The Met337Val variant in TARDBP has been reported in Western countries and Asia with autosomal dominant amyotrophic lateral sclerosis, segregated with the disease in over 10 affected relatives (Sreedharan 2008, Kirby 2010, Tamaoka 2010, Xu 2018), and was absent from large population studies. Additionally, studies indicate that the Met337Var variant transgenic mouse presented worsened dose-dependent disease phenotype in terms of motor dysfunction, neurodegeneration, gliosis, and development of ubiquitin and phosphorylated TDP-43 pathology (Janssens 2013). In summary, the Met337Val variant meets our criteria to be classified as pathogenic based upon segregation studies, absence from controls, and functional evidence.
ClinVar Genomic variation as it relates to human health
NM_007375.4(TARDBP):c.1009A>G (p.Met337Val)
Germline
Classification
Help
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.
(6)
Help
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.
Pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007375.4(TARDBP):c.1009A>G (p.Met337Val)
Variation ID: 5228 Accession: VCV000005228.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.22 1: 11022418 (GRCh38) [ NCBI UCSC ] 1: 11082475 (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 Oct 20, 2024 Mar 15, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007375.4:c.1009A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_031401.1:p.Met337Val missense NC_000001.11:g.11022418A>G NC_000001.10:g.11082475A>G NG_008734.1:g.14797A>G LRG_659:g.14797A>G LRG_659t1:c.1009A>G LRG_659p1:p.Met337Val Q13148:p.Met337Val - Protein change
- -
- Other names
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M337V
- Canonical SPDI
- NC_000001.11:11022417:A:G
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00001
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| TARDBP | No evidence available | No evidence available |
GRCh38 GRCh37 |
246 | 360 | |
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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, single submitter
|
Mar 15, 2023 | RCV000005539.14 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 18, 2023 | RCV000693006.17 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 23, 2020 | RCV001090806.29 |
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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|---|---|---|---|---|---|
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Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446728.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Amyotrophic lateral sclerosis (present) , Spasticity (present) , Dysarthria (present) , Fasciculations (present) , Muscular atrophy (present)
Sex: male
|
|
|
Pathogenic
(Mar 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Amyotrophic lateral sclerosis type 10
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline,
unknown
|
Department of Neurology-Cell Therapy Center, Hanyang University
Accession: SCV004023203.1
First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023 |
Comment:
The Met337Val variant in TARDBP has been reported in Western countries and Asia with autosomal dominant amyotrophic lateral sclerosis, segregated with the disease in over … (more)
The Met337Val variant in TARDBP has been reported in Western countries and Asia with autosomal dominant amyotrophic lateral sclerosis, segregated with the disease in over 10 affected relatives (Sreedharan 2008, Kirby 2010, Tamaoka 2010, Xu 2018), and was absent from large population studies. Additionally, studies indicate that the Met337Var variant transgenic mouse presented worsened dose-dependent disease phenotype in terms of motor dysfunction, neurodegeneration, gliosis, and development of ubiquitin and phosphorylated TDP-43 pathology (Janssens 2013). In summary, the Met337Val variant meets our criteria to be classified as pathogenic based upon segregation studies, absence from controls, and functional evidence. (less)
Observation 1:
Clinical Features:
Amyotrophic lateral sclerosis (present)
Age: 40-49 years
Sex: male
Ethnicity/Population group: Korean
Geographic origin: Asia
Method: Sequencing libraries were prepared according to the manufacturer's instructions, and the flow cell was loaded on a NextSeq 500 sequencing system (Illumina) for sequencing with 2x100 bp read lengths. Reads were mapped to the GRCh37/hg19 build using the Burrows-Wheeler Aligner (BWA), and variants were called using GATK software.
Testing laboratory: GC Genome, Yongin, Republic of Korea
Date variant was reported to submitter: 2021-12-02
Testing laboratory interpretation: Pathogenic
Observation 2:
Clinical Features:
Amyotrophic lateral sclerosis (present)
Age: 40-49 years
Sex: female
Ethnicity/Population group: Korean
Geographic origin: Asia
Method: Sequencing libraries were prepared according to the manufacturer's instructions, and the flow cell was loaded on a NextSeq 500 sequencing system (Illumina) for sequencing with 2x100 bp read lengths. Reads were mapped to the GRCh37/hg19 build using the Burrows-Wheeler Aligner (BWA), and variants were called using GATK software.
Testing laboratory: GC Genome, Yongin, Republic of Korea
Date variant was reported to submitter: 2022-08-17
Testing laboratory interpretation: Pathogenic
Observation 3:
Clinical Features:
Amyotrophic lateral sclerosis (present)
Age: 60-69 years
Sex: male
Ethnicity/Population group: Korean
Geographic origin: Asia
Method: Sequencing libraries were prepared according to the manufacturer's instructions, and the flow cell was loaded on a NextSeq 500 sequencing system (Illumina) for sequencing with 2x100 bp read lengths. Reads were mapped to the GRCh37/hg19 build using the Burrows-Wheeler Aligner (BWA), and variants were called using GATK software.
