Submissions for variant NM_012123.4(MTO1):c.791C>T (p.Pro264Leu)

gnomAD frequency: 0.00001  dbSNP: rs1025884753

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851313	SCV002275555	uncertain significance	Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 264 of the MTO1 protein (p.Pro264Leu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MTO1-related conditions. ClinVar contains an entry for this variant (Variation ID: 426615). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000489964	SCV003799100	uncertain significance	not provided	2022-10-03	criteria provided, single submitter	clinical testing	PM2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387857	SCV004099613	uncertain significance	not specified	2023-09-07	criteria provided, single submitter	clinical testing	Variant summary: MTO1 c.791C>T (p.Pro264Leu) results in a non-conservative amino acid change located in the MnmG, N-terminal domain (IPR040131) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251190 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.791C>T in individuals affected with Combined Oxidative Phosphorylation Deficiency 10 and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (uncertain significance, n = 2; likely pathogenic, n = 1). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000489964	SCV000577099	likely pathogenic	not provided	2018-03-20	flagged submission	clinical testing	The P264L variant in the MTO1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). The P264L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, we interpret P264L as a likely pathogenic variant.