ClinVar Miner

Submissions for variant NM_013254.4(TBK1):c.1330C>T (p.Arg444Ter)

gnomAD frequency: 0.00001  dbSNP: rs142030898
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Genomic and Experimental Medicine, University of Edinburgh RCV000492391 SCV000323242 other Motor neuron disease 2016-08-31 criteria provided, single submitter case-control Loss-of-function but lacking segregation data
GeneDx RCV000760460 SCV000890347 pathogenic not provided 2019-01-11 criteria provided, single submitter clinical testing The R444X nonsense variant in the TBK1 gene has been reported previously in association with ALS with and without FTLD (Black et al., 2017; Tsai et al., 2016). In vitro functional studies shower lower protein expression and loss of kinase activity (Tsai et al., 2016). The R444X variant is predicted to result in nonsense-mediated mRNA decay or protein truncation. In vitro functional studies indicate that the truncated protein lacked kinase activity (Tsai et al., 2016). This variant is not observed in large population cohorts (Lek et al., 2016). Based on the currently available clinical and molecular information, we interpret R444X as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV001859503 SCV002234003 pathogenic Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 2024-10-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg444*) in the TBK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TBK1 are known to be pathogenic (PMID: 25803835, 26476236, 26581300). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 26804609, 28089114). ClinVar contains an entry for this variant (Variation ID: 266072). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects TBK1 function (PMID: 26804609). For these reasons, this variant has been classified as Pathogenic.

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