M-14709-T-C
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
Variant has been reported in ClinVar as Likely pathogenic (★★★).
Frequency
Mitomap GenBank:
Absent
Consequence
TRNE
missense
missense
Scores
Mitotip
Uncertain
Clinical Significance
MM+DMDF-/-Encephalomyopathy-/-Dementia+diabetes+ophthalmoplegia
Conservation
PhyloP100: 0.942
Genes affected
TRNE (HGNC:7479): (mitochondrially encoded tRNA glutamic acid)
CYTB (HGNC:7427): (mitochondrially encoded cytochrome b) Predicted to enable metal ion binding activity. Predicted to be involved in several processes, including electron transport coupled proton transport; response to cobalamin; and response to glucagon. Located in mitochondrion. Implicated in ovarian carcinoma and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]
ND6 (HGNC:7462): (mitochondrially encoded NADH dehydrogenase 6) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy; Leigh disease; and spinal muscular atrophy with lower extremity predominante 2B. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
No frequency data in Mitomap. Probably very rare.
PP5
Variant M-14709-T-C is Pathogenic according to our data. Variant chrM-14709-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9617.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TRNE | unassigned_transcript_4817 | c.34A>G | p.Ile12Val | missense_variant | Exon 1 of 1 | |||
| CYTB | unassigned_transcript_4818 | c.-38T>C | upstream_gene_variant | |||||
| ND6 | unassigned_transcript_4816 | c.-36A>G | upstream_gene_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|
Frequencies
GnomAD4 exome Cov.: 0
GnomAD4 exome
Cov.:
0
We have no GnomAD4 genomes data on this position. Probably position not covered by the project.
Mitomap
MM+DMDF-/-Encephalomyopathy-/-Dementia+diabetes+ophthalmoplegia
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:6
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Mitochondrial disease Pathogenic:2
| Likely pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Jan 23, 2023 | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Wellcome Centre for Mitochondrial Research, Newcastle University | May 22, 2017 | - - |
Myopathy, mitochondrial, with diabetes mellitus Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2004 | - - |
MELAS syndrome Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Jul 12, 2019 | The NC_012920.1:m.14709T>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, PP3, PP4, PP6 - |
Inborn mitochondrial myopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Kids Research, The Children's Hospital at Westmead | - | - - |
Diabetes-deafness syndrome maternally transmitted Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2004 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Mitotip
Uncertain
Hmtvar
Pathogenic
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at