ClinVar Genomic variation as it relates to human health

ACMG criteria used to clasify this variant: PS3, PM2, PS4, PP2, PM1

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 287 of the TARDBP protein (p.Gly287Ser). This variant is present in population databases (rs80356719, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of amyotrophic lateral sclerosis (PMID: 18372902, 19224587, 19760257, 23881933, 28089114, 28430856; Invitae). ClinVar contains an entry for this variant (Variation ID: 21483). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TARDBP protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects TARDBP function (PMID: 25442115). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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).

Previously reported in individuals with ALS; however segregation data were not available (Kabashi et al., 2008; Corrado et al., 2009; Kirby et al., 2010; Kenna et al., 2013); Published functional studies demonstrate that G287S leads to cytoplasmic mislocalization and accumulation of insoluble TDP-43 and phopho-TDP-43 (Fazal et al., 2021); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28089114, 28430856, 19224587, 19760257, 23881933, 20806063, 31325016, 32409511, 26883171, 29379112, 19515851, 25442115, 18372902, 29653316, 20301761, 27535533, 33694180)

The TARDBP c.859G>A variant is predicted to result in the amino acid substitution p.Gly287Ser. This variant was reported in multiple individuals with amyotrophic lateral sclerosis (Kabashi et al. 2008. PubMed ID: 18372902; Table S4, Black et al. 2017. PubMed ID: 28089114; Morgan et al. 2017. PubMed ID: 28430856; McCann et al. 2020. PubMed ID: 32409511). Functional studies suggested that this variant leads to subcellular mislocalization, accumulation of insoluble mutant TARDBP protein, and axonal transport defects (Vanden Broeck et al. 2015. PubMed ID: 25442115; Figure S5, Fazal et al. 2021. PubMed ID: 33694180). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is located within the known mutational hotspot of TARDBP and has been classified as likely pathogenic/pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/21483/). This variant is interpreted as likely pathogenic.