VARS2

Inheritance Pattern: AR

Disease ID:MONDO:0014397

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *VARS2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 19, 2022. The *VARS2* gene encodes mitochondrial valyl-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 *VARS2* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2014 (PMIDs: 25058219, 24827421). While various names have been given to the constellation of features seen in those with *VARS2*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *VARS2* 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 nine unique variants, including eight missense variants and one splice-site variant. A nonsense variant has been reported, but parental testing was not performed to confirm compound heterozygous state so this proband was not included in the curation (PMID: 29314548). Of note, there are two commonly referenced transcripts for this gene, NM_020442.6 and NM_001167734, which result in alternative variant nomenclature, (i.e NM_001167734.1:c.1100C>T, p.Thr367Ile; and NM_020442.6:c.1010C>T, p.Thr337Ile). The c.1010C>T (p.Thr337Ile) is a recurrent variant seen in multiple probands in either the homozygous or compound heterozygous state. It has been reported in individuals from a multitude of ethnic backgrounds (Portuguese, Polish, Italian - N. Sardinia, Afghan, and Greek). More than 12 probands were reported between 2014-2021 (PMIDs: 25058219, 24827421, 29314548, 27502409, 33937156). *VARS2*-related disorders were first described in a 10-year-old male with ataxia, myopathy, and ophthalmoplegia; and an 8-year-old male with refractory epilepsy, developmental delay, and microcephaly, both of whom had muscle biopsy findings supportive of a mitochondrial translation defect (PMIDs: 25058219, 24827421). Subsequent publications have shown the *VARS2* phenotype is predominantly an infantile-onset, neurodegenerative disorder with microcephaly, developmental delay, refractory epilepsy, spasticity, global brain atrophy, and cardiomyopathy. The most common cause of fatality is cardiopulmonary failure. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease, patient cell data showing profound respiratory chain deficiencies and mis-assembly, yeast model studies incorporating the orthologous variant to p.Thr337Ile which showed respiratory growth defects, and rescue of respiration in patient fibroblast cells (PMIDs: 24827421, 29980628, 29314548, 33937156). 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 19, 2022 (SOP Version 8).

Inheritance Pattern: AR

Disease ID:MONDO:0014397

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014397

Submitter: PanelApp Australia