Submission Details

The relationship between MT-TS1 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 19, 2023. MT-TS1 encodes one of the two mitochondrial transfer RNAs (tRNAs) for serine (UCN). 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-TS1 was first reported in relation to maternally-inherited primary mitochondrial disease in 1995 (PMID: 7669057), in a 26-year-old woman with a history of seizures, intellectual disability, basal ganglia calcification, hearing loss and increased cerebrospinal fluid (CSF) and serum lactate. While various names could be given to the constellation of features seen in those with MT-TS1-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-TS1 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 five unique variants including one insertion (m.7451A>T, m.7453G>A, m.7471dupC - also referred to as m7472insC, m.7497G>A, m.7512T>C; of note m.7497G>A, m.7453G>A, m.7471dupC, and m.7512T>C have been reported in multiple probands) observed in eight probands across six publications (PMIDs: 7669057, 9778262, 14605505, 23696415, 33279600, 7581383). Clinical features seen in affected individuals range from isolated hearing loss to mitochondrial myopathy to mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and myoclonus epilepsy, ragged red fibers (MERRF). One case of fatal neonatal lactic acidosis has been reported. Intrafamilial variability has been observed. Muscle biopsy often shows COX-negative fibers and/or ragged red fibers. A combined mitochondrial chain respiratory deficiency (commonly involving complexes I and IV) may also be observed in muscle biopsies. Heteroplasmy levels in affected individuals are often near homoplasmy in muscle and lower in tissues such as blood and urine, although homoplasmy across multiple tissues has also been seen. One individual had mitochondrial myopathy with heteroplasmy levels as low as 37% heteroplasmy in muscle Multiple single fiber studies and cybrid analyses were performed in these patients and supportive of variant pathogenicity (PMIDs: 16199753, 23696415, 33279600, 11919191). The mechanism of disease appears to be loss of function. This gene-disease association is further supported by a known biochemical function shared with other genes associated with primary mitochondrial disease and functional alteration in patient cells (PMIDs: 30030363, 17894844, 22453297, 20153673).

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. No convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 19, 2023 (SOP Version 9).