ClinVar Genomic variation as it relates to human health
NM_000157.4(GBA1):c.625C>T (p.Arg209Cys)
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.625C>T (p.Arg209Cys)
Variation ID: 93455 Accession: VCV000093455.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 155238270 (GRCh38) [ NCBI UCSC ] 1: 155208061 (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 Jun 28, 2015 Sep 1, 2024 Aug 24, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000157.4:c.625C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000148.2:p.Arg209Cys missense NM_001005741.3:c.625C>T NP_001005741.1:p.Arg209Cys missense NM_001005742.3:c.625C>T NP_001005742.1:p.Arg209Cys missense NM_001171811.2:c.364C>T NP_001165282.1:p.Arg122Cys missense NM_001171812.2:c.478C>T NP_001165283.1:p.Arg160Cys missense NC_000001.11:g.155238270G>A NC_000001.10:g.155208061G>A NG_009783.1:g.11428C>T NG_042867.1:g.4732G>A P04062:p.Arg209Cys - Protein change
- R209C, R160C, R122C
- Other names
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- Canonical SPDI
- NC_000001.11:155238269: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) 0.00003
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
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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 | 398 | |
LOC106627981 | - | - | - |
GRCh38 GRCh38 |
- | 353 |
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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 17, 2023 | RCV000179793.14 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004133.9 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 13, 2020 | RCV000780284.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 24, 2024 | RCV004698469.1 |
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
(Dec 11, 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: SCV000917427.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: The GBA c.625C>T (p.Arg209Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant … (more)
Variant summary: The GBA c.625C>T (p.Arg209Cys) variant involves the alteration of a conserved nucleotide. 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 3/227084 control chromosomes at a frequency of 0.0000132, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). The variant has been reported in affected individuals in the literature and functional studies have shown completely absent transcript in a patient carrying the variant in the homozygous state (Dominissini_2005). In addition, one other clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Jul 18, 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: SCV000232100.5
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
Number of individuals with the variant: 2
Sex: mixed
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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: SCV001162864.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Pathogenic
(May 17, 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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004228231.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
PP3, PP4, PM2, PM3_strong, PS4_moderate
Number of individuals with the variant: 1
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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: SCV001422956.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 05, 2022 |
Comment:
The p.Arg209Cys variant in GBA has been reported in at least 14 individuals with Gaucher disease, segregated with disease in 4 affected relatives from 2 … (more)
The p.Arg209Cys variant in GBA has been reported in at least 14 individuals with Gaucher disease, segregated with disease in 4 affected relatives from 2 families (PMID: 10369158, 30115580, 12204005, 10796875, 26756743, 28727984, 16329099, 21704274; DOI: 10.13140/RG.2.1.3564.6481), and has been identified in 0.007% (1/14436) of African chromosomes, 0.003% (1/28708) of South Asian chromosomes, and 0.001% (1/103466) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123532). 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: 93455) as pathogenic by EGL Genetic Diagnostics. 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 two affected homozygotes and in combination with reported pathogenic variants in 4 individuals with Gaucher disease increases the likelihood that the p.Arg209Cys variant is pathogenic (VariationId: 4288, 4290; PMID: 10369158, 30115580, 12204005, 10796875). The phenotype of an individual compound heterozygous for this variant is highly specific for Gaucher disease based on low residual enzyme activity consistent with disease (PMID: 16329099). One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg209Pro, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 12204005, 9683600, 10796875). 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 affected homozygotes and compound heterozygotes, cosegregation of the variant with Gaucher disease, and a patient's phenotype being highly specific for Gaucher disease. ACMG/AMP Criteria applied: PM3_strong, PM2, PP3, PP4, PM5_supporting, PP1 (Richards 2015). (less)
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Likely pathogenic
(Dec 23, 2020)
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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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503550.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Aug 24, 2024)
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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: SCV005199940.1
First in ClinVar: Sep 01, 2024 Last updated: Sep 01, 2024 |
Comment:
A heterozygous variant in exon 6 of the GBA gene that results in the amino acid substitution of Cysteine for Arginine at codon 209 was … (more)
A heterozygous variant in exon 6 of the GBA gene that results in the amino acid substitution of Cysteine for Arginine at codon 209 was detected. The observed variant c.625C>T have MAF of 0.0013% in the gnomAD database. The in silico predictions is damaging by MutationTaster, DANN and FATHMM. In summary, the variant meets our criteria to be classified as pathogenic. (less)
Clinical Features:
Thrombocytopenia (present) , Hepatosplenomegaly (present) , Anemia (present)
Age: 10-19 years
Sex: female
Method: DNA extracted from blood was used to perform targeted gene capture using a custom smMIP panel. The libraries were sequenced to mean >100-300X coverage on the Illumina MiSeq sequencing platform. The sequences obtained are aligned to the human reference genome (GRCh37) using the BWA program and analyzed using Picard and GATK version 4.1.2 to identify variants relevant to the clinical indication.
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Pathogenic
(Sep 16, 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: SCV001461744.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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High-frequency component in flash visual evoked potentials in type 3 Gaucher disease. | Oguri M | Brain & development | 2020 | PMID: 31561936 |
Prevalence and predictors of liver fibrosis evaluated by vibration controlled transient elastography in type 1 Gaucher disease. | Nascimbeni F | Molecular genetics and metabolism | 2018 | PMID: 30115580 |
GBA Analysis in Next-Generation Era: Pitfalls, Challenges, and Possible Solutions. | Zampieri S | The Journal of molecular diagnostics : JMD | 2017 | PMID: 28727984 |
Impaired gait kinematics in type 1 Gaucher's Disease. | Sorrentino P | Journal of Parkinson's disease | 2016 | PMID: 26756743 |
Identification of recombinant alleles using quantitative real-time PCR implications for Gaucher disease. | Velayati A | The Journal of molecular diagnostics : JMD | 2011 | PMID: 21704274 |
Characterization of two novel GBA mutations causing Gaucher disease that lead to aberrant RNA species by using functional splicing assays. | Dominissini S | Human mutation | 2006 | PMID: 16329099 |
Reciprocal and nonreciprocal recombination at the glucocerebrosidase gene region: implications for complexity in Gaucher disease. | Tayebi N | American journal of human genetics | 2003 | PMID: 12587096 |
Analysis of the glucocerebrosidase gene and mutation profile in 144 Italian gaucher patients. | Filocamo M | Human mutation | 2002 | PMID: 12204005 |
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 |
Two novel polymorphic sequences in the glucocerebrosidase gene region enhance mutational screening and founder effect studies of patients with Gaucher disease. | Lau EK | Human genetics | 1999 | PMID: 10369158 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GBA | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/f5c9e4ac-8527-4f4a-a689-539bb22b6ae8 | - | - | - | - |
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Text-mined citations for rs398123532 ...
HelpRecord last updated Sep 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.