Testing laboratory: GC Genome, Yongin, Republic of Korea
Date variant was reported to submitter: 2022-06-29
Testing laboratory interpretation: Pathogenic
Observation 4:
Clinical Features:
Amyotrophic lateral sclerosis (present)
Age: 60-69 years
Sex: female
Ethnicity/Population group: Korean
Geographic origin: Asia
Method: Sequencing libraries were prepared according to the manufacturer's instructions, and the flow cell was loaded on a NextSeq 500 sequencing system (Illumina) for sequencing with 2x100 bp read lengths. Reads were mapped to the GRCh37/hg19 build using the Burrows-Wheeler Aligner (BWA), and variants were called using GATK software.
Testing laboratory: Department of laboratory medicine, Seoul national university hospital
Date variant was reported to submitter: 2022-05-03
Testing laboratory interpretation: Pathogenic
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Pathogenic
(Feb 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Amyotrophic lateral sclerosis type 10
TARDBP-related frontotemporal dementia
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000820859.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 337 of the TARDBP protein (p.Met337Val). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 337 of the TARDBP protein (p.Met337Val). This variant is present in population databases (rs80356730, gnomAD 0.002%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (ALS) (PMID: 18309045, 20154440, 28430856, 28709720). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5228). 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) performed at Invitae indicates that this missense variant is not expected to disrupt TARDBP protein function. Experimental studies have shown that this missense change affects TARDBP function (PMID: 18309045, 19465477, 20600671, 23401527, 23827948, 24143176, 24507191). For these reasons, this variant has been classified as Pathogenic. (less)
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|
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Pathogenic
(May 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246537.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
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Pathogenic
(Mar 21, 2008)
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no assertion criteria provided
Method: literature only
|
AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000025721.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In an English family segregating autosomal dominant amyotrophic lateral sclerosis without frontotemporal dementia (612069), Sreedharan et al. (2008) identified an A-to-G transition at nucleotide 1009 … (more)
In an English family segregating autosomal dominant amyotrophic lateral sclerosis without frontotemporal dementia (612069), Sreedharan et al. (2008) identified an A-to-G transition at nucleotide 1009 in exon 6 of the TARDBP gene, resulting in a methionine-to-valine substitution at codon 337 (M337V). Methionine at this position is invariant in human, orangutan, mouse, opossum, chicken, frog, and zebrafish. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Amyotrophic lateral sclerosis type 10
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000041191.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
Comment:
Convincing evidence of segregation.
|
Comment:
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 337 of the TARDBP protein (p.Met337Val). This variant is present in population databases (rs80356730, gnomAD 0.002%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (ALS) (PMID: 18309045, 20154440, 28430856, 28709720). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5228). 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) performed at Invitae indicates that this missense variant is not expected to disrupt TARDBP protein function. Experimental studies have shown that this missense change affects TARDBP function (PMID: 18309045, 19465477, 20600671, 23401527, 23827948, 24143176, 24507191). For these reasons, this variant has been classified as Pathogenic.
Comment:
Convincing evidence of segregation.
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. |
Comment:
The Met337Val variant in TARDBP has been reported in Western countries and Asia with autosomal dominant amyotrophic lateral sclerosis, segregated with the disease in over 10 affected relatives (Sreedharan 2008, Kirby 2010, Tamaoka 2010, Xu 2018), and was absent from large population studies. Additionally, studies indicate that the Met337Var variant transgenic mouse presented worsened dose-dependent disease phenotype in terms of motor dysfunction, neurodegeneration, gliosis, and development of ubiquitin and phosphorylated TDP-43 pathology (Janssens 2013). In summary, the Met337Val variant meets our criteria to be classified as pathogenic based upon segregation studies, absence from controls, and functional evidence.
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 337 of the TARDBP protein (p.Met337Val). This variant is present in population databases (rs80356730, gnomAD 0.002%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (ALS) (PMID: 18309045, 20154440, 28430856, 28709720). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5228). 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) performed at Invitae indicates that this missense variant is not expected to disrupt TARDBP protein function. Experimental studies have shown that this missense change affects TARDBP function (PMID: 18309045, 19465477, 20600671, 23401527, 23827948, 24143176, 24507191). For these reasons, this variant has been classified as Pathogenic.
Comment:
Convincing evidence of segregation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| TARDBP-Related Amyotrophic Lateral Sclerosis-Frontotemporal Dementia. | Adam MP | - | 2023 | PMID: 20301761 |
| Burden of rare variants in ALS genes influences survival in familial and sporadic ALS. | Pang SY | Neurobiology of aging | 2017 | PMID: 28709720 |
| A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK. | Morgan S | Brain : a journal of neurology | 2017 | PMID: 28430856 |
| Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. | Alami NH | Neuron | 2014 | PMID: 24507191 |
| Downregulation of microRNA-9 in iPSC-derived neurons of FTD/ALS patients with TDP-43 mutations. | Zhang Z | PloS one | 2013 | PMID: 24143176 |
| The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons. | Wang W | Human molecular genetics | 2013 | PMID: 23827948 |
| Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. | Serio A | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 23401527 |
| Mutant TAR DNA-binding protein-43 induces oxidative injury in motor neuron-like cell. | Duan W | Neuroscience | 2010 | PMID: 20600671 |
| TDP-43 M337V mutation in familial amyotrophic lateral sclerosis in Japan. | Tamaoka A | Internal medicine (Tokyo, Japan) | 2010 | PMID: 20154440 |
| TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. | Johnson BS | The Journal of biological chemistry | 2009 | PMID: 19465477 |
| TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. | Sreedharan J | Science (New York, N.Y.) | 2008 | PMID: 18309045 |
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Text-mined citations for rs80356730 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 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.