ClinVar Miner

Submissions for variant NM_007375.3(TARDBP):c.1144G>A (p.Ala382Thr) (rs367543041)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413910 SCV000491006 likely pathogenic not provided 2016-06-22 criteria provided, single submitter clinical testing The A382T variant in the TARDBP gene was originally reported as a pathogenic variant in two French individuals with personal and family histories of amyotrophic sclerosis (ALS) (Kabashi et al., 2008). This variant has since been reported in association with both familial and sporadic ALS and has also been identified in individuals with frontotemporal lobe dementia with or without motor neuron disease (Chio et al., 2010; Chio et al., 2011; Quadei et al., 2011). In addition, the A382T variant has been reported in individuals with a clinical diagnosis of Parkinson disease (Quadri et al., 2011). Although the precise disease mechanism is unclear, functional studies indicate that expression of the A382T variant protein results in cellular toxicity of motor neurons (Kabashi et al., 2010; Watanabe et al., 2013). Missense variants in nearby residues (N378D, N378S, S379P, S379C, A382P, I383V, G384R, W385G, N390D) have been reported in the Human Gene Mutation Database in association with amyotrophic lateral sclerosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. The A382T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A382T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. The A382T variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory,Koc University RCV000020663 SCV001251065 likely pathogenic Amyotrophic lateral sclerosis type 10 2020-03-31 criteria provided, single submitter research
GeneReviews RCV000020663 SCV000041201 pathogenic Amyotrophic lateral sclerosis type 10 2015-03-12 no assertion criteria provided literature only Identified in both FALS and SALS. Familial and simplex cases share founder haplotype.
OMIM RCV000020663 SCV000044687 pathogenic Amyotrophic lateral sclerosis type 10 2014-05-01 no assertion criteria provided literature only
OMIM RCV000106321 SCV000143882 pathogenic FRONTOTEMPORAL DEMENTIA WITH TDP43 INCLUSIONS, TARDBP-RELATED 2014-05-01 no assertion criteria provided literature only

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