1) |
no assertion criteria provided
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Jul 15, 2004 | RCV000004519.5 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 15, 2004 | RCV000004518.5 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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May 23, 2021 | RCV000020154.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 6, 2020 | RCV001250522.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 22, 2022 | RCV001781178.4 |
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
Help
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
Help
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
Help
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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Likely pathogenic
(May 06, 2020)
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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 Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001425323.1
First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020 |
Comment:
GBA c.476G>A has been reported in multiple individuals presenting with Gaucher disease. This GBA variant (rs79653797) is rare (<0.1%) in a large population dataset (gnomAD: … (more)
GBA c.476G>A has been reported in multiple individuals presenting with Gaucher disease. This GBA variant (rs79653797) is rare (<0.1%) in a large population dataset (gnomAD: 2/251180 total alleles; 0.0008%; no homozygotes). This variant is located within a mutational hotpspot, which is in proximity to glucocerebrosidase catalytic sites. An alternate pathogenic missense change (p.Arg159Trp) has been reported at the same amino acid residue. This variant has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is highly evolutionarily conserved across most species assessed. We consider this variant to be likely pathogenic. (less)
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Pathogenic
(May 23, 2021)
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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: SCV001737811.1
First in ClinVar: Jun 23, 2021 Last updated: Jun 23, 2021 |
Comment:
Variant summary: GBA c.476G>A (p.Arg159Gln) results in a conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) of the encoded … (more)
Variant summary: GBA c.476G>A (p.Arg159Gln) results in a conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251180 control chromosomes. c.476G>A has been reported in the literature as p.Arg120Gln in multiple individuals affected with Gaucher Disease (example, Theophilus_1989, Beutler_1993, Koprivica_2000, Felderhoff-Meuser_2004, Rozenberg_2006, Mercimek-Mahmutoglu_2007, Sonder_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in compound heterozygosity with a 12 nucleotide insertion. The most pronounced variant effect results in <1% of normal activity in the patient derived fibroblast homogenate (Felderhoff-Mueser_2004). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 22, 2022)
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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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Revvity Omics, Revvity
Accession: SCV002018401.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 22, 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: SCV001423035.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Arg159Gln variant in GBA has been reported in at least 6 individuals with Gaucher disease (PMID: 15214004, 17560820, 17059888, 22658918) and has been identified … (more)
The p.Arg159Gln variant in GBA has been reported in at least 6 individuals with Gaucher disease (PMID: 15214004, 17560820, 17059888, 22658918) and has been identified in 0.002891% (1/34592) of Latino chromosomes and 0.0008814% (1/113462) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs79653797). 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: 4291) as pathogenic by OMIM. In vitro functional studies showing that fibroblasts cultured from a patient with Gaucher disease had <1% wild-type activity provide some evidence that the p.Arg159Gln variant may impact protein function (PMID: 15214004). 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. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg159Trp, has been reported in association with Gaucher disease in the literature and ClinVar, supporting that this variant may be pathogenic (VariationID: 65570; PMID: 28727984, 22623374, 17395504, 27865684, 29685539, 30764785, 23936319). Additionally, the presence of this variant in combination with reported pathogenic and likely pathogenic variants and in 4 individuals with Gaucher disease increases the likelihood that the p.Arg159Gln variant is pathogenic (VariationID: 4290, 4333; PMID: 15214004, 17560820, 17059888). 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 reported pathogenic variants, the significantly reduced activity of the protein in fibroblasts derived from a proband, and the presence of a pathogenic variant at the same position. ACMG/AMP Criteria applied: PM3_strong, PM2, PS3_moderate, PM5, PP3 (Richards 2015). (less)
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Pathogenic
(Jul 15, 2004)
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no assertion criteria provided
