The p.Ala468Thr variant in MTO1 has been reported in 1 homozygous and 2 compound heterozygous individuals with infantile-onset HCM, lactic acidosis, and defecti ve mitochondrial respiratory chain activity in muscle biopsies, and segregated w ith disease in 1 affected relative (Ghezzi 2012, Baruffini 2013). This variant h as been identified in 12/126720 European chromosomes by the Genome Aggregation D atabase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs143747297). Although this variant has been seen in the general population, its frequency is low enoug h to be consistent with a recessive carrier frequency. Yeast studies provide som e evidence that the p.Ala468Thr variant may impact protein function (Ghezzi 2012 , Baruffini 2013). However, these types of assays may not accurately represent b iological function in humans. Computational prediction tools and conservation an alysis suggest that the p.Ala468Thr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, alt hough additional studies are required to fully establish its clinical significan ce, the p.Ala468Thr variant is likely pathogenic. ACMG/AMP Criteria applied: PM2 ,PM3,PS3_M, PP3
ClinVar Genomic variation as it relates to human health
NM_012123.4(MTO1):c.1282G>A (p.Ala428Thr)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(10)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_012123.4(MTO1):c.1282G>A (p.Ala428Thr)
Variation ID: 35496 Accession: VCV000035496.25
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 6q13 6: 73482061 (GRCh38) [ NCBI UCSC ] 6: 74191784 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 28, 2016 Nov 24, 2024 Jan 24, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_012123.4:c.1282G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_036255.2:p.Ala428Thr missense NM_001123226.2:c.1402G>A NP_001116698.1:p.Ala468Thr missense NM_133645.3:c.1357G>A NP_598400.1:p.Ala453Thr missense NC_000006.12:g.73482061G>A NC_000006.11:g.74191784G>A NG_032856.2:g.25331G>A Q9Y2Z2:p.Ala453Thr - Protein change
- A428T, A453T, A468T
- Other names
-
p.Ala428Thr
- Canonical SPDI
- NC_000006.12:73482060:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00003
Exome Aggregation Consortium (ExAC) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| MTO1 | - | - |
GRCh38 GRCh37 |
714 | 732 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 24, 2024 | RCV000029168.23 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 17, 2023 | RCV000519673.10 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 12, 2017 | RCV000826120.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 1, 2019 | RCV001255405.4 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000861615.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Likely pathogenic
(Dec 12, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial oxidative phosphorylation disorder
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967628.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The p.Ala468Thr variant in MTO1 has been reported in 1 homozygous and 2 compound heterozygous individuals with infantile-onset HCM, lactic acidosis, and defecti ve mitochondrial … (more)
The p.Ala468Thr variant in MTO1 has been reported in 1 homozygous and 2 compound heterozygous individuals with infantile-onset HCM, lactic acidosis, and defecti ve mitochondrial respiratory chain activity in muscle biopsies, and segregated w ith disease in 1 affected relative (Ghezzi 2012, Baruffini 2013). This variant h as been identified in 12/126720 European chromosomes by the Genome Aggregation D atabase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs143747297). Although this variant has been seen in the general population, its frequency is low enoug h to be consistent with a recessive carrier frequency. Yeast studies provide som e evidence that the p.Ala468Thr variant may impact protein function (Ghezzi 2012 , Baruffini 2013). However, these types of assays may not accurately represent b iological function in humans. Computational prediction tools and conservation an alysis suggest that the p.Ala468Thr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, alt hough additional studies are required to fully establish its clinical significan ce, the p.Ala468Thr variant is likely pathogenic. ACMG/AMP Criteria applied: PM2 ,PM3,PS3_M, PP3 (less)
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Oct 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000617785.5
First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023 |
Comment:
Reported in multiple unrelated individuals with clinical features are consistent with COXPD10 who were homozygous for A428T or heterozygous for A428T and another variant in … (more)
Reported in multiple unrelated individuals with clinical features are consistent with COXPD10 who were homozygous for A428T or heterozygous for A428T and another variant in MTO1 (Ghezzi et al., 2012; Baruffini et al., 2013; O'Byrne et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23929671, 22608499, 25058219, 29440775, 29331171, 31589614) (less)
|
|
|
Pathogenic
(Jan 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000818226.5
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 428 of the MTO1 protein (p.Ala428Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 428 of the MTO1 protein (p.Ala428Thr). This variant is present in population databases (rs143747297, gnomAD 0.009%). This missense change has been observed in individuals with oxidative phosphorylation deficiency (PMID: 22608499, 23929671, 25058219). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 35496). 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: 22608499, 23929671). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jan 14, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001150170.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: male
Tissue: blood
|
|
|
Pathogenic
(Nov 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Global developmental delay
Affected status: yes
Allele origin:
germline
|
Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV001431805.1
First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020 |
Comment:
homozygous
|
|
|
Pathogenic
(Jan 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002809935.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Likely pathogenic
