NM_007375.4(TARDBP):c.1054A>G (p.Asn352Asp) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 28, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002761523.3

Allele description [Variation Report for NM_007375.4(TARDBP):c.1054A>G (p.Asn352Asp)]

NM_007375.4(TARDBP):c.1054A>G (p.Asn352Asp)

Gene:

TARDBP:TAR DNA binding protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.22

Genomic location:

Preferred name:

NM_007375.4(TARDBP):c.1054A>G (p.Asn352Asp)

HGVS:

NC_000001.11:g.11022463A>G
NG_008734.1:g.14842A>G
NM_007375.4:c.1054A>GMANE SELECT
NP_031401.1:p.Asn352Asp
NP_031401.1:p.Asn352Asp
LRG_659t1:c.1054A>G
LRG_659:g.14842A>G
LRG_659p1:p.Asn352Asp
NC_000001.10:g.11082520A>G
NM_007375.3:c.1054A>G

Protein change:

N352D

Molecular consequence:

NM_007375.4:c.1054A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Amyotrophic lateral sclerosis type 10 (ALS10)
Synonyms:: AMYOTROPHIC LATERAL SCLEROSIS 10 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA; TARDBP-Related Amyotrophic Lateral Sclerosis; AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012790; MedGen: C2677565; Orphanet: 275872; Orphanet: 803; OMIM: 612069

Name:: TARDBP-related frontotemporal dementia
Synonyms:: FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, TARDBP-RELATED
Identifiers:: MedGen: C3150169

Recent activity

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Homo sapiens anoctamin 7 (ANO7), transcript variant 2, mRNA
gi|1664162098|ref|NM_001001666.4|

Nucleotide
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Nucleotide
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Idris sp. 5 NM-2013 voucher M457 cytochrome oxidase subunit 1 gene, partial cds; mitochondrial
gi|575448588|gb|KF679299.1|

Nucleotide
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Fibrous dysplasia/McCune-Albright syndrome

MedGen
C5680283[conceptid] (1)
MedGen

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003023247	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 28, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 18779421, 22406069, 23327806, 24117534, 24237396, 24440310, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003023247

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 28, 2022)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations.

Kühnlein P, Sperfeld AD, Vanmassenhove B, Van Deerlin V, Lee VM, Trojanowski JQ, Kretzschmar HA, Ludolph AC, Neumann M.

Arch Neurol. 2008 Sep;65(9):1185-9. doi: 10.1001/archneur.65.9.1185.

PubMed [citation]

PMID:: 18779421
PMCID:: PMC2742976

Role of selected mutations in the Q/N rich region of TDP-43 in EGFP-12xQ/N-induced aggregate formation.

Budini M, Romano V, Avendaño-Vázquez SE, Bembich S, Buratti E, Baralle FE.

Brain Res. 2012 Jun 26;1462:139-50. doi: 10.1016/j.brainres.2012.02.031. Epub 2012 Feb 22.

PubMed [citation]

PMID:: 22406069

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003023247.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 352 of the TARDBP protein (p.Asn352Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TARDBP-related conditions. 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. This variant disrupts the p.Asn352 amino acid residue in TARDBP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18779421, 22406069, 23327806, 24117534, 24237396, 24440310). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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