Submissions for variant NM_020810.3(TRMT5):c.312_315del (p.Ile105fs)

dbSNP: rs755184077

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513771	SCV000610714	pathogenic	not provided	2017-07-24	criteria provided, single submitter	clinical testing
Invitae	RCV000513771	SCV001053996	uncertain significance	not provided	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile105Serfs*4) in the TRMT5 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TRMT5 cause disease. This variant is present in population databases (rs755184077, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with features of combined oxidative phosphorylation deficiency (PMID: 26189817, 29021354). ClinVar contains an entry for this variant (Variation ID: 372246). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000513771	SCV001246883	likely pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing	TRMT5: PS4, PM4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000412579	SCV002511860	likely pathogenic	Combined oxidative phosphorylation defect type 26	2022-04-21	criteria provided, single submitter	clinical testing	Variant summary: TRMT5 c.312_315delAATA (p.Ile105SerfsX4) 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, which are commonly known mechanisms for disease. 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.Ile105Serfs*4 frameshift mutation is upstream of the methyltransferase motif, predicting a truncated protein that is expected to be non-functional (Powell_2015). The variant allele was found at a frequency of 0.00087 in 251378 control chromosomes, predominantly at a frequency of 0.0013 within the Non-Finnish European subpopulation in the gnomAD database. As the prevalence of Combined Oxidative Phosphorylation Defect Type 26 and attributable risk of TRMT5 gene and variants cannot be estimated, this frequency does not allow conclusions about variant significance. c.312_315delAATA has been reported in the literature as a compound heterozygous genotype with other TRMT5 missense variants in at-least four probands from three separate families presenting with features of Combined Oxidative Phosphorylation Defect Type 26, Complex I and IV deficiencies (example, Powell_2015, Tarnopolsky_2017). Each of these probands were comprehensively evaluated to rule out other genetic conditions prior to whole exome sequencing (WES). It has also been reported as a non-informative genotype (zygosity/genotype not specified) in an autistic proband who underwent whole genome sequencing (example, Callaghan_2019) but has not been considered as a relevant correlation in the context of this evaluation. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic/Likely Pathogenic, n=3; Likely Benign, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	RCV000412579	SCV003920742	pathogenic	Combined oxidative phosphorylation defect type 26	2023-04-27	criteria provided, single submitter	research
GeneDx	RCV000513771	SCV004036831	uncertain significance	not provided	2023-09-14	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 34426522, 31038196, 26189817, 29021354, 35342985)
OMIM	RCV000412579	SCV000490321	pathogenic	Combined oxidative phosphorylation defect type 26	2022-06-01	no assertion criteria provided	literature only