VCV000005234.33 - ClinVar

NM_007375.4(TARDBP):c.1042G>T (p.Gly348Cys)

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.

(6)

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

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.1042G>T (p.Gly348Cys)

Variation ID: 5234 Accession: VCV000005234.33

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.22 1: 11022451 (GRCh38) [ NCBI UCSC ] 1: 11082508 (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 20, 2024	Jul 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_007375.4:c.1042G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_031401.1:p.Gly348Cys	missense
NC_000001.11:g.11022451G>T
NC_000001.10:g.11082508G>T
NG_008734.1:g.14830G>T
LRG_659:g.14830G>T
LRG_659t1:c.1042G>T	LRG_659p1:p.Gly348Cys
	Q13148:p.Gly348Cys

... more HGVS ... less HGVS

Protein change

Other names

G348C

Canonical SPDI

NC_000001.11:11022450:G:T

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.

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

Links

ClinGen: CA340379 UniProtKB: Q13148#VAR_045665 OMIM: 605078.0007 dbSNP: rs80356733 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	Likely pathogenic (3)	criteria provided, single submitter	Mar 31, 2020	RCV000005545.16
Amyotrophic lateral sclerosis type 10 TARDBP-related frontotemporal dementia	Pathogenic (1)	criteria provided, single submitter	Jul 27, 2023	RCV001851671.14
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 1, 2021	RCV000516886.29

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.
Likely pathogenic (Mar 31, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Amyotrophic lateral sclerosis type 10 Affected status: yes Allele origin: germline	Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University Accession: SCV001251063.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Number of individuals with the variant: 3 Geographic origin: Anatolian Peninsula
Pathogenic (Jul 27, 2023)	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: SCV002247251.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024	Publications: PubMed (9) PubMed: 18372902‚ 18779421‚ 19236453‚ 29621978‚ 30553531‚ 19959528‚ 21173160‚ 21752789‚ 22406069 Comment: This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 348 of the TARDBP protein … (more) This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 348 of the TARDBP protein (p.Gly348Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 18372902, 18779421, 19236453, 29621978, 30553531). ClinVar contains an entry for this variant (Variation ID: 5234). 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 disruptive. Experimental studies have shown that this missense change affects TARDBP function (PMID: 19959528, 21173160, 21752789, 22406069). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 19, 2016)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000615746.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Publications: PubMed (18) PubMed: 23345247‚ 22406069‚ 19429692‚ 21173160‚ 21752789‚ 20806063‚ 23235148‚ 18779421‚ 18931000‚ 19236453‚ 20577002‚ 20031275‚ 21829392‚ 22563080‚ 23457265‚ 21403029‚ 18372902‚ 19959528
Pathogenic (Oct 01, 2021)	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: SCV001246538.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Pathogenic (Sep 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: SCV000025727.4 First in ClinVar: Apr 04, 2013 Last updated: Sep 17, 2016	Publications: PubMed (2) PubMed: 18372902‚ 18779421 Comment on evidence: In a 30-year-old female patient with amyotrophic lateral sclerosis (612069), Kabashi et al. (2008) detected a heterozygous G-to-T transversion at nucleotide 1176 in exon 6 … (more) In a 30-year-old female patient with amyotrophic lateral sclerosis (612069), Kabashi et al. (2008) detected a heterozygous G-to-T transversion at nucleotide 1176 in exon 6 of the TARDBP gene that resulted in substitution of cys for gly at codon 348 of TDP43 (G348C). The mutation, which introduced a cysteine to the C-terminal hnRNP interaction region, was predicted to increase the propensity for aggregation through the formation of intermolecular disulfide bridges. Kuhnlein et al. (2008) identified the G348C mutation in affected members of a German family with ALS10. The proband presented at age 55 years with paresis of the right hand, which progressed rapidly to involve the arms and lower limbs and left her wheelchair-bound within 2.5 years. She died of respiratory insufficiency 3 years after disease onset. The patient's mother had died of respiratory insufficiency due to a similar disorder. There were no clinically relevant bulbar symptoms and no cognitive impairment. (less)
not provided (-)	no classification provided Method: literature only	Amyotrophic lateral sclerosis type 10 Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000041194.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: BookShelf: NBK5942 BookShelf: NBK5942 Comment: Identified in both FALS and SALS.

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 348 of the TARDBP protein (p.Gly348Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 18372902, 18779421, 19236453, 29621978, 30553531). ClinVar contains an entry for this variant (Variation ID: 5234). 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 disruptive. Experimental studies have shown that this missense change affects TARDBP function (PMID: 19959528, 21173160, 21752789, 22406069). For these reasons, this variant has been classified 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
TARDBP-Related Amyotrophic Lateral Sclerosis-Frontotemporal Dementia.	Adam MP	-	2023	PMID: 20301761
Mutation screening of SLC52A3, C19orf12, and TARDBP in Iranian ALS patients.	Khani M	Neurobiology of aging	2019	PMID: 30553531
High frequency of the TARDBP p.M337 V mutation among south-eastern Chinese patients with familial amyotrophic lateral sclerosis.	Xu GR	BMC neurology	2018	PMID: 29621978
Loss of ALS-associated TDP-43 in zebrafish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth.	Schmid B	Proceedings of the National Academy of Sciences of the United States of America	2013	PMID: 23457265
Calcium channel agonists protect against neuromuscular dysfunction in a genetic model of TDP-43 mutation in ALS.	Armstrong GA	The Journal of neuroscience : the official journal of the Society for Neuroscience	2013	PMID: 23345247
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
Requirements for stress granule recruitment of fused in sarcoma (FUS) and TAR DNA-binding protein of 43 kDa (TDP-43).	Bentmann E	The Journal of biological chemistry	2012	PMID: 22563080
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
FUS and TARDBP but not SOD1 interact in genetic models of amyotrophic lateral sclerosis.	Kabashi E	PLoS genetics	2011	PMID: 21829392
Pathological hallmarks of amyotrophic lateral sclerosis/frontotemporal lobar degeneration in transgenic mice produced with TDP-43 genomic fragments.	Swarup V	Brain : a journal of neurology	2011	PMID: 21752789
No effect on SOD1 splicing by TARDP or FUS mutations.	Belzil VV	Archives of neurology	2011	PMID: 21403029
TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic and oxidative stressor.	Dewey CM	Molecular and cellular biology	2011	PMID: 21173160
Mutational analysis of TARDBP in neurodegenerative diseases.	Ticozzi N	Neurobiology of aging	2011	PMID: 20031275
TDP-43-mediated neuron loss in vivo requires RNA-binding activity.	Voigt A	PloS one	2010	PMID: 20806063
SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations.	Millecamps S	Journal of medical genetics	2010	PMID: 20577002
Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo.	Kabashi E	Human molecular genetics	2010	PMID: 19959528
Functional mapping of the interaction between TDP-43 and hnRNP A2 in vivo.	D'Ambrogio A	Nucleic acids research	2009	PMID: 19429692
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
Contribution of TARDBP mutations to sporadic amyotrophic lateral sclerosis.	Daoud H	Journal of medical genetics	2009	PMID: 18931000
Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations.	Kühnlein P	Archives of neurology	2008	PMID: 18779421
TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis.	Kabashi E	Nature genetics	2008	PMID: 18372902
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Text-mined citations for rs80356733 ...

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 03, 2024

ClinVar Genomic variation as it relates to human health

NM_007375.4(TARDBP):c.1042G>T (p.Gly348Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80356733 ...