ACMG criteria used to clasify this variant: PS3, PM2, PS4, PP2
ClinVar Genomic variation as it relates to human health
NM_007375.4(TARDBP):c.1055A>G (p.Asn352Ser)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
5 out of 9 submissions contributed to this 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.
9
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.1055A>G (p.Asn352Ser)
Variation ID: 21468 Accession: VCV000021468.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.22 1: 11022464 (GRCh38) [ NCBI UCSC ] 1: 11082521 (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 19, 2018 May 25, 2025 Jan 21, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007375.4:c.1055A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_031401.1:p.Asn352Ser missense NC_000001.11:g.11022464A>G NC_000001.10:g.11082521A>G NG_008734.1:g.14843A>G LRG_659:g.14843A>G LRG_659t1:c.1055A>G LRG_659p1:p.Asn352Ser - Protein change
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- Other names
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- Canonical SPDI
- NC_000001.11:11022463: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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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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 | ||
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| 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. |
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| TARDBP | No evidence available | No evidence available |
GRCh38 GRCh37 |
260 | 383 | |
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) |
criteria provided, multiple submitters, no conflicts
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Aug 24, 2022 | RCV000020657.14 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 1, 2023 | RCV000993301.25 | |
| Pathogenic (1) |
criteria provided, single submitter
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Jan 21, 2024 | RCV001851975.16 | |
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TARDBP-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Aug 9, 2024 | RCV004754269.1 |
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
(Aug 24, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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Amyotrophic lateral sclerosis type 10
Affected status: yes
Allele origin:
germline
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Human Genetics Bochum, Ruhr University Bochum
Accession: SCV002758560.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Comment:
ACMG criteria used to clasify this variant: PS3, PM2, PS4, PP2
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Pathogenic
(Feb 20, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics
Accession: SCV001146151.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
Comment:
Not found in the total gnomAD dataset, and the data is high quality (0/281796 chr). Found in at least one symptomatic patient. Conflicting predictions of … (more)
Not found in the total gnomAD dataset, and the data is high quality (0/281796 chr). Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Located in potentially critical domain of the protein. Damaging to protein function(s) relevant to disease mechanism. Statistically associated with disease, but in a single family. (p < 0.05) (less)
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Pathogenic
(Jan 21, 2024)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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Amyotrophic lateral sclerosis type 10
FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, TARDBP-RELATED
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: SCV002242980.4
First in ClinVar: Mar 28, 2022 Last updated: Mar 04, 2025 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 352 of the TARDBP protein (p.Asn352Ser). … (more)
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 352 of the TARDBP protein (p.Asn352Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 18779421, 23327806, 24117534, 24237396). ClinVar contains an entry for this variant (Variation ID: 21468). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects TARDBP function (PMID: 22406069, 24440310). This variant disrupts the p.Asn352 amino acid residue in TARDBP. Other variant(s) that disrupt this residue have been observed in individuals with TARDBP-related conditions (PMID: 20031275), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Oct 11, 2021)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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Amyotrophic lateral sclerosis type 10
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580412.2
First in ClinVar: Oct 15, 2022 Last updated: Apr 13, 2025
Comment:
ACMG criteria applied: PS3, PM1, PM5, PM2_SUP
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Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Nov 01, 2023)
C
Contributing to aggregate classification
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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: SCV004184991.13
First in ClinVar: Dec 24, 2023 Last updated: May 25, 2025 |
Comment:
TARDBP: PP1:Strong, PM1, PM2, PS4:Moderate, PP2, PS3:Supporting
Number of individuals with the variant: 1
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Likely pathogenic
(-)
N
Not contributing to aggregate classification
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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, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001929760.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(Aug 09, 2024)
N
Not contributing to aggregate classification
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no assertion criteria provided
Method: clinical testing
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TARDBP-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005365263.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The TARDBP c.1055A>G variant is predicted to result in the amino acid substitution p.Asn352Ser. This variant has been reported in multiple unrelated families and is … (more)
The TARDBP c.1055A>G variant is predicted to result in the amino acid substitution p.Asn352Ser. This variant has been reported in multiple unrelated families and is causative for amyotrophic lateral sclerosis (Kühnlein et al. 2008. PubMed ID: 18779421; Budini et al. 2012. PubMed ID: 22406069; Watanabe et al. 2012. PubMed ID: 23235148; Czell et al. 2013. PubMed ID: 23327806; Homma et al. 2014. PubMed ID: 24117534). This variant has not been reported in a large population database, indicating this variant is rare. This variant is within the known TARDBP mutational hotspot and has also been consistently classified as pathogenic/likely pathogenic in ClinVar. This variant is interpreted as pathogenic. (less)
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Likely pathogenic
(-)
N
Not contributing to aggregate classification
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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: SCV001967817.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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not provided
(-)
N
Not contributing to aggregate classification
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no classification provided
Method: literature only
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Amyotrophic lateral sclerosis type 10
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000041195.2
First in ClinVar: Apr 19, 2018 Last updated: Oct 01, 2022 |
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Comment:
Comment:
Not found in the total gnomAD dataset, and the data is high quality (0/281796 chr). Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Located in potentially critical domain of the protein. Damaging to protein function(s) relevant to disease mechanism. Statistically associated with disease, but in a single family. (p < 0.05)
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 352 of the TARDBP protein (p.Asn352Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 18779421, 23327806, 24117534, 24237396). ClinVar contains an entry for this variant (Variation ID: 21468). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects TARDBP function (PMID: 22406069, 24440310). This variant disrupts the p.Asn352 amino acid residue in TARDBP. Other variant(s) that disrupt this residue have been observed in individuals with TARDBP-related conditions (PMID: 20031275), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Comment:
TARDBP: PP1:Strong, PM1, PM2, PS4:Moderate, PP2, PS3:Supporting
Comment:
The TARDBP c.1055A>G variant is predicted to result in the amino acid substitution p.Asn352Ser. This variant has been reported in multiple unrelated families and is causative for amyotrophic lateral sclerosis (Kühnlein et al. 2008. PubMed ID: 18779421; Budini et al. 2012. PubMed ID: 22406069; Watanabe et al. 2012. PubMed ID: 23235148; Czell et al. 2013. PubMed ID: 23327806; Homma et al. 2014. PubMed ID: 24117534). This variant has not been reported in a large population database, indicating this variant is rare. This variant is within the known TARDBP mutational hotspot and has also been consistently classified as pathogenic/likely pathogenic in ClinVar. This variant is interpreted as pathogenic.
