ClinVar Genomic variation as it relates to human health
NM_000157.4(GBA1):c.1223C>T (p.Thr408Met)
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.
Uncertain significance(2); Benign(4); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000157.4(GBA1):c.1223C>T (p.Thr408Met)
Variation ID: 93447 Accession: VCV000093447.49
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 155236246 (GRCh38) [ NCBI UCSC ] 1: 155206037 (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 8, 2016 Apr 15, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000157.4:c.1223C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000148.2:p.Thr408Met missense NM_001005741.3:c.1223C>T NP_001005741.1:p.Thr408Met missense NM_001005742.2:c.1223C>T NM_001005742.3:c.1223C>T NP_001005742.1:p.Thr408Met missense NM_001171811.2:c.962C>T NP_001165282.1:p.Thr321Met missense NM_001171812.2:c.1076C>T NP_001165283.1:p.Thr359Met missense NC_000001.11:g.155236246G>A NC_000001.10:g.155206037G>A NG_009783.1:g.13452C>T NG_042867.1:g.2708G>A P04062:p.Thr408Met - Protein change
- T408M, T359M, T321M
- Other names
- -
- Canonical SPDI
- NC_000001.11:155236245: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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0.00180 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00180
1000 Genomes Project 30x 0.00187
The Genome Aggregation Database (gnomAD), exomes 0.00594
Exome Aggregation Consortium (ExAC) 0.00657
Trans-Omics for Precision Medicine (TOPMed) 0.00546
The Genome Aggregation Database (gnomAD) 0.00627
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00515
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 |
28 | 378 | |
LOC106627981 | - | - | - |
GRCh38 GRCh38 |
- | 337 |
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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Benign/Likely benign (7) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000079335.41 | |
Benign (3) |
criteria provided, multiple submitters, no conflicts
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Jan 2, 2018 | RCV000244995.18 | |
Uncertain significance (1) |
no assertion criteria provided
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Sep 8, 2015 | RCV000416597.10 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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May 18, 2021 | RCV001196545.14 | |
Uncertain significance (2) |
criteria provided, single submitter
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Jan 22, 2020 | RCV001249086.13 | |
Likely benign (1) |
criteria provided, single submitter
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Feb 5, 2018 | RCV002460911.8 |
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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Benign
(-)
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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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PreventionGenetics, part of Exact Sciences
Accession: SCV000305637.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
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Uncertain significance
(Sep 28, 2018)
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criteria provided, single submitter
Method: clinical testing
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Gaucher disease perinatal lethal
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367153.2
First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020 |
Comment:
This variant was classified as: Uncertain significance. The available evidence favors the benign nature of this variant, however the evidence is insufficent to prove its … (more)
This variant was classified as: Uncertain significance. The available evidence favors the benign nature of this variant, however the evidence is insufficent to prove its benign nature. The following ACMG criteria were applied in classifying this variant: BP4. (less)
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Likely benign
(May 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Gaucher disease perinatal lethal
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001716371.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Sex: mixed
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Uncertain significance
(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: SCV001423048.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 05, 2022 |
Comment:
The p.Thr408Met variant in GBA has been reported in at least 4 individuals with Gaucher disease (PMID: 12734541, 12694238, 10796875) and has been identified in … (more)
The p.Thr408Met variant in GBA has been reported in at least 4 individuals with Gaucher disease (PMID: 12734541, 12694238, 10796875) and has been identified in 0.992% (249/25102) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs75548401). This variant has also been reported in ClinVar (VariationID: 93447) as a VUS by DST/NWU Preclinical Drug Development Platform, as likely benign by CeGaT Praxis fuer Humangnetik Tuebingen and Children's Mercy Hospital and Clinics, and as benign by PreventionGenetics, EGL Genetic Diagnostics, and Integrated Genetics. In vitro functional studies provide some evidence that the p.Thr408Met variant may not impact protein function (PMID: 12734541). 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. This variant was reported with a reported pathogenic variant in an unknown phase in 2 individuals with Gaucher disease (VariationID: 4290; PMID: 12734541, 10796875). However, this variant was also found in cis with other pathogenic variants, suggesting that it may not cause disease (VariationID: 65570, 4293; PMID: 12734541, 12694238). In summary, the clinical significance of the p.Thr408Met variant is uncertain. ACMG/AMP Criteria applied: BS1, PP3, BP2, BS3_supporting (Richards 2015). (less)
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Likely benign
(Feb 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002756031.1
First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Number of individuals with the variant: 1
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Likely benign
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000780298.21
First in ClinVar: Dec 06, 2016 Last updated: Apr 15, 2024 |
Comment:
GBA1: BS2
Number of individuals with the variant: 51
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Likely Benign
(Dec 23, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000281415.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
Comment:
Converted during submission to Likely benign.
