MT-TS2

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0044970

Submitter: ClinGen

The *MT-TS2* gene encodes one of two mitochondrial transfer RNAs (tRNAs) for serine (AGU/C). Defects of this tRNA lead to impaired mitochondrial translation, which leads to decreased synthesis of mtDNA-encoded subunits of oxidative phosphorylation (OXPHOS) complexes I, III, IV, and V, resulting in impaired OXPHOS enzyme activities. *MT-TS2* was first reported in relation to maternally-inherited primary mitochondrial disease in 1998 in a mother and daughter who were both affected with bilateral cataracts, hearing loss, and diabetes (PMID: 9792552). While various names could be given to the constellation of features seen in those with *MT-TS2*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MT-TS2* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting the gene-disease relationship between *MT-TS2* and primary mitochondrial disease includes case-level data and experimental data. This curation includes six variants (m.12207G>A, m.12213G>A, m.12258C>A, m.12261T>C, m.12262C>A, m.12264C>T) observed in nine probands in eight publications (PMIDs: 9792552, 10090882, 16950817, 21257182, 22369973, 22378285, 36967720, 38465286). Affected individuals had varying clinical features including cataracts, retinal dystrophy, optic atrophy, hearing loss, myopathy, ataxia, seizures, global developmental delay, diabetes, Wolff-Parkinson-White arrhythmia, hypertrophic cardiomyopathy, short stature, and hypogonadotropic hypogonadism. Labs revealed elevated blood lactate and elevated creatine kinase. Muscle biopsy, when performed, generally showed reduced activities of complexes I, I+III, III, and/or IV. Brain imaging was normal in some cases. In one individual brain imaging revealed changes in the basal ganglia and diffuse atrophy with an enlarged cisterna magna and in another showed changes in the cerebral white matter. Heteroplasmy levels were variable – some individuals had the highest levels in muscle with the variant being undetectable in other tissues while others had the variant present at homoplasmy in multiple tissues. Northern blotting and single fiber testing further supported variant pathogenicity for case-level scoring (PMIDs: 22378285, 21257182, 9792552). The mechanism of pathogenicity appears to be loss of function due to altered RNA secondary structure. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease and in vitro assays demonstrating altered function in non-patient cells as a result of variants in *MT-TS2* (PMID: 16671096, 33340416). This gene-disease pair was originally evaluated by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on December 5, 2022. It was re-evaluated on July 14, 2025. As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of two cases (PMIDs: 36967720, 38465286). This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on July 14, 2025 (SOP Version 11).