ClinVar Miner

Submissions for variant NM_013254.4(TBK1):c.1000A>G (p.Ile334Val)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV005076604 SCV005724487 uncertain significance Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 2025-01-17 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 334 of the TBK1 protein (p.Ile334Val). This variant is present in population databases (rs759007508, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of semantic dementia (internal data). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TBK1 protein function with a negative predictive value of 95%. This variant disrupts the p.Ile334 amino acid residue in TBK1. Other variant(s) that disrupt this residue have been observed in individuals with TBK1-related conditions (PMID: 27260353), 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.

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