TBK1 was first reported in relation to autosomal dominant amyotrophic lateral sclerosis in 2015 (Cirulli et al. Science (2015); PMID: 25700176 and Freischmidt et al. Nat Neurosci (2015); PMID: 25803835). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in molecular mechanism(s) and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, amyotrophic lateral sclerosis (OMIM:616439) and herpes simplex virus encephalitis (OMIM:617900). A case-control genome-wide gene burden analysis of whole-exome sequencing data from 4,187 cases and 8,776 controls identified a burden of "dominant not benign" variants in TBK1 among ALS cases compared to controls (PMID: 25700176). A further seven loss of function variants that have been reported in seven probands in two publications (PMIDs: 25803835, 30033073) are also included in this curation, as well as two splicing and nine missense variants publications (PMIDs: 25803835, 30033073). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease association is also supported by experimental evidence including protein interactions, expression studies, in vitro functional assays, cell models and an animal models (PMIDs: 25803835, 32413959, 30033073, 30939964, 33312375, 22921120, 25613900, 36201573). In summary, TBK1 is definitively associated with autosomal dominant amyotrophic lateral sclerosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen ALS GCEP on the meeting date June 23, 2022 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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