ClinVar Genomic variation as it relates to human health
NM_000157.4(GBA1):c.1603C>T (p.Arg535Cys)
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.1603C>T (p.Arg535Cys)
Variation ID: 242383 Accession: VCV000242383.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 155235003 (GRCh38) [ NCBI UCSC ] 1: 155204794 (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 Mar 8, 2017 Oct 8, 2024 Jun 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000157.4:c.1603C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000148.2:p.Arg535Cys missense NM_001005741.3:c.1603C>T NP_001005741.1:p.Arg535Cys missense NM_001005742.3:c.1603C>T NP_001005742.1:p.Arg535Cys missense NM_001171811.2:c.1342C>T NP_001165282.1:p.Arg448Cys missense NM_001171812.2:c.1456C>T NP_001165283.1:p.Arg486Cys missense NC_000001.11:g.155235003G>A NC_000001.10:g.155204794G>A NG_009783.1:g.14695C>T NG_042867.1:g.1465G>A P04062:p.Arg535Cys - Protein change
- R535C, R448C, R486C
- Other names
- R496C
- Canonical SPDI
- NC_000001.11:155235002:G:A
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00004
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 | 401 | |
LOC106627981 | - | - | - |
GRCh38 GRCh38 |
- | 355 |
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 (2) |
criteria provided, single submitter
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Jan 22, 2020 | RCV000417294.5 | |
Pathogenic (2) |
criteria provided, single submitter
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Mar 1, 2020 | RCV001175549.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 1, 2023 | RCV001782727.11 | |
Pathogenic (1) |
criteria provided, single submitter
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May 20, 2023 | RCV004720248.1 |
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
(Mar 01, 2020)
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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: SCV001339173.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: GBA c.1603C>T (p.Arg535Cys) also widely reported as p.Arg496Cys, results in a non-conservative amino acid change in the encoded protein sequence. Five of five … (more)
Variant summary: GBA c.1603C>T (p.Arg535Cys) also widely reported as p.Arg496Cys, results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 172274 control chromosomes. c.1603C>T has been well reported in the literature in multiple individuals from diverse ethnicities affected with Gaucher Disease (example, Kawame_1992, Karaca_2012, Ankleshwaria_2014 and Feng_2018). These data indicate that the variant is very likely to be associated with disease. No experimental evidence demonstrating an impact on protein function was ascertained. Although at-least one publication reported its identification in a enzymatically and clinically diagnosed Gaucher disease homozygous individual with no primary data provided (Kawame_1992). One researcher has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. This submitter cites an overlapping publication utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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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: SCV001422766.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 02, 2022 |
Comment:
The p.Arg535Cys variant in GBA has been reported at least 10 individuals with Gaucher disease (PMID: 27865684, 30637984, 30764785) and has been identified in 0.004% … (more)
The p.Arg535Cys variant in GBA has been reported at least 10 individuals with Gaucher disease (PMID: 27865684, 30637984, 30764785) and has been identified in 0.004% (1/24272) of South Asian chromosomes and 0.004% (1/25702) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs747506979). 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: 242383) as likely pathogenic by the Institute of Human Genetics. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg535His, has been reported in association with the disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 17059888, 24756352, 17427031, 20629126, 7655857, 28947706, 23430543, 8432537; VariationID: 4311). The phenotype of an individual compound heterozygous for this variant is highly specific for Gaucher disease based on the levels of beta-glucosidase detected in the BGL test being significantly below 8.7 nmol/mg/h consistent with disease (PMID: 27865684). Additionally, the homozygous occurrence of this variant in two affected individuals and the presence of this variant in combination with reported pathogenic variants (VariationID: 4288, 4295, 4290; PMID: 30764785, 27865684, 30637984) and in five individuals with Gaucher disease increases the likelihood that the p.Arg535Cys variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the detection of the variant in combination with other pathogenic variants in affected individuals, the presence of another pathogenic variant at the same location, and the presence of the variant in an individual with a phenotype specific for the disease. ACMG/AMP Criteria applied: PM3_very-Strong, PM2, PM5, PP4 (Richards, 2015). (less)
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Pathogenic