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:
ACMG criteria used to clasify this variant: PS3, PM2, PS4, PP2
Comment:
Not found in the total gnomAD dataset, and the data is high quality (0/281796 chr). Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Located in potentially critical domain of the protein. Damaging to protein function(s) relevant to disease mechanism. Statistically associated with disease, but in a single family. (p < 0.05)
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 352 of the TARDBP protein (p.Asn352Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 18779421, 23327806, 24117534, 24237396). ClinVar contains an entry for this variant (Variation ID: 21468). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects TARDBP function (PMID: 22406069, 24440310). This variant disrupts the p.Asn352 amino acid residue in TARDBP. Other variant(s) that disrupt this residue have been observed in individuals with TARDBP-related conditions (PMID: 20031275), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Comment:
TARDBP: PP1:Strong, PM1, PM2, PS4:Moderate, PP2, PS3:Supporting
Comment:
The TARDBP c.1055A>G variant is predicted to result in the amino acid substitution p.Asn352Ser. This variant has been reported in multiple unrelated families and is causative for amyotrophic lateral sclerosis (Kühnlein et al. 2008. PubMed ID: 18779421; Budini et al. 2012. PubMed ID: 22406069; Watanabe et al. 2012. PubMed ID: 23235148; Czell et al. 2013. PubMed ID: 23327806; Homma et al. 2014. PubMed ID: 24117534). This variant has not been reported in a large population database, indicating this variant is rare. This variant is within the known TARDBP mutational hotspot and has also been consistently classified as pathogenic/likely pathogenic in ClinVar. This variant is interpreted as pathogenic.
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 |
| Large-scale screening in sporadic amyotrophic lateral sclerosis identifies genetic modifiers in C9orf72 repeat carriers. | Dekker AM | Neurobiology of aging | 2016 | PMID: 26777436 |
| An autopsy case of familial amyotrophic lateral sclerosis with a TARDBP Q343R mutation. | Okamoto K | Neuropathology : official journal of the Japanese Society of Neuropathology | 2015 | PMID: 26096467 |
| "Structural characterization of the minimal segment of TDP-43 competent for aggregation". | Mompeán M | Archives of biochemistry and biophysics | 2014 | PMID: 24440310 |
| Clinical variability and additional mutations in amyotrophic lateral sclerosis patients with p.N352S mutations in TARDBP. | van Blitterswijk M | Neuropathology and applied neurobiology | 2014 | PMID: 24237396 |
| Neuropathological features of Japanese familial amyotrophic lateral sclerosis with p.N352S mutation in TARDBP. | Homma T | Neuropathology and applied neurobiology | 2014 | PMID: 24117534 |
| Phenotypes in Swiss patients with familial ALS carrying TARDBP mutations. | Czell D | Neuro-degenerative diseases | 2013 | PMID: 23327806 |
| 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 |
| Evidence for an oligogenic basis of amyotrophic lateral sclerosis. | van Blitterswijk M | Human molecular genetics | 2012 | PMID: 22645277 |
| Role of selected mutations in the Q/N rich region of TDP-43 in EGFP-12xQ/N-induced aggregate formation. | Budini M | Brain research | 2012 | PMID: 22406069 |
| Large-scale screening of TARDBP mutation in amyotrophic lateral sclerosis in Japanese. | Iida A | Neurobiology of aging | 2012 | PMID: 20675015 |
| Mutational analysis of TARDBP in neurodegenerative diseases. | Ticozzi N | Neurobiology of aging | 2011 | PMID: 20031275 |
| Screening for TARDBP mutations in Japanese familial amyotrophic lateral sclerosis. | Kamada M | Journal of the neurological sciences | 2009 | PMID: 19411082 |
| Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations. | Kühnlein P | Archives of neurology | 2008 | PMID: 18779421 |
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Text-mined citations for rs80356734 ...
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 Jun 14, 2025
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.