ClinVar Genomic variation as it relates to human health
NM_000157.4(GBA1):c.1504C>T (p.Arg502Cys)
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.1504C>T (p.Arg502Cys)
Variation ID: 4295 Accession: VCV000004295.79
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 155235196 (GRCh38) [ NCBI UCSC ] 1: 155204987 (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 Jul 23, 2024 Jan 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000157.4:c.1504C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000148.2:p.Arg502Cys missense NM_000157.3:c.1504C>T NM_001005741.3:c.1504C>T NP_001005741.1:p.Arg502Cys missense NM_001005742.2:c.1504C>T NM_001005742.3:c.1504C>T NP_001005742.1:p.Arg502Cys missense NM_001171811.2:c.1243C>T NP_001165282.1:p.Arg415Cys missense NM_001171812.2:c.1357C>T NP_001165283.1:p.Arg453Cys missense NC_000001.11:g.155235196G>A NC_000001.10:g.155204987G>A NG_009783.1:g.14502C>T NG_042867.1:g.1658G>A P04062:p.Arg502Cys - Protein change
- R502C, R415C, R453C
- Other names
- R463C
- (p.Arg502Cys)
- Canonical SPDI
- NC_000001.11:155235195:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Unknown function
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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) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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
Help
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 |
31 | 393 | |
LOC106627981 | - | - | - |
GRCh38 GRCh38 |
- | 349 |
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
Help
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 1, 2009 | RCV000004530.14 | |
Pathogenic (2) |
criteria provided, single submitter
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May 3, 2021 | RCV000004531.16 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 1, 2009 | RCV000004529.14 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jul 30, 2022 | RCV000004528.28 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jun 24, 2022 | RCV000020151.19 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 17, 2024 | RCV000079343.34 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 1, 2021 | RCV000762852.11 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004110.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 2, 2015 | RCV004018558.1 |
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
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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Pathogenic
(-)
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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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Baylor Genetics
Accession: SCV001162841.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Pathogenic
(Dec 10, 2019)
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criteria provided, single submitter
Method: clinical testing
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Gaucher disease type I
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001194027.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_001005741.2(GBA):c.1504C>T(R502C, aka R463C) is classified as pathogenic in the context of Gaucher disease, and can be associated with Type 1, 2, or 3 of the … (more)
NM_001005741.2(GBA):c.1504C>T(R502C, aka R463C) is classified as pathogenic in the context of Gaucher disease, and can be associated with Type 1, 2, or 3 of the disease. Sources cited for classification include the following: PMID 24522292, 12595585, 1348297, 1972019, 24482953, 18586596, 1704891, 8294487, 8118463 and 9279145. Classification of NM_001005741.2(GBA):c.1504C>T(R502C, aka R463C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(May 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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Parkinson disease, late-onset
Affected status: yes
Allele origin:
germline
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Fulgent Genetics, Fulgent Genetics
Accession: SCV001652788.1
First in ClinVar: May 29, 2021 Last updated: May 29, 2021 |
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Pathogenic
(Oct 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Gaucher disease type I
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV002034825.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
Comment:
The GBA c.1504C>T (p.Arg502Cys) variant is a missense variant, also described in the literature as p.Arg463Cys, and is associated with Gaucher disease (GD). Across a … (more)
