The VARS1 gene is located on chromosome 6 at 6p21.33 and encodes the valyl-tRNA synthetase 1 protein. VARS1 plays a key role in protein translation as the cytoplasmic aminoacyl-tRNA synthetase responsible for catalyzing the attachment of valine to its cognate transfer RNA (tRNA) molecule. VARS1 was first reported in relation to autosomal recessive neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy in 2015 (Karaca et al. 2015 26539891). The disorder is characterized by a severe global developmental delay, acquired microcephaly (typically present by 6 months of age) and an onset of seizures during early infancy (Friedman et al. 2019; Siekierska et al. 2019). Seizure types vary between affected cases and may include myoclonia, focal clonic seizures and or generalized seizures. Brain abnormalities detected by MRI are also variable, cortical atrophy being the most common feature. Partial agenesis or hypoplasia of the corpus callosum are frequently seen, as well as cerebellar atrophy. Seventeen variants (including 14 missense, 1 frameshift, 1 stop gained and 1 canonical splice site variant), that have been reported in 12 probands in five publications (PMIDs: 26539891, 29137650, 29691655, 30755616, 30755602) are included in this curation. The mechanism of disease is biallelic loss of function. This gene-disease relationship is also supported by expression studies and other aminoacyl-tRNA synthetases have been associated with gene disease relationships characterized neurodevelopmental phenotypes (PMID: 25035493). A zebrafish vars1 knockout model, generated using CRISPR/Cas9 technology, recapitulates the brain malformation, developmental delay and seizure phenotypes observed in the clinical phenotype. In summary, there is definitive evidence to support the relationship between VARS1 and autosomal recessive neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy. 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 Syndromic Disorders GCEP on the meeting date December 6th, 2023 (SOP Version 10).
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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