VCV000291734.77 - ClinVar

NM_007375.4(TARDBP):c.198T>C (p.Ala66=)

Germline

Classification

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.

(13)

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.

Benign/Likely benign

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.198T>C (p.Ala66=)

Variation ID: 291734 Accession: VCV000291734.77

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.22 1: 11013925 (GRCh38) [ NCBI UCSC ] 1: 11073982 (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	Dec 6, 2016	Oct 20, 2024	Jan 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_007375.4:c.198T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_031401.1:p.Ala66=	synonymous
NC_000001.11:g.11013925T>C
NC_000001.10:g.11073982T>C
NG_008734.1:g.6304T>C
LRG_659:g.6304T>C
LRG_659t1:c.198T>C	LRG_659p1:p.Ala66=

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000001.11:11013924:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00519 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00292

Trans-Omics for Precision Medicine (TOPMed) 0.00352

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00438

1000 Genomes Project 30x 0.00484

1000 Genomes Project 0.00519

Exome Aggregation Consortium (ExAC) 0.00641

Links

ClinGen: CA586315 dbSNP: rs61730366 VarSome

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
Gene	OMIM	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.
Amyotrophic lateral sclerosis type 10 TARDBP-related frontotemporal dementia	Benign (1)	criteria provided, single submitter	Jan 27, 2024	RCV000646151.20
Amyotrophic lateral sclerosis type 10	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Jul 15, 2021	RCV000625045.18
not specified	Benign (1)	criteria provided, single submitter	Jul 25, 2017	RCV000516412.12
not provided	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Oct 1, 2023	RCV001668630.29
Inborn genetic diseases	Likely benign (1)	criteria provided, single submitter	May 19, 2022	RCV002418140.9

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.
Benign (Jul 25, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000615748.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Publications: PubMed (16) PubMed: 25588603‚ 19786775‚ 20645878‚ 19204172‚ 18779421‚ 18068872‚ 18288693‚ 18372902‚ 18545701‚ 18802454‚ 18931000‚ 19224587‚ 19236453‚ 19695877‚ 19760257‚ 19864663
Likely benign (Jun 28, 2017)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Amyotrophic lateral sclerosis type 10 Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000744937.1 First in ClinVar: Apr 20, 2018 Last updated: Apr 20, 2018
Benign (Oct 10, 2014)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Amyotrophic lateral sclerosis type 10 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743618.1 First in ClinVar: Apr 20, 2018 Last updated: Apr 20, 2018
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Amyotrophic lateral sclerosis type 10 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000347104.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (3) PubMed: 18779421‚ 19808791‚ 18802454 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Jan 09, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001890008.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: This variant is associated with the following publications: (PMID: 18545701, 25588603)
Benign (Jul 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Amyotrophic lateral sclerosis type 10 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002062211.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Benign (Sep 22, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001159167.3 First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024
Benign (Jan 27, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) 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: SCV000767909.8 First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024
Likely benign (May 19, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002717583.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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)
Benign (Oct 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV003916049.13 First in ClinVar: Apr 23, 2023 Last updated: Oct 20, 2024	Comment: TARDBP: BP4, BP7, BS1, BS2 Number of individuals with the variant: 7
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005260660.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (Dec 29, 2015)	no assertion criteria provided (ACGS Guidelines, 2013) Method: clinical testing	Amyotrophic lateral sclerosis type 10 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV000745748.1 First in ClinVar: Apr 20, 2018 Last updated: Apr 20, 2018
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001921792.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
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Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Investigation of next-generation sequencing technologies as a diagnostic tool for amyotrophic lateral sclerosis.	Morgan S	Neurobiology of aging	2015	PMID: 25588603
TARDBP mutations in frontotemporal lobar degeneration: frequency, clinical features, and disease course.	Borroni B	Rejuvenation research	2010	PMID: 20645878
Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis.	Kirby J	Neurogenetics	2010	PMID: 19760257
TARDBP in amyotrophic lateral sclerosis: identification of a novel variant but absence of copy number variation.	Bäumer D	Journal of neurology, neurosurgery, and psychiatry	2009	PMID: 19864663
Mutations in TDP-43 link glycine-rich domain functions to amyotrophic lateral sclerosis.	Pesiridis GS	Human molecular genetics	2009	PMID: 19808791
Absence of TARDBP gene mutations in an italian series of patients with frontotemporal lobar degeneration.	Gallone S	Dementia and geriatric cognitive disorders	2009	PMID: 19786775
Genetic variants in the promoter of TARDBP in sporadic amyotrophic lateral sclerosis.	Luquin N	Neuromuscular disorders : NMD	2009	PMID: 19695877
TARDBP (TDP-43) sequence analysis in patients with familial and sporadic ALS: identification of two novel mutations.	Del Bo R	European journal of neurology	2009	PMID: 19236453
High frequency of TARDBP gene mutations in Italian patients with amyotrophic lateral sclerosis.	Corrado L	Human mutation	2009	PMID: 19224587
No TARDBP mutations in a French Canadian population of patients with Parkinson disease.	Kabashi E	Archives of neurology	2009	PMID: 19204172
Contribution of TARDBP mutations to sporadic amyotrophic lateral sclerosis.	Daoud H	Journal of medical genetics	2009	PMID: 18931000
Neuronal inclusion protein TDP-43 has no primary genetic role in FTD and ALS.	Gijselinck I	Neurobiology of aging	2009	PMID: 18068872
Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis.	Rutherford NJ	PLoS genetics	2008	PMID: 18802454
Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations.	Kühnlein P	Archives of neurology	2008	PMID: 18779421
TDP-43 is not a common cause of sporadic amyotrophic lateral sclerosis.	Guerreiro RJ	PloS one	2008	PMID: 18545701
TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis.	Kabashi E	Nature genetics	2008	PMID: 18372902
TDP-43 A315T mutation in familial motor neuron disease.	Gitcho MA	Annals of neurology	2008	PMID: 18288693
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Text-mined citations for rs61730366 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_007375.4(TARDBP):c.198T>C (p.Ala66=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61730366 ...