Method: literature only
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GAUCHER DISEASE, PERINATAL LETHAL
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024693.4
First in ClinVar: Apr 04, 2013 Last updated: Jun 24, 2017 |
Comment on evidence:
The arg119-to-gln (R119Q) substitution in the GBA gene has been reported to result from a 3060G-A transition (Graves et al., 1988) and a 476G-A transition … (more)
The arg119-to-gln (R119Q) substitution in the GBA gene has been reported to result from a 3060G-A transition (Graves et al., 1988) and a 476G-A transition (Felderhoff-Mueser et al., 2004), depending upon the reference sequence cited. This mutation has also been referred to as ARG120GLN by others (Latham et al., 1990; Felderhoff-Mueser et al., 2004). Graves et al. (1988) identified a heterozygous R119Q substitution in the GBA gene in 2 Ashkenazi Jewish cousins with Gaucher disease type I (230800). In a premature infant with the perinatal lethal form of Gaucher disease (608013), Felderhoff-Mueser et al. (2004) identified compound heterozygosity for the R120Q mutation and an IVS10-1G-A substitution (606463.0046) in the GBA gene. (less)
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Pathogenic
(Jul 15, 2004)
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no assertion criteria provided
Method: literature only
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GAUCHER DISEASE, TYPE I
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024692.4
First in ClinVar: Apr 04, 2013 Last updated: Jun 24, 2017 |
Comment on evidence:
The arg119-to-gln (R119Q) substitution in the GBA gene has been reported to result from a 3060G-A transition (Graves et al., 1988) and a 476G-A transition … (more)
The arg119-to-gln (R119Q) substitution in the GBA gene has been reported to result from a 3060G-A transition (Graves et al., 1988) and a 476G-A transition (Felderhoff-Mueser et al., 2004), depending upon the reference sequence cited. This mutation has also been referred to as ARG120GLN by others (Latham et al., 1990; Felderhoff-Mueser et al., 2004). Graves et al. (1988) identified a heterozygous R119Q substitution in the GBA gene in 2 Ashkenazi Jewish cousins with Gaucher disease type I (230800). In a premature infant with the perinatal lethal form of Gaucher disease (608013), Felderhoff-Mueser et al. (2004) identified compound heterozygosity for the R120Q mutation and an IVS10-1G-A substitution (606463.0046) in the GBA gene. (less)
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Pathogenic
(May 06, 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: SCV002086479.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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Gaucher disease
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000040481.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 29, 2022 |
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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. | Adam MP | - | 2023 | PMID: 20301446 |
Persistent immune alterations and comorbidities in splenectomized patients with Gaucher disease. | Sønder SU | Blood cells, molecules & diseases | 2016 | PMID: 27282561 |
Perinatal lethal form of Gaucher disease. Clinical and molecular characterization of a Greek case. | Michelakakis H | Blood cells, molecules & diseases | 2010 | PMID: 20005137 |
Neurological and brain MRS findings in patients with Gaucher disease type 1. | Mercimek-Mahmutoglu S | Molecular genetics and metabolism | 2007 | PMID: 17560820 |
Detection of 12 new mutations in Gaucher disease Brazilian patients. | Rozenberg R | Blood cells, molecules & diseases | 2006 | PMID: 17059888 |
Mutation analysis of Gaucher disease patients in Taiwan: high prevalence of the RecNciI and L444P mutations. | Wan L | Blood cells, molecules & diseases | 2006 | PMID: 16546416 |
Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations. | Liou B | The Journal of biological chemistry | 2006 | PMID: 16293621 |
Intrauterine onset of acute neuropathic type 2 Gaucher disease: identification of a novel insertion sequence. | Felderhoff-Mueser U | American journal of medical genetics. Part A | 2004 | PMID: 15214004 |
Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease. | Koprivica V | American journal of human genetics | 2000 | PMID: 10796875 |
Gaucher disease mutations in non-Jewish patients. | Beutler E | British journal of haematology | 1993 | PMID: 8280613 |
Heterogeneity of mutations in the acid beta-glucosidase gene of Gaucher disease patients. | Latham TE | DNA and cell biology | 1991 | PMID: 1899336 |
Gaucher disease: molecular heterogeneity and phenotype-genotype correlations. | Theophilus B | American journal of human genetics | 1989 | PMID: 2502917 |
Gaucher disease type 1: cloning and characterization of a cDNA encoding acid beta-glucosidase from an Ashkenazi Jewish patient. | Graves PN | DNA (Mary Ann Liebert, Inc.) | 1988 | PMID: 3180993 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/58a7c1b8-3a84-43e8-adac-02ec45b5218e | - | - | - | - |
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Text-mined citations for rs79653797 ...
HelpRecord last updated Mar 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.