Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_012123.4(MTO1):c.1639G>A(p.Ala547Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,448,790 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A547V) has been classified as Uncertain significance.
MTO1 (HGNC:19261): (mitochondrial tRNA translation optimization 1) This gene encodes a mitochondrial protein thought to be involved in mitochondrial tRNA modification. The encoded protein may also play a role in the expression of the non-syndromic and aminoglycoside-induced deafness phenotypes associated with a specific mutation in the mitochondrial 12S rRNA gene. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
EEF1A1 (HGNC:3189): (eukaryotic translation elongation factor 1 alpha 1) This gene encodes an isoform of the alpha subunit of the elongation factor-1 complex, which is responsible for the enzymatic delivery of aminoacyl tRNAs to the ribosome. This isoform (alpha 1) is expressed in brain, placenta, lung, liver, kidney, and pancreas, and the other isoform (alpha 2) is expressed in brain, heart and skeletal muscle. This isoform is identified as an autoantigen in 66% of patients with Felty syndrome. This gene has been found to have multiple copies on many chromosomes, some of which, if not all, represent different pseudogenes. [provided by RefSeq, Jul 2008]
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Dec 02, 2022
The c.1759G>A (p.A587T) alteration is located in exon 11 (coding exon 11) of the MTO1 gene. This alteration results from a G to A substitution at nucleotide position 1759, causing the alanine (A) at amino acid position 587 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Jun 14, 2021
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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MTO1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 547 of the MTO1 protein (p.Ala547Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. -