The GBA c.1504C>T (p.Arg502Cys) variant is a missense variant, also described in the literature as p.Arg463Cys, and is associated with Gaucher disease (GD). Across a selection of the available literature, the p.Arg502Cys variant is reported in a homozygous state in two individuals with GD, and in a compound heterozygous state in 37 individuals with GD patients (Hatton et al. 1997; Koprivica et al. 2000; Emre et al 2008; Huang et al. 2020). The phenotypes and age of onset in affected individuals is variable and includes type 1 and type 3 Gaucher disease. The p.Arg502Cys variant is reported at a frequency of 0.000118 in the European (non-Finnish) population of the Genome Aggregation Database (version 3.1.1). In vitro functional studies have demonstrated reduced enzymatic activity for the p.Arg502Cys variant protein compared to wild-type (Grace et al. 1994). Based on the evidence, the p.Arg502Cys variant is classified as pathogenic for Gaucher disease. (less)
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Pathogenic
(Jul 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Gaucher disease type I
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002578224.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Comment:
A homozygous missense variation in exon 10 of the GBA gene that results in the amino acid substitution of Argenine for Cytosine at codon502 was … (more)
A homozygous missense variation in exon 10 of the GBA gene that results in the amino acid substitution of Argenine for Cytosine at codon502 was detected. The observed variant c.1504C>T (p.Arg502Cys) has not been reported in the 1000 genomes and has a MAF of 0.007% in the gnomAD databases. The in silico prediction of the variant is by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. (less)
Clinical Features:
Hepatosplenomegaly (present)
Age: 0-9 years
Sex: female
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Pathogenic
(Dec 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Lewy body dementia
Parkinson disease, late-onset Gaucher disease type I Gaucher disease type II Gaucher disease type III Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome Gaucher disease perinatal lethal
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893212.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Nov 20, 2023)
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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: SCV002024205.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 17, 2024)
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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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Invitae
Accession: SCV000964939.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 502 of the GBA protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 502 of the GBA protein (p.Arg502Cys). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individuals with Gaucher disease and Parkinson's disease (PMID: 1972019, 8733893, 17427031, 21704274, 24482953). This variant is also known as p.Arg463Cys or R463C. ClinVar contains an entry for this variant (Variation ID: 4295). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GBA function (PMID: 8294487, 11259172). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Gaucher disease
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557873.2
First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Gaucher disease (MIM# 230800, 230900, 231000, 231005, 608013). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Gaucher disease is associated with marked clinical variability, even within the same family (PMID: 31010158). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (19 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glycosyl hydrolase family 30 beta sandwich domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is also known as p.(Arg463Cys) in the literature. It has previously been reported in >20 Gaucher disease type 1 and 3 patients, however the phenotypic consequence of this variant has been suggested as being particularly inconsistent (ClinVar, PMIDs: 10796875; 33334373; 30764785). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies demonstrated that this variant results in reduced GBA enzymatic activity (PMID: 11259172). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Aug 25, 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: SCV000697584.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment:
Variant summary: The GBA c.1504C>T (p.Arg502Cys) variant involves the alteration of a non-conserved nucleotide, resulting in a missense change within the glycosyl hydrolase family 30, … (more)
Variant summary: The GBA c.1504C>T (p.Arg502Cys) variant involves the alteration of a non-conserved nucleotide, resulting in a missense change within the glycosyl hydrolase family 30, beta sandwich domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 7/121382 control chromosomes at a frequency of 0.0000577, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). The variant has been identified in numerous patients with Gaucher disease type I and type III, both as a compound heterozygous and homozygous allele. The variant is considered a recurrent mutation and has been associated with mild and severe Gaucher-related phenotypes in patients. Functional studies showed a significant reduction in enzyme activity (Grace_1994). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Jul 24, 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: SCV000225256.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 6
