Submissions for variant NM_013254.4(TBK1):c.452C>G (p.Ser151Cys)

dbSNP: rs55824172

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001998036	SCV002257233	uncertain significance	Frontotemporal dementia and/or amyotrophic lateral sclerosis 4	2024-07-24	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 151 of the TBK1 protein (p.Ser151Cys). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (Invitae). ClinVar contains an entry for this variant (Variation ID: 1464768). 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 with a negative predictive value of 95%. Experimental studies have shown that this missense change affects TBK1 function (PMID: 31748271). This variant disrupts the p.Ser151 amino acid residue in TBK1. Other variant(s) that disrupt this residue have been observed in individuals with TBK1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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.
PreventionGenetics, part of Exact Sciences	RCV003426267	SCV004118145	uncertain significance	TBK1-related disorder	2023-08-15	criteria provided, single submitter	clinical testing	The TBK1 c.452C>G variant is predicted to result in the amino acid substitution p.Ser151Cys. To our knowledge, this variant has not been reported in individuals with TBK1-related disorders. The p.Ser151Cys substitution has been reported to decrease TBK1 kinase activity (Ye et al. 2019. PubMed ID: 31748271). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-64860774-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.