MITOMAP: Mitochondrial DNA Base Substitution Diseases:
rRNA/tRNA Mutations with Crfm Status

Last Edited: May 17, 2019

For Mitomap to assign a status of "Cfrm" to a possibly pathogenic variant, we look for confirming reports which address the criteria outlined in Mitchell et al 2006, Yarham et al 2011, Wong 2007, and Gonzalez-Viogue et al 2014. These criteria include the following: (1) independent reports of two or more unrelated families with evidence of similar disease; (2) evolutionary conservation of the nucleotide (for RNA variants) or amino acid (for coding variants); (3) presence of heteroplasmy; (4) correlation of variant with phenotype / segregation of the mutation with the disease within a family; (5) biochemical defects in complexes I, III, or IV in affected or multiple tissues; (6) functional studies showing differential defects segregating with the mutation (cybrid or single fiber studies); (7) histochemical evidence of a mitochondrial disorder; and (8) for fatal or severe phenotypes, the absence or extremely rare occurrence of the variant in large mtDNA sequence databases. For the exact scoring systems of Yarham et al 2011 and Mitchell et al 2006, please see the respective papers above. A new scoring system is under development for these criteria, and will be linked here once published.

When investigating a novel variant or a variant of uncertain significance (VUS) in cases of suspected mitochondrial disease, further studies which address any or all of the above criteria are strongly recommended. We encourage publication of such case reports as they are extremely helpful to the mitochondrial research community.

The GB frequency data in Mitomap is derived from 48882 GenBank sequences with size greater than 15.4kbp and 71421 Control Region sequences with size 0.4-1.6kbp. These sequences have been pre-loaded into Mitomaster and represent almost all haplogroups known to date. We will be updating and refining this set of sequences on a regular basis. As a caveat, please note that GenBank sequences may not be of equal quality (Yao, et al, 2009), that some of these sequences are from individuals with past, current or future disease, and that this portion of our data set has not been hand-curated by Mitomap.

For more details about the current GenBank sequence set, please see GB Frequency Info.

For information about the predictive MitoTIP scoring for tRNA variants, see MitoTIP Info.

Locus Disease Allele RNA Homo-plasmy Hetero-Plasmy Status References
583 MT-TF MELAS / MM & EXIT G583A tRNA Phe - + Cfrm Pathogenic 0 3
616 MT-TF Maternally inherited epilepsy / kidney disease T616C tRNA Phe + + Cfrm Pathogenic 1 2
1494 MT-RNR1 DEAF C1494T 12S rRNA + - Cfrm N/A 4 24
1555 MT-RNR1 DEAF; autism spectrum intellectual disability; possibly antiatherosclerotic A1555G 12S rRNA + - Cfrm N/A 71 132
1606 MT-TV AMDF G1606A tRNA Val - + Cfrm Pathogenic 0 4
1630 MT-TV MNGIE-like disease / MELAS A1630G tRNA Val - + Cfrm Pathogenic 0 3
1644 MT-TV LS / HCM / MELAS G1644A tRNA Val - + Cfrm Pathogenic 0 4
3243 MT-TL1 MELAS / LS / DMDF / MIDD / SNHL / CPEO / MM / FSGS / ASD / Cardiac+multi-organ dysfunction A3243G tRNA Leu (UUR) - + Cfrm Pathogenic 9 374
3243 MT-TL1 MM / MELAS / SNHL / CPEO A3243T tRNA Leu (UUR) - + Cfrm Pathogenic 0 6
3256 MT-TL1 MELAS; possible atherosclerosis risk C3256T tRNA Leu (UUR) - + Cfrm Pathogenic 0 18
3258 MT-TL1 MELAS / Myopathy T3258C tRNA Leu (UUR) - + Cfrm Pathogenic 1 5
3260 MT-TL1 MMC / MELAS A3260G tRNA Leu (UUR) - + Cfrm Pathogenic 0 10
3271 MT-TL1 PEM / retinal dystrophy in MELAS T3271del tRNA Leu (UUR) - + Cfrm Pathogenic 0 3
3271 MT-TL1 MELAS / DM T3271C tRNA Leu (UUR) - + Cfrm Pathogenic 0 25
3280 MT-TL1 Myopathy A3280G tRNA Leu (UUR) - + Cfrm Pathogenic 0 6
3291 MT-TL1 MELAS / Myopathy / Deafness+Cognitive Impairment T3291C tRNA Leu (UUR) - + Cfrm Pathogenic 0 14
3302 MT-TL1 MM A3302G tRNA Leu (UUR) - + Cfrm Pathogenic 0 10
3303 MT-TL1 MMC C3303T tRNA Leu (UUR) + + Cfrm Pathogenic 0 12
4298 MT-TI CPEO / MS G4298A tRNA Ile - + Cfrm Pathogenic 0 9
4300 MT-TI MICM A4300G tRNA Ile + + Cfrm Pathogenic 0 9
4308 MT-TI CPEO G4308A tRNA Ile - + Cfrm Pathogenic 0 2
4332 MT-TQ Encephalopathy / MELAS G4332A tRNA Gln - + Cfrm Pathogenic 0 4
4450 MT-TM Myopathy / MELAS G4450A tRNA Met - + Cfrm Pathogenic 0 3
5521 MT-TW Mitochondrial myopathy G5521A tRNA Trp - + Cfrm Pathogenic 0 4
5537 MT-TW Leigh Syndrome A5537insT tRNA Trp - + Cfrm - 0 5
5650 MT-TA Myopathy G5650A tRNA Ala - + Cfrm Pathogenic 1 6
5690 MT-TN CPEO+ptosis+proximal myopathy A5690G tRNA Asn - + Cfrm Pathogenic 0 2
5703 MT-TN CPEO / MM G5703A tRNA Asn - + Cfrm Pathogenic 0 5
7445 MT-TS1 precursor SNHL A7445G tRNA Ser (UCN) precursor + + Cfrm - 1 32
7471 MT-TS1 PEM / AMDF / Motor neuron disease-like C7471insC tRNA Ser (UCN) + + Cfrm - 7 27
7497 MT-TS1 MM / EXIT G7497A tRNA Ser (UCN) + + Cfrm Pathogenic 1 6
7510 MT-TS1 SNHL T7510C tRNA Ser (UCN) - + Cfrm Pathogenic 1 13
7511 MT-TS1 SNHL T7511C tRNA Ser (UCN) + + Cfrm Pathogenic 1 18
8344 MT-TK MERRF; Other - LD / Depressive mood disorder / leukoencephalopathy / HiCM A8344G tRNA Lys - + Cfrm Pathogenic 4 119
8356 MT-TK MERRF T8356C tRNA Lys - + Cfrm Pathogenic 0 10
8363 MT-TK MICM+DEAF / MERRF / Autism / LS / Ataxia+Lipomas G8363A tRNA Lys - + Cfrm Pathogenic 0 20
10010 MT-TG PEM T10010C tRNA Gly - + Cfrm Pathogenic 0 9
12147 MT-TH MERRF-MELAS / Encephalopathy G12147A tRNA His - + Cfrm Pathogenic 0 5
12258 MT-TS2 DMDF / RP+SNHL C12258A tRNA Ser (AGY) - + Cfrm Pathogenic 1 6
12276 MT-TL2 CPEO G12276A tRNA Leu (CUN) - + Cfrm Pathogenic 1 3
12294 MT-TL2 CPEO / EXIT+Ophthalmoplegia G12294A tRNA Leu (CUN) - + Cfrm Pathogenic 0 2
12315 MT-TL2 CPEO / KSS / possible carotid atherosclerosis risk, trend toward myocardial infarction risk G12315A tRNA Leu (CUN) - + Cfrm Pathogenic 0 13
12316 MT-TL2 CPEO G12316A tRNA Leu (CUN) - + Cfrm Pathogenic 0 2
14674 MT-TE Reversible COX deficiency myopathy T14674C tRNA Glu + - Cfrm Pathogenic 7 5
14709 MT-TE MM+DMDF / Encephalomyopathy / Dementia+diabetes+ophthalmoplegia T14709C tRNA Glu + + Cfrm Pathogenic 1 20
14710 MT-TE Encephalomyopathy + Retinopathy G14710A tRNA Glu - + Cfrm Pathogenic 0 5


