TRMT5

Inheritance Pattern: AR

Disease ID:MONDO:0014684

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0014684

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *TRMT5* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 18, 2022. The *TRMT5* gene encodes tRNA methyltransferase 5 which methylates the N1 position of guanosine-37 (G37) in selected mitochondrial tRNAs (mt-tRNALeu(CUN), mt-tRNA Pro, mt-tRNA Met, mt-tRNA Ile, mt-tRNA Asp, mt-tRNA Gln, mt-tRNA Ala) using S-adenosyl methionine. The *TRMT5* gene was first reported in relation to autosomal recessive mitochondrial disease in 2015 (PMID: 26189817). While various names have been given to the constellation of features seen in those with *TRMT5*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *TRMT5* 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 six unique variants: five missense variants and one frameshift variant resulting in protein truncation from seven probands across four publications. Of note, this Expert Panel opted to include the cases in Powel et al 2015 (73901 II:1 and 65205 II:1), at a reduced score, despite the inability to confirm biparental inheritance for the following reasons: clinical and biochemical phenotype were both compelling and uniparental inheritance of a single variant was confirmed. This condition was first described in two patients, an adult female with myopathy, lactic acidosis, neuropathy, spasticity, and diabetes (who was first described in 1989; PMID: 2544623) and a 7-year-old male with lactic acidosis, neuropathy, cardiomyopathy, hypotonia, and global delays. Both patients had muscle biopsy supportive of a mitochondrial translation defect. Subsequent publications have shown the *TRMT5* phenotype is predominantly an infancy- to childhood-onset sensory neuropathy with exercise intolerance and myopathy, developmental delays, and spasticity with or without cerebellar atrophy (PMIDs: 29021354, 35342985, 35460901). Of note, the c.312_315del (p.Ile105SerfsX4) variant is a predicted null allele that has been reported in most reported cases (6/7). There is also a case report of a Chinese proband with multisystemic symptoms including delays, seizures, muscle weakness, and gastrointestinal dysmotility, who died from stroke and respiratory failure, who was found to have three variants in *MRPS22* with confirmed biparental inheritance (PMID:35109800). Since there was no functional evidence for this case, and the maximum case score for genetic evidence had been reached, this case was not scored. This gene-disease association is also supported by known protein interaction with other mitochondrial translation proteins and multiple mitochondrial tRNAs, yeast model studies incorporating the orthologous variant to the p.Arg291His and p.Met386Val variants which showed respiratory growth defects, and rescue with incorporation of wild-type TRMT5 (PMIDs: 34360765, 26189817). 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 July 18, 2022 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0014684

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0014684

Submitter: Ambry Genetics