tRNA-histidine guanylyltransferase 1-like protein (THG1L) was first reported in relation to autosomal recessive spinocerebellar ataxia in 2016 (Edvardson et al., PMID: 27307223). Cases with THG1L variants have been reported with a variety of phenotypes that can include but are not limited to: cerebellar ataxia, cerebellar atrophy or hypoplasia, global developmental delay, and seizures. Dysmorphic features like microcephaly and micrognathia have been reported but in a minority of cases. Five variants (4 missense and 1 splice-region) that have been reported in eight probands in five publications (PMIDs: 27307223, 30214071, 31168944, 33682303, 37670026) are included in this curation. Two families were observed with variation in THG1L where an ataxia-like disease segregated with the variants (PMIDs: 27307223, 33682303). The mechanism of pathogenicity is unclear but thought to be loss of function leading to abnormalities in mitochondrial localization and morphology (PMID: 27307223). No conclusive experimental evidence was found to support this gene-disease relationship in a literature review. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Cerebellar Ataxia GCEP on the meeting date September 10, 2025 (SOP Version 11).
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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