Notes:

LHON Leber Hereditary Optic Neuropathy MM Mitochondrial Myopathy
AD Alzeimer's Disease LIMM Lethal Infantile Mitochondrial Myopathy
ADPD Alzeimer's Disease and Parkinsons's Disease MMC Maternal Myopathy and Cardiomyopathy
NARP Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa; alternate phenotype at this locus is reported as Leigh Disease FICP Fatal Infantile Cardiomyopathy Plus, a MELAS-associated cardiomyopathy
MELAS Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes LDYT Leber's hereditary optic neuropathy and DYsTonia
MERRF Myoclonic Epilepsy and Ragged Red Muscle Fibers MHCM Maternally inherited Hypertrophic CardioMyopathy
CPEO Chronic Progressive External Ophthalmoplegia KSS Kearns Sayre Syndrome
DM Diabetes Mellitus DMDF Diabetes Mellitus + DeaFness
CIPO Chronic Intestinal Pseudoobstruction with myopathy and Ophthalmoplegia DEAF Maternally inherited DEAFness or aminoglycoside-induced DEAFness
PEM Progressive encephalopathy SNHL SensoriNeural Hearing Loss

  • Homoplasmy = pure mutant mtDNAs.
  • Heteroplasmy = mixture of mutant and normal mtDNAs.
  • nd = not determined.
  • "Reported" status indicates that one or more publications have considered the mutation as possibly pathologic. This is not an assignment of pathogenicity by MITOMAP but is a report of literature. Previously, mutations with this status were termed "Prov" (provisional).
  • "Cfrm"(confirmed) status indicates that at least two or more independent laboratories have published reports on the pathogenicity of a specific mutation. These mutations are generally accepted by the mitochondrial research community as being pathogenic. A status of "Cfrm" is not an assignment of pathogenicity by MITOMAP but is a report of published literature. Researchers and clinicians are cautioned that additional data and/or analysis may still be necessary to confirm the pathological significance of some of these mutations.
  • "P.M." (point mutation/polymorphism) status indicates that some published reports have determined the mutation to be a non-pathogenic polymorphism.

This topic: MITOMAP > WebHome > MutationsRNACfrmIE
Topic revision: 12 Jun 2019, ShipingZhang
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