Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Centre for Genomic and Experimental Medicine, |
RCV000492371 | SCV000323239 | likely pathogenic | Motor neuron disease | 2016-08-31 | criteria provided, single submitter | case-control | |
Gene |
RCV000520272 | SCV000617837 | uncertain significance | not provided | 2017-09-25 | criteria provided, single submitter | clinical testing | The L277V variant in the TBK1 gene has been reported previously in an individual with motor neuron disease, however, this individual also harbored the pathogenic hexanucleotide repeat expansion in the C9orf72 gene (Black et al., 2017). The L277V variant is not observed in large population cohorts (Lek et al., 2016). The L277V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution 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. We interpret L277V as a variant of uncertain significance. |
Invitae | RCV001855020 | SCV002135314 | uncertain significance | Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 | 2021-08-13 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine with valine at codon 277 of the TBK1 protein (p.Leu277Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis and/or motor neuron disease (PMID: 25700176, 28089114). ClinVar contains an entry for this variant (Variation ID: 266069). 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 TBK1 protein function. 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. |