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NC_012920.1(MT-TE):m.14709T>C AND Mitochondrial disease

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Jan 23, 2023
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV000495337.3

Allele description [Variation Report for NC_012920.1(MT-TE):m.14709T>C]

NC_012920.1(MT-TE):m.14709T>C

Gene:
MT-TE:mitochondrially encoded tRNA glutamic acid [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Genomic location:
Preferred name:
NC_012920.1(MT-TE):m.14709T>C
Other names:
MT-TE m.14709T>C
HGVS:
NC_012920.1:m.14709T>C
Nucleotide change:
14709T-C
Links:
OMIM: 590025.0001; dbSNP: rs121434453
NCBI 1000 Genomes Browser:
rs121434453
Observations:
1

Condition(s)

Name:
Mitochondrial disease
Synonyms:
Mitochondrial diseases; Mitochondrial disorder
Identifiers:
MONDO: MONDO:0044970; MeSH: D028361; MedGen: C0751651; Orphanet: 68380

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000577893Wellcome Centre for Mitochondrial Research, Newcastle University
no assertion criteria provided
Pathogenic
(May 22, 2017)
germlineclinical testing

SCV003915451ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(McCormick et al. (Hum Mutat. 2020))
Likely pathogenic
(Jan 23, 2023)
germlinecuration

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Segregation patterns of a novel mutation in the mitochondrial tRNA glutamic acid gene associated with myopathy and diabetes mellitus.

Hao H, Bonilla E, Manfredi G, DiMauro S, Moraes CT.

Am J Hum Genet. 1995 May;56(5):1017-25.

PubMed [citation]
PMID:
7726154
PMCID:
PMC1801448

Molecular and functional effects of the T14709C point mutation in the mitochondrial DNA of a patient with maternally inherited diabetes and deafness.

Perucca-Lostanlen D, Taylor RW, Narbonne H, Mousson de Camaret B, Hayes CM, Saunieres A, Paquis-Flucklinger V, Turnbull DM, Vialettes B, Desnuelle C.

Biochim Biophys Acta. 2002 Dec 12;1588(3):210-6.

PubMed [citation]
PMID:
12393175
See all PubMed Citations (5)

Details of each submission

From Wellcome Centre for Mitochondrial Research, Newcastle University, SCV000577893.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen, SCV003915451.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (5)

Description

The m.14709T>C variant in MT-TE has been reported in at least 39 affected individuals from 20 kindreds (PMIDs: 7726155, 7726154, 9353617, 10392369, 11437868, 15048886, 15880407, 15607216, 17161635, 17891417, 20045353, 26469001, 26885883, 29941710, 32313153, 33304817, 32948797; web story: https://www.chop.edu/stories/mitochondrial-disease-noras-story; PS4). Age of onset ranged from shortly after birth to 50s, although there are some reports of decreased fetal movements and hydrops fetalis. Features in affected individuals include myopathy, diabetes, pulmonary hypertension, ataxia, neuropathy, global developmental delay, dysarthria, hearing loss, hypertrophic cardiomyopathy, and dilated cardiomyopathy. Furthermore, this variant has been reported in some individuals with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)/Leigh syndrome spectrum overlap and myoclonic epilepsy with ragged red fibers (MERRF). Muscle biopsies in affected individuals showed ragged red fibers, COX deficiency, and reduced respiratory chain enzyme activities. The variant was present at variable levels in affected and unaffected individuals. Some healthy family members had the variant present at homoplasmy, however heteroplasmy levels were generally higher in more severely affected individuals. The variant was present at 78% to homoplasmy in muscle and was variable among tissues from the same individual. There are no reported de novo occurrences to our knowledge. The variant segregates with manifestations in several families (PMIDs: 7726155, 7726154, 9353617, 10392369, 11437868, 15607216, 17161635, 17891417, 20045353; PP1_moderate). The computational predictor MitoTIP suggests this variant is pathogenic (56.2 percentile) and HmtVAR predicts it to be pathogenic score of 0.9 (PP3). There is one occurrence in the GenBank population database, and the variant is absent in the Helix dataset and gnomAD v.3.1.2. Although there is one occurrence, the frequency is still low (PM2_supporting). Single fiber testing showed higher levels of heteroplasmy in COX-negative fibers (97.4 ± 3.5%; n=16) than in COX-positive fibers (89.6 ± 9.3%; n=15; P<0.004; PMID: 7726154), and cybrid studies, Northern blot analyses, and protein synthesis assays further support the functional impact of this variant (PMIDs: 15048886, 7726155, 12393175; 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, PP1_moderate, PM2_supporting, PP3, PS3_supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 23, 2024