(Oct 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV003799033.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
PS3_Moderate, PM3_Strong, PM2
|
|
|
Pathogenic
(Nov 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005413734.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PP3, PM2, PM3_strong, PS3
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Nov 01, 2013)
|
no assertion criteria provided
Method: literature only
|
COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 10
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000051813.4
First in ClinVar: Apr 04, 2013 Last updated: Oct 28, 2016 |
Comment on evidence:
In 2 sibs with severe, fatal combined oxidative phosphorylation deficiency-10 (COXPD10; 614702), Ghezzi et al. (2012) detected compound heterozygosity for a frameshift mutation in the … (more)
In 2 sibs with severe, fatal combined oxidative phosphorylation deficiency-10 (COXPD10; 614702), Ghezzi et al. (2012) detected compound heterozygosity for a frameshift mutation in the MTO1 gene (614667.0001) and a c.1282G-A transition resulting in an ala428-to-thr (A428T) substitution. They also found the A428T mutation in homozygosity in a 19-year-old COXPD10 patient with a comparatively mild course. Ghezzi et al. (2012) found that ala428 is invariant in all animal, plant, and yeast species available for testing, including S. cerevisiae. The Exome Variant Server reports a frequency of 0.028% (2/7,020) for the 1282G-A change in Americans of European origin. A428T was not found in 973 genomes from Europeans or in 300 control alleles from northern Italy. RT-PCR showed that the mutant transcript was expressed. This mutation resulted in mtDNA protein synthesis similar to wildtype. In yeast mutants, respiration and growth defects were partially corrected by the missense mutation. These results reflected the less severe phenotype in the patient homozygous for the A428T mutation. Baruffini et al. (2013) reported a patient with COXPD10 who was compound heterozygous for the A428T mutation, caused by a 1402G-A transition, and another missense mutation in the MTO1 gene (see 614667.0003). Baruffini et al. (2013) demonstrated that expression of the yeast equivalent (A431T) of the A428T mutation into Mto1-null yeast resulted in a slight decrease in complex IV activity (70% compared to wildtype), but mitochondrial protein synthesis and complex IV activity were similar to wildtype. (less)
|
Comment:
Comment:
Reported in multiple unrelated individuals with clinical features are consistent with COXPD10 who were homozygous for A428T or heterozygous for A428T and another variant in MTO1 (Ghezzi et al., 2012; Baruffini et al., 2013; O'Byrne et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23929671, 22608499, 25058219, 29440775, 29331171, 31589614)
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 428 of the MTO1 protein (p.Ala428Thr). This variant is present in population databases (rs143747297, gnomAD 0.009%). This missense change has been observed in individuals with oxidative phosphorylation deficiency (PMID: 22608499, 23929671, 25058219). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 35496). 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: 22608499, 23929671). For these reasons, this variant has been classified as Pathogenic.
Comment:
homozygous
Comment:
PS3_Moderate, PM3_Strong, PM2
Comment:
PP3, PM2, PM3_strong, PS3
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The p.Ala468Thr variant in MTO1 has been reported in 1 homozygous and 2 compound heterozygous individuals with infantile-onset HCM, lactic acidosis, and defecti ve mitochondrial respiratory chain activity in muscle biopsies, and segregated w ith disease in 1 affected relative (Ghezzi 2012, Baruffini 2013). This variant h as been identified in 12/126720 European chromosomes by the Genome Aggregation D atabase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs143747297). Although this variant has been seen in the general population, its frequency is low enoug h to be consistent with a recessive carrier frequency. Yeast studies provide som e evidence that the p.Ala468Thr variant may impact protein function (Ghezzi 2012 , Baruffini 2013). However, these types of assays may not accurately represent b iological function in humans. Computational prediction tools and conservation an alysis suggest that the p.Ala468Thr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, alt hough additional studies are required to fully establish its clinical significan ce, the p.Ala468Thr variant is likely pathogenic. ACMG/AMP Criteria applied: PM2 ,PM3,PS3_M, PP3
Comment:
Reported in multiple unrelated individuals with clinical features are consistent with COXPD10 who were homozygous for A428T or heterozygous for A428T and another variant in MTO1 (Ghezzi et al., 2012; Baruffini et al., 2013; O'Byrne et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23929671, 22608499, 25058219, 29440775, 29331171, 31589614)
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 428 of the MTO1 protein (p.Ala428Thr). This variant is present in population databases (rs143747297, gnomAD 0.009%). This missense change has been observed in individuals with oxidative phosphorylation deficiency (PMID: 22608499, 23929671, 25058219). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 35496). 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: 22608499, 23929671). For these reasons, this variant has been classified as Pathogenic.
Comment:
homozygous
Comment:
PS3_Moderate, PM3_Strong, PM2
Comment:
PP3, PM2, PM3_strong, PS3
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
| Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies. | Taylor RW | JAMA | 2014 | PMID: 25058219 |
| MTO1 mutations are associated with hypertrophic cardiomyopathy and lactic acidosis and cause respiratory chain deficiency in humans and yeast. | Baruffini E | Human mutation | 2013 | PMID: 23929671 |
| Mutations of the mitochondrial-tRNA modifier MTO1 cause hypertrophic cardiomyopathy and lactic acidosis. | Ghezzi D | American journal of human genetics | 2012 | PMID: 22608499 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MTO1 | - | - | - | - |
Text-mined citations for rs143747297 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.