NM_012123.4(MTO1):c.1934G>A (p.Arg645His) AND Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 1, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000688039.5

Allele description [Variation Report for NM_012123.4(MTO1):c.1934G>A (p.Arg645His)]

NM_012123.4(MTO1):c.1934G>A (p.Arg645His)

Gene:

MTO1:mitochondrial tRNA translation optimization 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6q13

Genomic location:

Preferred name:

NM_012123.4(MTO1):c.1934G>A (p.Arg645His)

HGVS:

NC_000006.12:g.73500590G>A
NG_032856.2:g.43860G>A
NM_001123226.1:c.2054G>A
NM_001123226.2:c.2054G>A
NM_012123.4:c.1934G>AMANE SELECT
NM_133645.3:c.2009G>A
NP_001116698.1:p.Arg685His
NP_036255.2:p.Arg645His
NP_598400.1:p.Arg670His
NC_000006.11:g.74210313G>A
NG_032856.1:g.43860G>A
NM_012123.3:c.1934G>A

Protein change:

R645H

Links:

dbSNP: rs758448974

NCBI 1000 Genomes Browser:

rs758448974

Molecular consequence:

NM_001123226.2:c.2054G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_012123.4:c.1934G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133645.3:c.2009G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency
Synonyms:: CARDIOMYOPATHY, INFANTILE HYPERTROPHIC MITOCHONDRIAL, AND LACTIC ACIDOSIS; Combined oxidative phosphorylation deficiency 10
Identifiers:: MONDO: MONDO:0013865; MedGen: C4749921; Orphanet: 314637; OMIM: 614702

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000815635	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 1, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000815635

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 1, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000815635.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 645 of the MTO1 protein (p.Arg645His). This variant is present in population databases (rs758448974, gnomAD 0.004%). 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: 567850). 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. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 7, 2023

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