ClinVar Miner

Submissions for variant NM_007375.3(TARDBP):c.859G>A (p.Gly287Ser) (rs80356719)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Genomic and Experimental Medicine,University of Edinburgh RCV000492328 SCV000323233 pathogenic Motor neuron disease 2016-08-31 criteria provided, single submitter case-control
GeneDx RCV000412864 SCV000491331 likely pathogenic not provided 2016-01-13 criteria provided, single submitter clinical testing The G287S variant in the TARDBP gene has been reported previously in at least five unrelated individuals of varying ethnicity with ALS (Kabashi et al., 2008; Corrado et al., 2009; Kirby et al., 2010; Kenna et al., 2013). The G287Svariant 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 G287S variant is a non-conservative amino acid substitution which occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (G290A, S292N) have been reported in association with ALS (Stenson et al., 2014; Cruts et al., 2012), supporting the functional importance of this region of the protein. The G287S variant is a strong candidate for a pathogenic variant.
Invitae RCV000529539 SCV000647018 uncertain significance Amyotrophic lateral sclerosis type 10; TARDBP-related frontotemporal dementia 2017-08-02 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 287 of the TARDBP protein (p.Gly287Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs80356719, ExAC 0.001%). This variant has been reported in multiple individuals affected with sporadic amyotrophic lateral sclerosis (SALS)(PMID: 18372902, 19224587, 23881933, 28089114, 19760257). Segregation data is not available for this variant. ClinVar contains an entry for this variant (Variation ID: 21483). Experimental studies have shown that this missense change does not rescue neuronal development and function as efficiently as wild-type in a drosophila model system (PMID: 25442115). 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.
SIB Swiss Institute of Bioinformatics RCV000020672 SCV000803465 likely pathogenic Amyotrophic lateral sclerosis type 10 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Amyotrophic lateral sclerosis 10, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Variant is observed in multiple unrelated patients. (PMID:19224587,18372902,19760257). PS3-Moderate => Functional studies shows a deleterious effect (PMID:19760257) (PMID:25442115) (PMID:19760257).
GeneReviews RCV000020672 SCV000041211 pathogenic Amyotrophic lateral sclerosis type 10 2015-03-12 no assertion criteria provided literature only

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