Submission Details

The relationship between TRMT10C and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of September 13, 2022. The TRMT10C gene encodes tRNA methyltransferase 10C, a mitochondrial RNAse P subunit (MRPP1), and is involved in mitochondrial tRNA (mt-tRNA) maturation. MRPP1, MRPP2 and MRPP3 together form the mitochondrial ribonuclease P (mt-RNase P) complex that cleaves the 5’ ends of mt-tRNAs from polycistronic precursor transcripts. Additionally, a stable complex of MRPP1 and MRPP2 has m1R9 methyltransferase activity, which methylates mt-tRNAs at position 9 which is vital for folding mt-tRNAs into their correct tertiary structures.

The TRMT10C gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2016 (PMID: 27132592). While various names have been given to the constellation of features seen in those with TRMT10C-related disease (including combined oxidative phosphorylation deficiency 30), pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the TRMT10C 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 two variants [2 of 3 probands were homozygous for c.542G>T (p.Arg181Leu) and 1 of 3 probands was compound heterozygous for c.542G>T (p.Arg181Leu) and c.814A>G (p.Thr272Ala)] identified in three probands from two publications (PMIDs: 27132592, 33886802). Age of onset ranged from shortly after birth to two months old. Two of the three probands died at five months and the third proband was alive at least at 13 months of age. Features included infantile-onset multisystem disease including hypotonia, feeding difficulties/failure to thrive, hearing loss, and cognitive/neurologic deterioration. Muscle biopsy was performed in two of the three probands and deficiencies of complex I and IV were seen in both while CIII deficiency was seen in one. Imaging changes seen include bifrontal polymicrogyria, involvement of supratentorial regions particularly affecting the white matter and superficial cortex with deep gray matter having less evident atrophy with basal ganglia involvement. Lactic acidosis was also seen in affected individuals. The mechanism of disease appears to be loss of function. This gene-disease relationship is also supported by a biochemical function (mt-tRNA processing for mitochondrial translation) shared with other genes associated with primary mitochondrial disease and functional alteration in patient cells (PMID: 27132592).

In summary, there is moderate 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 classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on September 13, 2022 (SOP Version 9).