ClinVar Miner

Submissions for variant NM_013254.4(TBK1):c.1069C>T (p.Arg357Ter)

gnomAD frequency: 0.00001  dbSNP: rs1328949478
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000760459 SCV000890346 pathogenic not provided 2018-09-13 criteria provided, single submitter clinical testing The R357X nonsense variant in the TBK1 gene has been reported previously in an individual with amyotrophic lateral sclerosis and dysarthria (Tohnai et al., 2018). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R357X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Therefore, the R357X variant is considered a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV002536579 SCV003441143 pathogenic Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 2023-03-24 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 620149). This premature translational stop signal has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 29398122, 30033073). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Arg357*) 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).
Mayo Clinic Laboratories, Mayo Clinic RCV000760459 SCV005414093 pathogenic not provided 2024-05-31 criteria provided, single submitter clinical testing PM2, PS4_moderate, PVS1
PreventionGenetics, part of Exact Sciences RCV004745579 SCV005341436 pathogenic TBK1-related disorder 2024-07-03 no assertion criteria provided clinical testing The TBK1 c.1069C>T variant is predicted to result in premature protein termination (p.Arg357*). This variant has been reported in individuals with amyotrophic lateral sclerosis (Cirulli et al. 2015. PubMed ID: 25700176; Tohnai et al. 2017. PubMed ID: 29398122; de Majo et al. 2018. PubMed ID: 30033073). In vitro functional studies using HEK293T cells demonstrate that expression of this variant negatively impacts TBK1 function by impairing homodimerization, autophosphorylation, and binding to and phosphorylation of OPTN (Figures 2 and 3, de Majo et al. 2018. PubMed ID: 30033073). This variant is reported in 0.0018% of alleles in individuals of European (non-Finnish) descent in gnomAD and has been reported as pathogenic by other laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/620149/). Nonsense variants in TBK1 are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic.

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