Sex: mixed
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Pathogenic
(Mar 21, 2018)
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criteria provided, single submitter
Method: clinical testing
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Gaucher disease type I
Affected status: yes
Allele origin:
paternal
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Baylor Genetics
Accession: SCV001527534.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Sep 23, 2021)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002048388.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
The GBA c.1504C>T; p.Arg502Cys variant (rs80356771), also known as Arg463Cys, is reported in the literature in the homozygous and compound heterozygous state in multiple individuals … (more)
The GBA c.1504C>T; p.Arg502Cys variant (rs80356771), also known as Arg463Cys, is reported in the literature in the homozygous and compound heterozygous state in multiple individuals affected with Gaucher syndrome (Alfonso 2007, Chauhan 2013, Hatton 1997, Tayebi 1996). Functional analyses of the variant protein show a dramatic reduction in GBA enzyme activity (Grace 1994, Liou 2006). This variant is also reported in ClinVar (Variation ID: 4295). This variant is found in the non-Finnish European population with an allele frequency of 0.011% (14/128876 alleles) in the Genome Aggregation Database. The arginine at codon 502 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.817). Additionally, other amino acid substitutions at this codon (His, Pro, Cys, Gln, Ser) have been reported in individuals with Gaucher syndrome (Alfonso 2007, Liou 2006, Beutler 1994, Jurecka 2011). Based on available information, this variant is considered to be pathogenic. References: Alfonso P et al. Mutation analysis and genotype/phenotype relationships of Gaucher disease patients in Spain. J Hum Genet. 2007;52(5):391-396.PMID: 17427031. Beutler E et al. Glucocerebrosidase mutations in Gaucher disease. Mol Med. 1994 Nov;1(1):82-92. PMID: 8790604. Chauhan V et al. Adult type 3 Gaucher disease as manifestation of R463C/Rec Nci I mutation: first reported case in the world literature. J Assoc Physicians India. 2013 May;61(5):346-8. PMID: 24482953. Grace ME et al. Analysis of human acid beta-glucosidase by site-directed mutagenesis and heterologous expression. J Biol Chem. 1994 Jan 21;269(3):2283-91. PMID: 8294487. Hatton CE et al. Mutation analysis in 46 British and Irish patients with Gaucher's disease. Arch Dis Child. 1997 Jul;77(1):17-22. PMID: 9279145. Jurecka A et al. Gaucher disease and dysgammaglobulinemia: a report of 61 patients, including 18 with GD type III. Blood Cells Mol Dis. 2011 Jan 15;46(1):85-7. PMID: 20729110. Liou B et al. Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations. J Biol Chem. 2006 Feb 17;281(7):4242-53. PMID: 16293621. Tayebi N et al. Genotype D399N/R463C in a patient with type 3 Gaucher disease previously assigned genotype N370S/R463C. Biochem Mol Med. 1996 Apr;57(2):149-51. PMID: 8733893. (less)
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Pathogenic
(Nov 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Gaucher disease type I
Affected status: yes
Allele origin:
germline
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Centogene AG - the Rare Disease Company
Accession: SCV002059260.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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Pathogenic
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Gaucher disease type I
(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: SCV001422765.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 05, 2022 |
Comment:
The p.Arg502Cys variant in GBA has been reported in at least 17 individuals with Gaucher disease (PMID: 9279145, 24522292, 18586596) and has been identified in … (more)
