Submissions for variant NM_020810.3(TRMT5):c.267_270delinsCTG (p.Ala89_Phe90insTer)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002510311	SCV002819369	likely pathogenic	Combined oxidative phosphorylation defect type 26	2022-12-08	criteria provided, single submitter	clinical testing	Variant summary: TRMT5 c.267_270delinsCTG (p.Phe90X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. The gene tRNA methyltransferase 5 (TRMT5) encodes a protein involved in methylation of a specific nucleotide (position 37) adjacent to the anticodon of mitochondrial-tRNA to enhance its translational efficiency/fidelity (Tarnopolsky_2017). The p.Phe90X truncating mutation is upstream of the methyltransferase motif, predicting a truncated protein that is expected to be non-functional (Powell_2015). At least one truncation downstream of this position have been observed and classified as pathogenic at our lab and reported in the literature in patients with Combined Oxidative Phosphorylation Defect Type 26. c.267_270delinsCTG was absent in 251276 control chromosomes. To our knowledge, no occurrence of c.267_270delinsCTG in individuals affected with Combined Oxidative Phosphorylation Defect Type 26 and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.