For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TARDBP function (PMID: 19515851, 20624952, 24477737, 26883171, 27348499, 30442180). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 5232). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 18396105, 20558945, 21857683, 28709720, 30324134, 32166880). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs4884357, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 298 of the TARDBP protein (p.Gly298Ser).
ClinVar Genomic variation as it relates to human health
NM_007375.4(TARDBP):c.892G>A (p.Gly298Ser)
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
-
NM_007375.4(TARDBP):c.892G>A (p.Gly298Ser)
Variation ID: 5232 Accession: VCV000005232.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.22 1: 11022301 (GRCh38) [ NCBI UCSC ] 1: 11082358 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 8, 2024 Jan 17, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007375.4:c.892G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_031401.1:p.Gly298Ser missense NC_000001.11:g.11022301G>A NC_000001.10:g.11082358G>A NG_008734.1:g.14680G>A LRG_659:g.14680G>A LRG_659t1:c.892G>A LRG_659p1:p.Gly298Ser Q13148:p.Gly298Ser - Protein change
- -
- Other names
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G298S
- Canonical SPDI
- NC_000001.11:11022300:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
- 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/Likely pathogenic (3) |
no assertion criteria provided
|
Feb 28, 2019 | RCV000005543.15 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 22, 2018 | RCV000713825.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 17, 2023 | RCV001851670.12 | |
|
TARDBP-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
May 13, 2024 | RCV004754243.1 |
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
(Jun 22, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000844462.1
First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018 |
|
|
|
Pathogenic
(Jan 17, 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: SCV002246395.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TARDBP function (PMID: 19515851, 20624952, 24477737, 26883171, 27348499, 30442180). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 5232). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 18396105, 20558945, 21857683, 28709720, 30324134, 32166880). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs4884357, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 298 of the TARDBP protein (p.Gly298Ser). (less)
|
|
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Pathogenic
(May 01, 2008)
|
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: SCV000025725.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 17, 2016 |
Comment on evidence:
In affected members of a Chinese family with autosomal dominant ALS10 (612069), Van Deerlin et al. (2008) identified a heterozygous 892G-A transition in exon 6 … (more)
In affected members of a Chinese family with autosomal dominant ALS10 (612069), Van Deerlin et al. (2008) identified a heterozygous 892G-A transition in exon 6 of the TARDBP gene, resulting in a gly298-to-ser (G298S) substitution in the C-terminal region of TDP43. The mutation was not identified in 747 white controls or 380 Chinese controls. Five patients in 2 generations were affected with onset between ages 41 and 60 years. Most showed rapid progression with death within 1 or 2 years. Postmortem examination of 2 patients showed changes consistent with ALS as well as TDP43-positive inclusions in upper and lower motor neurons and in various brain regions. (less)
|
|
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Likely pathogenic
(Feb 28, 2019)
|
no assertion criteria provided
Method: provider interpretation
|
Amyotrophic lateral sclerosis type 10
Affected status: yes
Allele origin:
germline
|
Codex Genetics Limited
Accession: SCV000996003.1
First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020 |
Age: 44-64 years
Sex: mixed
|
|
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Pathogenic
(May 13, 2024)
|
no assertion criteria provided
Method: clinical testing
|
TARDBP-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005352544.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The TARDBP c.892G>A variant is predicted to result in the amino acid substitution p.Gly298Ser. This variant has been reported in several individuals with amyotrophic lateral … (more)
The TARDBP c.892G>A variant is predicted to result in the amino acid substitution p.Gly298Ser. This variant has been reported in several individuals with amyotrophic lateral sclerosis (ALS, Van Deerlin et al. 2008. PubMed ID: 18396105; Nozaki et al. 2010. PubMed ID: 20558945; Pang et al. 2017. PubMed ID: 28709720; Chen et al. 2020. PubMed ID: 32166880) and has been described as a founder variant for ALS in the Southern Chinese population (Xu et al. 2022. PubMed ID: 35932023). Immunohistochemistry studies from patients' CNS tissues revealed TDP-43 immunopositive inclusions (Van Deerlin et al. 2008. PubMed ID: 18396105), and additional in vitro functional studies using human motor neurons derived from iPS cells have demonstrated that expression of this variant impairs axonal transportation of cytoplasmic granules to distal neuronal compartments (Alami et al. 2014. PubMed ID: 24507191). This variant is located within the conserved C-terminal region of TARDBP, where missense change is not expected to be tolerated and is considered a hot spot for ALS-causing variants (Tiloca et al. 2022. PubMed ID: 36247987). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD and has been consistently classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/5232/). This variant is interpreted as pathogenic. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Amyotrophic lateral sclerosis type 10
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000041217.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
Comment:
Limited evidence of segregation.