The p.Arg502Cys variant in GBA has been reported in at least 17 individuals with Gaucher disease (PMID: 9279145, 24522292, 18586596) and has been identified in 0.011% (14/128876) of European (non-Finnish) chromosomes, 0.010% (3/30616) of South Asian chromosomes, and 0.008% (2/24964) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs80356771). 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: 4295) as pathogenic by EGL Genetic diagnostics, GeneDx, Counsyl, Integrated Genetics, Fulgent Genetics, and OMIM. 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 variant, resulting in a different amino acid change at the same position, p.Arg502His, has been reported in association with disease in the literature and ClinVar, raising the possibility that a change at this position may not be tolerated (PMID: 21070, PMID: 23332636, 17427031, 28727984). The phenotype of an individual homozygous for this variant is highly specific for Gaucher disease based on Beta-glucosidase activity levels below the diagnostic marker of 8.7 nmol/h/mg protein consistent with disease (PMID: 24522292). Additionally, the homozygous occurrence of this variant in 3 individuals with Gaucher disease and the presence of this variant in combination with reported pathogenic variants in 9 individuals with Gaucher disease increases the likelihood that the p.Arg502Cys variant is pathogenic (VariationID: 4290, 4288, 4293; PMID: 9279145, 24522292, 18586596). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on multiple occurrences of the variant in affected individuals and in a homozygous or compound heterozygous state with other pathogenic variants, computational predictions, and the phenotype of a homozygote being highly specific for the disease. ACMG/AMP Criteria applied: PM3_very-strong, PM2_supporting, PP3, PP4 (Richards 2015). (less)
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Pathogenic
(Jun 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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Gaucher disease
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761818.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Feb 02, 2022)
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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: SCV000329942.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate that R502C has reduced enzyme activity (Hong et al., 1990; Grace et al., 1994); In silico analysis, which includes protein predictors … (more)
Published functional studies demonstrate that R502C has reduced enzyme activity (Hong et al., 1990; Grace et al., 1994); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Previously reported as R463C due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 12595585, 30537300, 10796875, 23413260, 22975760, 23588557, 24482953, 16293621, 8294487, 1972019, 1348297, 19286695, 27717005, 29140481, 8733893, 26008600, 9279145, 29625052, 34426522, 32658388) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
|
Gaucher Disease
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046060.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant is also known as p.Arg463Cys in the literature (PMID: 23588557). This variant has been previously reported as a compound heterozygous change most commonly … (more)
This variant is also known as p.Arg463Cys in the literature (PMID: 23588557). This variant has been previously reported as a compound heterozygous change most commonly in patients with Gaucher disease, but also among patients with Parkinson disease and renal cell carcinoma (PMID: 1972019, 24482953, 8733893, 17427031, 21704274, 29625052, 30537300). Functional studies indicate that this variant impairs the GBA enzyme activity (PMID: 11259172, 8294487). The frequency data for variants in the GBA gene in population databases may be unreliable due to the presence of pseudogenes and paralogs (PMID: 20301446). In silico analyses support a deleterious effect of the c.1504C>T (p.Arg502Cys) variant on protein function. Based on the available evidence, the c.1504C>T (p.Arg502Cys) variant is classified as Pathogenic. (less)
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Pathogenic
(Mar 02, 2015)
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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: SCV002754629.2
First in ClinVar: Dec 03, 2022 Last updated: May 01, 2024 |
Comment:
The p.R502C pathogenic mutation (also known as c.1504C>T and p.R463C in the literature), located in coding exon 10 of the GBA gene, results from a … (more)
The p.R502C pathogenic mutation (also known as c.1504C>T and p.R463C in the literature), located in coding exon 10 of the GBA gene, results from a C to T substitution at nucleotide position 1504. The arginine at codon 502 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was originally identified in combination with p.L444P in a non-Jewish patient with Gaucher disease type 1 and results in a significant reduction of normal enzyme activity (Hong CM et al. DNA Cell Biol. 1990;9(4):233-241) This mutation was also observed in 10 patients, 9 of whom were non-Ashkenazi Jewish, and affected with either Gaucher disease type 1 or type 3 (subacute nueronopathic type) (Koprivica V, Am. J. Hum. Genet. 2000 Jun; 66(6):1777-86). Another functional study found this mutation inactivated the enzyme function completely by rapid degredation (Liou B, J. Biol. Chem. 2006 Feb; 281(7):4242-53). Based on the supporting evidence, p.R502C is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jul 01, 2009)
