Submissions for variant NM_013254.4(TBK1):c.1072C>T (p.Arg358Cys)

gnomAD frequency: 0.00003  dbSNP: rs780192375

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810739	SCV000950972	uncertain significance	Frontotemporal dementia and/or amyotrophic lateral sclerosis 4	2022-01-14	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 654729). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 358 of the TBK1 protein (p.Arg358Cys). This variant is present in population databases (rs780192375, gnomAD 0.004%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 29398122). 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.
PreventionGenetics, part of Exact Sciences	RCV003892733	SCV004716925	uncertain significance	TBK1-related disorder	2024-03-27	no assertion criteria provided	clinical testing	The TBK1 c.1072C>T variant is predicted to result in the amino acid substitution p.Arg358Cys. This variant was reported in an individual with amyotrophic lateral sclerosis (Tohnai et al. 2018. PubMed ID: 29398122). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.