ClinVar Genomic variation as it relates to human health
m.14674T>C
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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m.14674T>C
Variation ID: 9618 Accession: VCV000009618.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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MT: 14674 (GRCh38) [ NCBI UCSC ] MT: 14674 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jun 8, 2016 Apr 15, 2023 Jan 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNC_012920.1:m.14674T>C - Protein change
- Other names
- 14674T-C
- Canonical SPDI
- NC_012920.1:14673:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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MT-TE | - | - | GRCh38 | 23 | 30 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Oct 1, 2011 | RCV000010243.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 26, 2014 | RCV000224954.2 | |
Likely pathogenic (3) |
reviewed by expert panel
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Jan 23, 2023 | RCV000495655.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 12, 2019 | RCV000851087.1 |
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
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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
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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
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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. |
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Likely pathogenic
(Jan 23, 2023)
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reviewed by expert panel
Method: curation
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Mitochondrial disease
(Mitochondrial inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen
Accession: SCV003915433.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Comment:
The m.14674T>C variant in MT-TE has been reported in at least 30 cases from 25 kindreds with primary mitochondrial disease. This variant is most commonly … (more)
The m.14674T>C variant in MT-TE has been reported in at least 30 cases from 25 kindreds with primary mitochondrial disease. This variant is most commonly associated with reversible infantile respiratory chain deficiency (RIRCD), and has an estimated penetrance of 30% in reported families. The variant has been reported in the homoplasmic state in both affected and unaffected family members. There is one report of a heteroplasmic occurrence (90%) in a healthy mother. Age of onset in affected individuals generally ranged from birth to six weeks old, however there have been reports of weak fetal movements and one report with onset at four years old. Features include severe myopathy, feeding difficulty, and hypotonia that gradually improve over time, however mild myopathic features persist in many reported cases. Muscle biopsy findings in affected individuals include ragged red fibers, COX deficiency, and reduced respiratory chain enzyme activities in early biopsies that normalize on subsequent biopsies (PS4; PMIDs: 8155739, 19720722, 21194154, 21931168, 31333056, 33832841, 34732400, 34806237). There are no reported de novo occurrences of this variant to our knowledge. This variant is present in population databases which is to be expected given the known reduced penetrance of this variant (Mitomap: 56,910 sequences, AF=0.018%; Helix: 195,983 sequences, AF=0.006%; gnomAD v3.1.2: 56,429 sequences, AF=0.004% - homoplasmic in two individuals and heteroplasmic in three individuals). The computational predictor MitoTIP suggests this variant is pathogenic (29.4 percentile but confirmed pathogenicity) and HmtVAR predicts it to be pathogenic score of 0.8 (PP3). Several studies in skeletal muscle and primary cell cultures of affected individuals (PMID: 19720722), cybrids (PMID: 21194154), and transcriptome and proteomic analyses (PMID: 33128823) support the functional impact of this variant (PS3_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP3, PS3_supporting. (less)
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Likely pathogenic
(Jul 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Juvenile myopathy, encephalopathy, lactic acidosis AND stroke
Affected status: unknown
Allele origin:
germline
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Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV000993321.1
First in ClinVar: Sep 22, 2019 Last updated: Sep 22, 2019 |
Comment:
The NC_012920.1:m.14674T>C variant in MT-TE gene is interpreted to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the … (more)
The NC_012920.1:m.14674T>C variant in MT-TE gene is interpreted to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS5, PP4, PP6 (less)
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Pathogenic
(Aug 26, 2014)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000281168.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial disease
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002517688.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(May 22, 2017)
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no assertion criteria provided
Method: clinical testing
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Mitochondrial disease
Affected status: yes
Allele origin:
germline
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Wellcome Centre for Mitochondrial Research, Newcastle University
Accession: SCV000577888.1
First in ClinVar: Jul 17, 2017 Last updated: Jul 17, 2017 |
Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Oct 01, 2011)
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no assertion criteria provided
Method: literature only
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MITOCHONDRIAL MYOPATHY, INFANTILE, TRANSIENT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030467.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 28, 2016 |
Comment on evidence:
In 17 affected individuals from 12 families with transient infantile mitochondrial myopathy (500009), Horvath et al. (2009) identified a homoplasmic 14674T-C transition in the MTTE … (more)
In 17 affected individuals from 12 families with transient infantile mitochondrial myopathy (500009), Horvath et al. (2009) identified a homoplasmic 14674T-C transition in the MTTE gene. The mutation occurred at a poorly conserved nucleotide in the last base at the 3-prime end of the molecule, affecting the discriminator base where the amino acid is attached to the molecule. The mutation was believed to impair mitochondrial translation, as reflected by the ragged-red fibers and COX-negative fibers in patient skeletal muscle. All patients presented at birth or in early infancy with severe hypotonia and muscle weakness, often requiring mechanical ventilation and tube feeding, and all children showed spontaneous recovery between age 4 and 20 months. Some had residual muscle weakness, but no nervous system abnormalities. Clinical improvement correlated with improvements in skeletal muscle biopsies and COX activity. Several unaffected family members carried the mutation, indicating incomplete penetrance. Horvath et al. (2009) suggested that tissue-specific, developmentally timed processes may play a role both in the age-dependent expression and in the reversibility of this disorder. The mutation was not found in 200 German controls and occurred on different haplotypes, indicating multiple independent mutation events. Mimaki et al. (2010) identified a homoplasmic 14674T-C mutation in 6 Japanese patients with infantile mitochondrial myopathy due to reversible COX deficiency. Studies of cybrids with the 14674T-C mutation showed decreased activities of complexes I, III, and IV. Two additional Japanese patients with the same disorder had a mutation affecting the same nucleotide (14674T-G; 590025.0003). Uusimaa et al. (2011) reported 5 patients from 4 families with transient acute infantile mitochondrial myopathy and lactic acidosis who were homoplasmic for the 14674T-C mutation. Age at presentation ranged from birth to 4 months, but all had subtle symptoms of hypotonia and feeding difficulties from birth. Two patients also had transient cardiac impairment, 2 had respiratory impairment, and 2 had eye muscle weakness. Only 1 had hepatomegaly. All recovered over months or years, but all showed delayed walking and had persistent muscle weakness, fatigability, or myalgia. Facial weakness, ptosis, and a myopathic facial appearance became more prominent with age. In 2 families, the mother of the index case had mild to moderate myopathic features without the typical infantile presentation. Two patients and the mother of a patient developed hypothyroidism. Muscle biopsies showed ragged-red fibers, increased glycogen and lipids, decreased COX activity, and deficiency of other mitochondrial respiratory enzymes, which improved with age. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency. | Hathazi D | The EMBO journal | 2020 | PMID: 33128823 |
Interpretation of mitochondrial tRNA variants. | Wong LC | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31965079 |
Reversible infantile respiratory chain deficiency is a unique, genetically heterogenous mitochondrial disease. | Uusimaa J | Journal of medical genetics | 2011 | PMID: 21931168 |
Reversible infantile respiratory chain deficiency: a clinical and molecular study. | Mimaki M | Annals of neurology | 2010 | PMID: 21194154 |
Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy. | Horvath R | Brain : a journal of neurology | 2009 | PMID: 19720722 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c3041f19-42e2-4b31-b407-b0847507f476 | - | - | - | - |
Text-mined citations for rs387906421 ...
HelpRecord last updated Dec 09, 2023
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.