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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: SCV000024702.5
First in ClinVar: Apr 04, 2013 Last updated: Sep 14, 2020 |
Comment on evidence:
Gaucher Disease In a non-Jewish patient with type I Gaucher disease (230800), Hong et al. (1990) identified a 1504C-T transition in exon 10 of the … (more)
Gaucher Disease In a non-Jewish patient with type I Gaucher disease (230800), Hong et al. (1990) identified a 1504C-T transition in exon 10 of the GBA gene, resulting in an arg463-to-cys (R463C) substitution. By the amplification refractory mutation system, Mistry et al. (1992) identified the R463C mutation and the L444P mutation (606463.0001) in association with rapidly progressive disease and neurologic involvement in non-Jewish patients (see 230900). Park et al. (2003) identified the R463C mutation in patients with type III Gaucher disease (231000). Parkinson Disease Neumann et al. (2009) identified a heterozygous R463C mutation in 3 (0.38%) of 790 British patients with Parkinson disease (PD; 168600) that was not found in 257 controls, suggesting that heterozygosity for the mutation increases susceptibility for development of PD. (less)
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risk factor
(Jul 01, 2009)
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no assertion criteria provided
Method: literature only
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PARKINSON DISEASE, LATE-ONSET, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024705.5
First in ClinVar: Apr 04, 2013 Last updated: Sep 14, 2020 |
Comment on evidence:
Gaucher Disease In a non-Jewish patient with type I Gaucher disease (230800), Hong et al. (1990) identified a 1504C-T transition in exon 10 of the … (more)
Gaucher Disease In a non-Jewish patient with type I Gaucher disease (230800), Hong et al. (1990) identified a 1504C-T transition in exon 10 of the GBA gene, resulting in an arg463-to-cys (R463C) substitution. By the amplification refractory mutation system, Mistry et al. (1992) identified the R463C mutation and the L444P mutation (606463.0001) in association with rapidly progressive disease and neurologic involvement in non-Jewish patients (see 230900). Park et al. (2003) identified the R463C mutation in patients with type III Gaucher disease (231000). Parkinson Disease Neumann et al. (2009) identified a heterozygous R463C mutation in 3 (0.38%) of 790 British patients with Parkinson disease (PD; 168600) that was not found in 257 controls, suggesting that heterozygosity for the mutation increases susceptibility for development of PD. (less)
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Pathogenic
(Jul 01, 2009)
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no assertion criteria provided
Method: literature only
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GAUCHER DISEASE, TYPE II
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024703.5
First in ClinVar: Apr 04, 2013 Last updated: Sep 14, 2020 |
Comment on evidence:
Gaucher Disease In a non-Jewish patient with type I Gaucher disease (230800), Hong et al. (1990) identified a 1504C-T transition in exon 10 of the … (more)
Gaucher Disease In a non-Jewish patient with type I Gaucher disease (230800), Hong et al. (1990) identified a 1504C-T transition in exon 10 of the GBA gene, resulting in an arg463-to-cys (R463C) substitution. By the amplification refractory mutation system, Mistry et al. (1992) identified the R463C mutation and the L444P mutation (606463.0001) in association with rapidly progressive disease and neurologic involvement in non-Jewish patients (see 230900). Park et al. (2003) identified the R463C mutation in patients with type III Gaucher disease (231000). Parkinson Disease Neumann et al. (2009) identified a heterozygous R463C mutation in 3 (0.38%) of 790 British patients with Parkinson disease (PD; 168600) that was not found in 257 controls, suggesting that heterozygosity for the mutation increases susceptibility for development of PD. (less)
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Pathogenic
(Jul 01, 2009)
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no assertion criteria provided
Method: literature only
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GAUCHER DISEASE, TYPE III
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024704.5
First in ClinVar: Apr 04, 2013 Last updated: Sep 14, 2020 |
Comment on evidence:
Gaucher Disease In a non-Jewish patient with type I Gaucher disease (230800), Hong et al. (1990) identified a 1504C-T transition in exon 10 of the … (more)