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Benign
(May 09, 2016)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000111205.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 6
Sex: mixed
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Benign
(Jan 02, 2018)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919416.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: The GBA c.1223C>T (p.Thr408Met, also known as Thr369Met) variant located in the glycosyl hydrolase family 30, TIM-barrel domain (via InterPro) involves the alteration … (more)
Variant summary: The GBA c.1223C>T (p.Thr408Met, also known as Thr369Met) variant located in the glycosyl hydrolase family 30, TIM-barrel domain (via InterPro) involves the alteration of a non-conserved nucleotide and 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index and p-value). This variant was found in 1708/277314 (7 homozygotes) control chromosomes (gnomAD and publication controls) at a frequency of 0.0061591, which is approximately 1 times the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005), suggesting this variant is likely a benign polymorphism. Multiple publications have cited the variant in affected individuals including a co-occurrence with another pathogenic GBA variant, D409H (also known as D448H - scored DV)(Hodanova_1999). Another publication, Walker_2003, cites the variant, T369M, as a polymorphism. A publication, Hodanova_2003, does indicate the variant could cause a functional impact but the authors state that at most would be a mild mutation even on the verge of a polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely benign/benign." Taken together, this variant is classified as benign. (less)
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Benign
(Dec 11, 2018)
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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: SCV001829252.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 32658388, 33281709, 32618053, 29487000, 28966932, 29842932, 30548430, 30146349, 30302829, 29396846, 28834018, 29140481, 27153395, 27648471, 28030538, 26000814, … (more)
This variant is associated with the following publications: (PMID: 32658388, 33281709, 32618053, 29487000, 28966932, 29842932, 30548430, 30146349, 30302829, 29396846, 28834018, 29140481, 27153395, 27648471, 28030538, 26000814, 27094865, 8774051, 22001711, 18987351, 22173904, 12694238) (less)
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Uncertain significance
(Sep 08, 2015)
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no assertion criteria provided
Method: research
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Parkinson disease, late-onset
Affected status: yes
Allele origin:
unknown
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DST/NWU Preclinical Drug Development Platform, North-West University
Study: GBA_PD_RSA
Accession: SCV000245439.1 First in ClinVar: Feb 08, 2017 Last updated: Feb 08, 2017 |
Number of individuals with the variant: 2
Family history: no
Age: 71-75 years
Sex: mixed
Ethnicity/Population group: Afrikaner
Geographic origin: South Africa
Method: Sequencing (Sanger)
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Benign
(May 17, 2017)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000800926.1
First in ClinVar: Aug 04, 2018 Last updated: Aug 04, 2018 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809374.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002037727.1 First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
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Likely benign
(Jun 14, 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: SCV002086460.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001744398.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 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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GBA mutations in Parkinson disease: earlier death but similar neuropathological features. | Adler CH | European journal of neurology | 2017 | PMID: 28834018 |
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson's Disease. | Benitez BA | Molecular neurodegeneration | 2016 | PMID: 27094865 |
Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations. | Alcalay RN | Brain : a journal of neurology | 2015 | PMID: 26117366 |
Transient expression of wild-type and mutant glucocerebrosidases in hybrid vaccinia expression system. | Hodanová K | European journal of human genetics : EJHG | 2003 | PMID: 12734541 |
Glucocerebrosidase mutation T369M appears to be another polymorphism. | Walker JM | Clinical genetics | 2003 | PMID: 12694238 |
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 |
Analysis of the beta-glucocerebrosidase gene in Czech and Slovak Gaucher patients: mutation profile and description of six novel mutant alleles. | Hodanová K | Blood cells, molecules & diseases | 1999 | PMID: 10744424 |
Glucocerebrosidase (Gaucher disease). | Beutler E | Human mutation | 1996 | PMID: 8889578 |
Gaucher disease: four families with previously undescribed mutations. | Beutler E | Proceedings of the Association of American Physicians | 1996 | PMID: 8774051 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GBA | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/aa916e1b-1839-474f-b18d-bc6d49e11024 | - | - | - | - |
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Text-mined citations for rs75548401 ...
HelpRecord last updated Apr 20, 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.