Submission Details

The relationship between MT-TC and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 20, 2023. The MT-TC gene encodes the mitochondrial tRNA for cysteine, which is located from m.5761-5826 on the light strand of the mitochondrial DNA (mtDNA). 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.

While various names have been given to the constellation of features seen in those with MT-TC-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-TC phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.

MT-TC was first reported in 1996 in association with primary mitochondrial disease (PMID:8829635), however, current population data suggests the variant reported in this publication, m.5814T>C, is benign (AF: 1.377% gnomAD v.3.1.2), so this case was not considered in this curation. The first case considered in this curation was reported in 2006 (PMID:17724295) in a 16-year-old male with dystonia, nocturnal seizures, tremor and weakness and his similarly affected family members. While there have been numerous publications (>10) on cases with MT-TC variants, only 3 cases met criteria for scoring for this curation. The phenotype in these cases was variable but included dystonia, neuropathy, myoclonic epilepsy, ataxia, retinitis pigmentosa, and muscle weakness.

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 3 unique missense variants. In 2 out of 3 cases, the variant was homoplasmic in all tissues tested. The m.5789T>C variant was heteroplasmic and present at highest level in the muscle tissue (PMID: 35252560). There are 3 scoreable probands across >10 publications from 1996-2022 (PMIDs: 8829635, 9185178, 17241783, 11453453, 16955414, 32169613, 36039763, 17724295, 35252560, 34433719). Notably, while cybrid analyses were performed (PMID:36039763), the m.5783G>A variant was excluded from scoring for three reasons: 1.) the reported phenotype of isolated hearing loss was non-specific and incompletely penetrant, but also 2.) the biochemical impact in cybrids was mild - moderate, and 3.) there was reduction in expression of mitochondrial replication genes (TWNK ~30% of control in cybrids) suggesting an alternative etiology might be responsible for the biochemical impact reported.

This gene-disease association for MT-TC is also supported by the known interaction with a multitude of other mitochondrial translation proteins (PMID:30030363) and respiratory chain studies and Northern blot analysis supporting MT-TC dysfunction leading to Complex I deficiency (PMID:35252560).

In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This GCEP notes that while at the time of this curation MT-TC has a limited association with primary mitochondrial disease, it is plausible, and even likely, that additional cases will be reported in the future given the crucial role of MT-TC in mitochondrial translation. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 20, 2023 (SOP Version 9).

This gene-disease relationship was reevaluated on July 14, 2025 by this Expert Panel. As a result of this reevaluation, the classification did not change.