Gaucher Disease In a non-Jewish patient with type I Gaucher disease (230800), Hong et al. (1990) identified a 1504C-T transition in exon 10 of the GBA gene, resulting in an arg463-to-cys (R463C) substitution. By the amplification refractory mutation system, Mistry et al. (1992) identified the R463C mutation and the L444P mutation (606463.0001) in association with rapidly progressive disease and neurologic involvement in non-Jewish patients (see 230900). Park et al. (2003) identified the R463C mutation in patients with type III Gaucher disease (231000). Parkinson Disease Neumann et al. (2009) identified a heterozygous R463C mutation in 3 (0.38%) of 790 British patients with Parkinson disease (PD; 168600) that was not found in 257 controls, suggesting that heterozygosity for the mutation increases susceptibility for development of PD. (less)
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Pathogenic
(Mar 17, 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: SCV002086448.1
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: SCV000040478.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 29, 2022 |
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Unknown function
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002578224.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Gaucher Disease. | Adam MP | - | 2023 | PMID: 20301446 |
Eye movement biomarkers allow for the definition of phenotypes in Gaucher Disease. | Donald A | Orphanet journal of rare diseases | 2020 | PMID: 33334373 |
High risk screening for Gaucher disease in patients with splenomegaly and/or thrombocytopenia in China: 55 cases identified. | Huang Y | Clinica chimica acta; international journal of clinical chemistry | 2020 | PMID: 32165122 |
GBA, Gaucher Disease, and Parkinson's Disease: From Genetic to Clinic to New Therapeutic Approaches. | Riboldi GM | Cells | 2019 | PMID: 31010158 |
Gaucher disease: single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation. | Sheth J | BMC medical genetics | 2019 | PMID: 30764785 |
Novel mutations in the glucocerebrosidase gene of Indian patients with Gaucher disease. | Ankleshwaria C | Journal of human genetics | 2014 | PMID: 24522292 |
Adult type 3 Gaucher disease as manifestation of R463C/Rec Nci I mutation: first reported case in the world literature. | Chauhan V | The Journal of the Association of Physicians of India | 2013 | PMID: 24482953 |
Identification of recombinant alleles using quantitative real-time PCR implications for Gaucher disease. | Velayati A | The Journal of molecular diagnostics : JMD | 2011 | PMID: 21704274 |
Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. | Neumann J | Brain : a journal of neurology | 2009 | PMID: 19286695 |
Molecular analysis of Turkish Gaucher disease patients: identification of novel mutations in glucocerebrosidase (GBA) gene. | Emre S | European journal of medical genetics | 2008 | PMID: 18586596 |
Mutation analysis and genotype/phenotype relationships of Gaucher disease patients in Spain. | Alfonso P | Journal of human genetics | 2007 | PMID: 17427031 |
Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations. | Liou B | The Journal of biological chemistry | 2006 | PMID: 16293621 |
Myoclonic epilepsy in Gaucher disease: genotype-phenotype insights from a rare patient subgroup. | Park JK | Pediatric research | 2003 | PMID: 12595585 |
Identification and characterization of a novel mutation c.1090G>T (G325W) and nine common mutant alleles leading to Gaucher disease in Spanish patients. | Torralba MA | Blood cells, molecules & diseases | 2001 | PMID: 11259172 |
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 |
Mutation analysis in 46 British and Irish patients with Gaucher's disease. | Hatton CE | Archives of disease in childhood | 1997 | PMID: 9279145 |
Genotype D399N/R463C in a patient with type 3 Gaucher disease previously assigned genotype N370S/R463C. | Tayebi N | Biochemical and molecular medicine | 1996 | PMID: 8733893 |
Analysis of human acid beta-glucosidase by site-directed mutagenesis and heterologous expression. | Grace ME | The Journal of biological chemistry | 1994 | PMID: 8294487 |
DNA mutational analysis of type 1 and type 3 Gaucher patients: how well do mutations predict phenotype? | Sidransky E | Human mutation | 1994 | PMID: 8118463 |
Genetic diagnosis of Gaucher's disease. | Mistry PK | Lancet (London, England) | 1992 | PMID: 1348297 |
Characterization of human glucocerebrosidase from different mutant alleles. | Ohashi T | The Journal of biological chemistry | 1991 | PMID: 1704891 |
Sequence of two alleles responsible for Gaucher disease. | Hong CM | DNA and cell biology | 1990 | PMID: 1972019 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GBA | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/99bd217d-a648-4183-bc16-12ba36813e27 | - | - | - | - |
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Text-mined citations for rs80356771 ...
HelpRecord last updated Jul 29, 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.