Submissions for variant NM_012123.4(MTO1):c.1430G>A (p.Arg477His)

gnomAD frequency: 0.00028  dbSNP: rs201544686

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224907	SCV000281268	likely pathogenic	not provided	2015-12-03	criteria provided, single submitter	clinical testing
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000074506	SCV000680300	pathogenic	Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency	2017-11-08	criteria provided, single submitter	clinical testing
Invitae	RCV000074506	SCV000958214	pathogenic	Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 477 of the MTO1 protein (p.Arg477His). This variant is present in population databases (rs201544686, gnomAD 0.08%). This missense change has been observed in individuals with combined oxidative phosphorylation deficiency (PMID: 23929671, 29331171, 29440775). ClinVar contains an entry for this variant (Variation ID: 89037). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MTO1 protein function. Experimental studies have shown that this missense change affects MTO1 function (PMID: 23929671). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000074506	SCV001366427	pathogenic	Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency	2019-08-16	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PS3,PP3.
CeGaT Center for Human Genetics Tuebingen	RCV000224907	SCV004042266	likely pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	MTO1: PM2, PM3, PM5
OMIM	RCV000074506	SCV000108591	pathogenic	Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency	2013-11-01	no assertion criteria provided	literature only