Submissions for variant NM_012123.4(MTO1):c.547A>G (p.Thr183Ala)

gnomAD frequency: 0.00006  dbSNP: rs779108851

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456391	SCV000547861	uncertain significance	Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency	2022-07-22	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 183 of the MTO1 protein (p.Thr183Ala). This variant is present in population databases (rs779108851, gnomAD 0.03%). 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: 408274). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786359	SCV000925154	uncertain significance	not provided	2017-03-21	no assertion criteria provided	provider interpretation	Given that there are no case reports for this variant and its low population frequency, we consider this variant a variant of uncertain significance. However, we do not think this variant is causative of the patient's phenotype since MTO1 is associated with an autosomal recessive syndrome. This syndrome has only been reported in three families. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant is novel. There is no case data available for review and it is not present in ClinVar. Three children with a syndrome consisting of hypertrophic cardiomyopathy, lactic acidosis and multiple defects of the mitochondrial respiratory chain have been reported in association with autosomal recessive variants in the MTO1 gene (Baruffini et al. 2013). According to the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The alanine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies." The threonine at codon 183 is moderately conserved across species. Neighboring amino acids are also moderately conserved. This variant is listed in 4 out of 121,115 individuals in the the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically, this variant is present in 4 out of 7627 individuals of African descent (MAF=0.026%). Of note, our patient is of African-American descent.