The relationship between RARS2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 4, 2022. The RARS2 gene encodes mitochondrial arginyl-tRNA synthetase 2, one of the mitochondrial aminoacyl-tRNA synthetases, which function in mitochondrial translation by catalyzing the attachment of amino acids to their cognate tRNAs. Defects in tRNA charging can result in impaired synthesis of oxidative phosphorylation complex protein subunits.
The RARS2 gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2007 (PMID: 17847012). While various names have been given to the constellation of features seen in those with RARS2-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the RARS2 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 17 unique variants including nine missense, three frameshift, three splice-site, one consensus splice-site and one 5'UTR variants from seven publications (PMIDs: 31536827, 33209735, 32071833, 17847012, 20635367, 25809939, 22569581). Affected individuals have been reported to have pontocerebellar hypoplasia type 6 (PCH6), seizures, neurodevelopmental regression, microcephaly, and optic atrophy. The mechanism of disease appears to be loss of function either at the transcript or protein level. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease, morpholino knockdown of rars2 in Zebrafish showing hypoplasia and loss of structural definition in the brain phenotype, and patient cells showing reduced RARS2 protein levels (PMIDs: 22569581, 24639874, 21273289).
In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 4, 2022 (SOP Version 8).
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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