|
Comment:
Comment:
The TARDBP c.892G>A variant is predicted to result in the amino acid substitution p.Gly298Ser. This variant has been reported in several individuals with amyotrophic lateral sclerosis (ALS, Van Deerlin et al. 2008. PubMed ID: 18396105; Nozaki et al. 2010. PubMed ID: 20558945; Pang et al. 2017. PubMed ID: 28709720; Chen et al. 2020. PubMed ID: 32166880) and has been described as a founder variant for ALS in the Southern Chinese population (Xu et al. 2022. PubMed ID: 35932023). Immunohistochemistry studies from patients' CNS tissues revealed TDP-43 immunopositive inclusions (Van Deerlin et al. 2008. PubMed ID: 18396105), and additional in vitro functional studies using human motor neurons derived from iPS cells have demonstrated that expression of this variant impairs axonal transportation of cytoplasmic granules to distal neuronal compartments (Alami et al. 2014. PubMed ID: 24507191). This variant is located within the conserved C-terminal region of TARDBP, where missense change is not expected to be tolerated and is considered a hot spot for ALS-causing variants (Tiloca et al. 2022. PubMed ID: 36247987). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD and has been consistently classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/5232/). This variant is interpreted as pathogenic.
Comment:
Limited 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:
For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TARDBP function (PMID: 19515851, 20624952, 24477737, 26883171, 27348499, 30442180). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 5232). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 18396105, 20558945, 21857683, 28709720, 30324134, 32166880). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs4884357, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 298 of the TARDBP protein (p.Gly298Ser).
Comment:
The TARDBP c.892G>A variant is predicted to result in the amino acid substitution p.Gly298Ser. This variant has been reported in several individuals with amyotrophic lateral sclerosis (ALS, Van Deerlin et al. 2008. PubMed ID: 18396105; Nozaki et al. 2010. PubMed ID: 20558945; Pang et al. 2017. PubMed ID: 28709720; Chen et al. 2020. PubMed ID: 32166880) and has been described as a founder variant for ALS in the Southern Chinese population (Xu et al. 2022. PubMed ID: 35932023). Immunohistochemistry studies from patients' CNS tissues revealed TDP-43 immunopositive inclusions (Van Deerlin et al. 2008. PubMed ID: 18396105), and additional in vitro functional studies using human motor neurons derived from iPS cells have demonstrated that expression of this variant impairs axonal transportation of cytoplasmic granules to distal neuronal compartments (Alami et al. 2014. PubMed ID: 24507191). This variant is located within the conserved C-terminal region of TARDBP, where missense change is not expected to be tolerated and is considered a hot spot for ALS-causing variants (Tiloca et al. 2022. PubMed ID: 36247987). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD and has been consistently classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/5232/). This variant is interpreted as pathogenic.
Comment:
Limited 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 |
| Clinical and genetic features of patients with amyotrophic lateral sclerosis in southern China. | Chen W | European journal of neurology | 2020 | PMID: 32166880 |
| Modeling hallmark pathology using motor neurons derived from the family and sporadic amyotrophic lateral sclerosis patient-specific iPS cells. | Sun X | Stem cell research & therapy | 2018 | PMID: 30442180 |
| Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS-derived muscle cells and optogenetic motor neurons. | Osaki T | Science advances | 2018 | PMID: 30324134 |
| Burden of rare variants in ALS genes influences survival in familial and sporadic ALS. | Pang SY | Neurobiology of aging | 2017 | PMID: 28709720 |
| The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. | Wang W | Nature medicine | 2016 | PMID: 27348499 |
| Structural analysis of disease-related TDP-43 D169G mutation: linking enhanced stability and caspase cleavage efficiency to protein accumulation. | Chiang CH | Scientific reports | 2016 | PMID: 26883171 |
| Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. | Alami NH | Neuron | 2014 | PMID: 24507191 |
| Disease-associated mutations of TDP-43 promote turnover of the protein through the proteasomal pathway. | Araki W | Molecular neurobiology | 2014 | PMID: 24477737 |
| Accelerated disease onset with stabilized familial amyotrophic lateral sclerosis (ALS)-linked mutant TDP-43 proteins. | Watanabe S | The Journal of biological chemistry | 2013 | PMID: 23235148 |
| Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations. | Corcia P | Neurology | 2012 | PMID: 22539580 |
| Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. | Deng HX | Nature | 2011 | PMID: 21857683 |
| ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS. | Ling SC | Proceedings of the National Academy of Sciences of the United States of America | 2010 | PMID: 20624952 |
| Familial ALS with G298S mutation in TARDBP: a comparison of CSF tau protein levels with those in sporadic ALS. | Nozaki I | Internal medicine (Tokyo, Japan) | 2010 | PMID: 20558945 |
| Truncation and pathogenic mutations facilitate the formation of intracellular aggregates of TDP-43. | Nonaka T | Human molecular genetics | 2009 | PMID: 19515851 |
| TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. | Van Deerlin VM | The Lancet. Neurology | 2008 | PMID: 18396105 |
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Text-mined citations for rs4884357 ...
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 Oct 27, 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.