For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 21476). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 383 of the TARDBP protein (p.Ile383Val). This variant is present in population databases (rs80356740, gnomAD 0.008%). This missense change has been observed in individuals with amyotrophic lateral sclerosis and/or frontotemporal lobar degeneration (PMID: 25681989, 26581115, 30773994, 33159016). It has also been observed to segregate with disease in related individuals.
ClinVar Genomic variation as it relates to human health
NM_007375.4(TARDBP):c.1147A>G (p.Ile383Val)
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.
(12)
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/Likely pathogenic
12
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.1147A>G (p.Ile383Val)
Variation ID: 21476 Accession: VCV000021476.26
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p36.22 1: 11022556 (GRCh38) [ NCBI UCSC ] 1: 11082613 (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 Feb 3, 2020 Oct 20, 2024 Dec 1, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007375.4:c.1147A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_031401.1:p.Ile383Val missense NC_000001.11:g.11022556A>G NC_000001.10:g.11082613A>G NG_008734.1:g.14935A>G LRG_659:g.14935A>G LRG_659t1:c.1147A>G LRG_659p1:p.Ile383Val - Protein change
- I383V
- Other names
- -
- Canonical SPDI
- NC_000001.11:11022555:A:G
-
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.
-
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
- 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) |
criteria provided, multiple submitters, no conflicts
|
Dec 18, 2020 | RCV000995885.11 | |
| Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Dec 1, 2023 | RCV001579671.14 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 16, 2023 | RCV001851976.5 | |
|
See cases
|
Likely pathogenic (1) |
criteria provided, single submitter
|
Apr 8, 2020 | RCV002251918.2 |
|
TARDBP-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Sep 26, 2024 | RCV004754270.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Aug 16, 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: SCV002235625.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function … (more)
For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 21476). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 383 of the TARDBP protein (p.Ile383Val). This variant is present in population databases (rs80356740, gnomAD 0.008%). This missense change has been observed in individuals with amyotrophic lateral sclerosis and/or frontotemporal lobar degeneration (PMID: 25681989, 26581115, 30773994, 33159016). It has also been observed to segregate with disease in related individuals. (less)
|
|
|
Pathogenic
(Jan 22, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Amyotrophic lateral sclerosis type 10
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001150275.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Zygosity: Single Heterozygote
Sex: male
Tissue: blood
|
|
|
Likely pathogenic
(Jun 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002569771.2
First in ClinVar: Sep 10, 2022 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31914217, 31019447, 33479441, … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31914217, 31019447, 33479441, 18802454, 25408367, 23692129, 26581115, 25681989, 22751173, 30773994, 33159016, 32843152, 33618928, 33427744, 33155043, 32409511, 20031275, 20301761, 34573259, 34333853, 35260199, 35239007, 33576076, 34717271, 34544842, 34271284, 32462798, 33452055) (less)
|
|
|
Pathogenic
(Dec 18, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Amyotrophic lateral sclerosis type 10
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018927.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Likely pathogenic
(Mar 31, 2020)
|
criteria provided, single submitter
Method: research
|
Amyotrophic lateral sclerosis type 10
Affected status: yes
Allele origin:
germline
|
Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University
Accession: SCV001251066.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Number of individuals with the variant: 2
Geographic origin: Anatolian Peninsula
|
|
|
Likely pathogenic
(Feb 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502897.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
|
Likely pathogenic
(Apr 08, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
See cases
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523655.1
First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022 |
Comment:
ACMG classification criteria: PS3, PS4, PM1, PM2, PP1, PP2
Clinical Features:
Abnormal peripheral nervous system morphology (present) , Polyneuropathy (present) , Muscle weakness (present) , Motor axonal neuropathy (present) , Fasciculations (present) , EMG: axonal abnormality … (more)
Abnormal peripheral nervous system morphology (present) , Polyneuropathy (present) , Muscle weakness (present) , Motor axonal neuropathy (present) , Fasciculations (present) , EMG: axonal abnormality (present) (less)
Geographic origin: Brazil
|
|
|
Likely pathogenic
(Dec 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004698559.8
First in ClinVar: Mar 10, 2024 Last updated: Oct 20, 2024 |
Comment:
TARDBP: PP1:Strong, PM1, PM2, PS4:Moderate, BP4
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Sep 26, 2024)
|
no assertion criteria provided
Method: clinical testing
|
TARDBP-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005357650.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The TARDBP c.1147A>G variant is predicted to result in the amino acid substitution p.Ile383Val. This variant has previously been reported in multiple unrelated individuals with … (more)