(Jun 01, 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: SCV002018399.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Sep 19, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002228247.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg535 amino acid residue in GBA. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg535 amino acid residue in GBA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16293621, 27735925). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GBA protein function. ClinVar contains an entry for this variant (Variation ID: 242383). This variant is also known as p.Arg496Cys or R496C. This missense change has been observed in individual(s) with Gaucher disease and/or Parkinson's disease (PMID: 1487244, 24522292, 28727984, 29140481). This variant is present in population databases (rs747506979, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 535 of the GBA protein (p.Arg535Cys). (less)
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Pathogenic
(May 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Parkinson disease, late-onset
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005329288.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The observed missense variant c.1603C>T(p.Arg535Cys) in GBA gene has been reported previously in homozygous, compound heterozygous and heterozygous state in individuals with Gaucher disease and/or … (more)
The observed missense variant c.1603C>T(p.Arg535Cys) in GBA gene has been reported previously in homozygous, compound heterozygous and heterozygous state in individuals with Gaucher disease and/or Parkinson's disease (Dimitriou E, et al., 2020. Sheth J, et al., 2019, Ankleshwaria C, et al., 2014). This variant disrupts the p.Arg535 amino acid residue in GBA and the other variant(s) that disrupt this residue have been determined to be pathogenic (Yang AC, et al., 2017). The c.1603C>T variant has 0.001% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic / Likely Pathogenic.The amino acid Arginine at position 535 is changed to a Cystiene changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen, SIFT and MutationTaster) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Arg535Cys in GBA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of the musculoskeletal system (present)
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Likely pathogenic
(Jun 10, 2016)
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no assertion criteria provided
Method: research
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Gaucher disease type I
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV000281966.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
USG abdomen s/o. storage disease; Bone-marrow s/o. Storage disease; Anaemia (Hb: 8.6 g%); Plasma Chitotriosidase: 11755.7 nmol/hr/ml plasma (N.R.: 28.66 - 62.94); Beta-Glucosidase: 1.45 nmol/hr/mg … (more)
USG abdomen s/o. storage disease; Bone-marrow s/o. Storage disease; Anaemia (Hb: 8.6 g%); Plasma Chitotriosidase: 11755.7 nmol/hr/ml plasma (N.R.: 28.66 - 62.94); Beta-Glucosidase: 1.45 nmol/hr/mg protein (N.R.: 4.0 - 32.0) (less)
Clinical Features:
Hepatosplenomegaly (present) , Global developmental delay (present) , Anemia (present) , increased chitotriosidase level (present) , decreased beta-glucosidase level (present)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Bauddha, Maharastrian, Indian
Geographic origin: Maharashtra, India
Method: Polymerase Chain Reaction followed by Bi-Directional Sanger sequencing was performed of GBA gene.
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Pathogenic
(May 04, 2020)
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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: SCV002086446.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 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: 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 |
Evaluation of the detection of GBA missense mutations and other variants using the Oxford Nanopore MinION. | Leija-Salazar M | Molecular genetics & genomic medicine | 2019 | PMID: 30637984 |
Clinical and molecular characteristics of patients with Gaucher disease in Southern China. | Feng Y | Blood cells, molecules & diseases | 2018 | PMID: 27865684 |
Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease. | Robak LA | Brain : a journal of neurology | 2017 | PMID: 29140481 |
GBA Analysis in Next-Generation Era: Pitfalls, Challenges, and Possible Solutions. | Zampieri S | The Journal of molecular diagnostics : JMD | 2017 | PMID: 28727984 |
Early manifestations of type 1 Gaucher disease in presymptomatic children diagnosed after parental carrier screening. | Yang AC | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27735925 |
Novel mutations in the glucocerebrosidase gene of Indian patients with Gaucher disease. | Ankleshwaria C | Journal of human genetics | 2014 | PMID: 24522292 |
Analysis of the β-glucocerebrosidase gene in Turkish Gaucher disease patients: mutation profile and description of a novel mutant allele. | Karaca E | Journal of pediatric endocrinology & metabolism : JPEM | 2012 | PMID: 23426826 |
Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations. | Liou B | The Journal of biological chemistry | 2006 | PMID: 16293621 |
Rapid identification of mutations in the glucocerebrosidase gene of Gaucher disease patients by analysis of single-strand conformation polymorphisms. | Kawame H | Human genetics | 1992 | PMID: 1487244 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/1ece6757-9431-4fb4-b1c4-77d81c19d975 | - | - | - | - |
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Text-mined citations for rs747506979 ...
HelpRecord last updated Oct 08, 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.