Submissions for variant NM_012123.4(MTO1):c.1391G>T (p.Arg464Leu)

dbSNP: rs141970072

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481072	SCV000565250	likely pathogenic	not provided	2014-05-06	criteria provided, single submitter	clinical testing	A R464L variant that is likely pathogenic was identified in the MTO1 gene. It has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The R464L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is highly conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Baylor Genetics	RCV001328641	SCV001519800	uncertain significance	Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency	2020-06-10	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001328641	SCV004046032	likely pathogenic	Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency		criteria provided, single submitter	clinical testing	This variant is also known as c.1391G>T (p.Arg464Leu), based on the alternative transcript, NM_012123.4. This variant has not been previously reported or functionally characterized in the literature to our knowledge. However, a different nucleotide change affecting the same amino acid, c.1510C>T (p.Arg504Cys) (also known in the literature as c.1390C>T p.Arg464Cys), has been previously reported as a homozygous and compound heterozygous change in several individuals affected with combined oxidative phosphorylation deficiency-10 (MIM: # 614702; PMID: 26061759, 27256614, 29331171). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0007% (2/251488) and thus is presumed to be rare. The c.1511G>T (p.Arg504Leu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1511G>T (p.Arg504Leu) variant is classified as Likely Pathogenic.