The TARDBP c.1147A>G variant is predicted to result in the amino acid substitution p.Ile383Val. This variant has previously been reported in multiple unrelated individuals with amyotrophic lateral sclerosis and/or frontotemporal dementia (Rutherford et al. 2008. PubMed ID: 18802454; Gelpi et al. 2014. PubMed ID: 23692129; McCann et al. 2020. PubMed ID: 32409511; Mol et al. 2020. PubMed ID: 32843152). It has been reported to segregate with TARDBP-related disease in two families (Acosta-Uribe et al. 2022. PubMed ID: 35260199; Internal Data, PreventionGenetics). This variant is reported in 0.0077% of alleles in individuals of South Asian descent in gnomAD. This variant is located within the known hotspot of pathogenic mutations and has been classified as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/21476/). This variant is interpreted as pathogenic. (less)
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808096.1 First in ClinVar: Aug 26, 2021 Last updated: Aug 26, 2021 |
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001930150.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001968705.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
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Comment:
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31914217, 31019447, 33479441, 18802454, 25408367, 23692129, 26581115, 25681989, 22751173, 30773994, 33159016, 32843152, 33618928, 33427744, 33155043, 32409511, 20031275, 20301761, 34573259, 34333853, 35260199, 35239007, 33576076, 34717271, 34544842, 34271284, 32462798, 33452055)
Comment:
ACMG classification criteria: PS3, PS4, PM1, PM2, PP1, PP2
Comment:
TARDBP: PP1:Strong, PM1, PM2, PS4:Moderate, BP4
Comment:
The TARDBP c.1147A>G variant is predicted to result in the amino acid substitution p.Ile383Val. This variant has previously been reported in multiple unrelated individuals with amyotrophic lateral sclerosis and/or frontotemporal dementia (Rutherford et al. 2008. PubMed ID: 18802454; Gelpi et al. 2014. PubMed ID: 23692129; McCann et al. 2020. PubMed ID: 32409511; Mol et al. 2020. PubMed ID: 32843152). It has been reported to segregate with TARDBP-related disease in two families (Acosta-Uribe et al. 2022. PubMed ID: 35260199; Internal Data, PreventionGenetics). This variant is reported in 0.0077% of alleles in individuals of South Asian descent in gnomAD. This variant is located within the known hotspot of pathogenic mutations and has been classified as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/21476/). 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:
For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 21476). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 383 of the TARDBP protein (p.Ile383Val). This variant is present in population databases (rs80356740, gnomAD 0.008%). This missense change has been observed in individuals with amyotrophic lateral sclerosis and/or frontotemporal lobar degeneration (PMID: 25681989, 26581115, 30773994, 33159016). It has also been observed to segregate with disease in related individuals.
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31914217, 31019447, 33479441, 18802454, 25408367, 23692129, 26581115, 25681989, 22751173, 30773994, 33159016, 32843152, 33618928, 33427744, 33155043, 32409511, 20031275, 20301761, 34573259, 34333853, 35260199, 35239007, 33576076, 34717271, 34544842, 34271284, 32462798, 33452055)
Comment:
ACMG classification criteria: PS3, PS4, PM1, PM2, PP1, PP2
Comment:
TARDBP: PP1:Strong, PM1, PM2, PS4:Moderate, BP4
Comment:
The TARDBP c.1147A>G variant is predicted to result in the amino acid substitution p.Ile383Val. This variant has previously been reported in multiple unrelated individuals with amyotrophic lateral sclerosis and/or frontotemporal dementia (Rutherford et al. 2008. PubMed ID: 18802454; Gelpi et al. 2014. PubMed ID: 23692129; McCann et al. 2020. PubMed ID: 32409511; Mol et al. 2020. PubMed ID: 32843152). It has been reported to segregate with TARDBP-related disease in two families (Acosta-Uribe et al. 2022. PubMed ID: 35260199; Internal Data, PreventionGenetics). This variant is reported in 0.0077% of alleles in individuals of South Asian descent in gnomAD. This variant is located within the known hotspot of pathogenic mutations and has been classified as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/21476/). This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Underlying genetic variation in familial frontotemporal dementia: sequencing of 198 patients. | Mol MO | Neurobiology of aging | 2021 | PMID: 32843152 |
| Identification of novel FUS and TARDBP gene mutations in Chinese amyotrophic lateral sclerosis patients with HRM analysis. | Wang F | Aging | 2020 | PMID: 33159016 |
| Evidence for polygenic and oligogenic basis of Australian sporadic amyotrophic lateral sclerosis. | McCann EP | Journal of medical genetics | 2020 | PMID: 32409511 |
| TARDBP mutation associated with semantic variant primary progressive aphasia, case report and review of the literature. | González-Sánchez M | Neurocase | 2018 | PMID: 30773994 |
| A single nucleotide TDP-43 mutation within a Taiwanese family: A multifaceted demon. | Cheng YW | Amyotrophic lateral sclerosis & frontotemporal degeneration | 2016 | PMID: 26581115 |
| The distinct genetic pattern of ALS in Turkey and novel mutations. | Özoğuz A | Neurobiology of aging | 2015 | PMID: 25681989 |
| Clinical phenotypes and radiological findings in frontotemporal dementia related to TARDBP mutations. | Floris G | Journal of neurology | 2015 | PMID: 25408367 |
| TARDBP mutation p.Ile383Val associated with semantic dementia and complex proteinopathy. | Gelpi E | Neuropathology and applied neurobiology | 2014 | PMID: 23692129 |
| Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. | Rutherford NJ | PLoS genetics | 2008 | PMID: 18802454 |
Text-mined citations for rs80356740 ...
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 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.