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MITOMAP: Mitochondrial DNA Base Substitution Diseases:
Coding and Control Region Point Mutations with Cfrm Status

Last Edited: Jun 21, 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.

Locus Disease Allele Nucleotide
Position 		Nucleotide
Change 		Amino Acid Change Homo-plasmy Hetero-plasmy Status References
3376 MT-ND1 LHON MELAS overlap G3376A G-A E-K + + Cfrm 0 3
3460 MT-ND1 LHON G3460A G-A A-T + + Cfrm 23 152
3635 MT-ND1 LHON G3635A G-A S-N + - Cfrm 9 9
3697 MT-ND1 MELAS / LS / LDYT / BSN G3697A G-A G-S + + Cfrm 0 12
3700 MT-ND1 LHON G3700A G-A A-T + - Cfrm 3 2
3733 MT-ND1 LHON G3733A G-A E-K + + Cfrm 2 6
3890 MT-ND1 Progressive Encephalomyopathy / LS / Optic Atrophy G3890A G-A R-Q - + Cfrm 1 5
3902 MT-ND1 EXIT+myalgia / severe LA+cardiac / 3-MGA aciduria 3902_3908invACCTTGC inversion DLA-GKV - + Cfrm 0 3
4171 MT-ND1 LHON / Leigh-like phenotype C4171A C-A L-M + + Cfrm 2 8
7445 MT-CO1 SNHL A7445G A-G Ter-Ter + + Cfrm 1 31
8528 MT-ATP8/6 Infantile cardiomyopathy T8528C T-C ATP8:W-R ATP6:M-T + + Cfrm 0 3
8851 MT-ATP6 BSN / Leigh syndrome T8851C T-C W-R + + Cfrm 3 5
8969 MT-ATP6 Mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) / IgG nephropathy G8969A G-A S-N - + Cfrm 0 3
8993 MT-ATP6 NARP / Leigh Disease / MILS / other T8993C T-C L-P - + Cfrm 2 33
8993 MT-ATP6 NARP / Leigh Disease / MILS / other T8993G T-G L-R + + Cfrm 6 107
9035 MT-ATP6 Ataxia syndromes T9035C T-C L-P + + Cfrm 0 2
9176 MT-ATP6 FBSN / Leigh Disease T9176C T-C L-P + + Cfrm 3 19
9176 MT-ATP6 Leigh Disease / Spastic Paraplegia T9176G T-G L-R + + Cfrm 1 8
9185 MT-ATP6 Leigh Disease / Ataxia syndromes / NARP-like disease T9185C T-C L-P + + Cfrm 3 13
9205 MT-ATP6 Encephalopathy / Seizures / Lacticacidemia 9205_9206delTA TA-del Ter-M + - Cfrm 0 7
10158 MT-ND3 Leigh Disease / MELAS T10158C T-C S-P + + Cfrm 0 24
10191 MT-ND3 Leigh Disease / Leigh-like Disease / ESOC T10191C T-C S-P - + Cfrm 0 21
10197 MT-ND3 Leigh Disease / Dystonia / Stroke / LDYT G10197A G-A A-T + + Cfrm 4 11
10663 MT-ND4L LHON T10663C T-C V-A + - Cfrm 1 9
11777 MT-ND4 Leigh Disease C11777A C-A R-S - + Cfrm 0 12
11778 MT-ND4 LHON / Progressive Dystonia G11778A G-A R-H + + Cfrm 120 286
12706 MT-ND5 Leigh Disease T12706C T-C F-L - + Cfrm 0 10
13042 MT-ND5 Optic neuropathy/ retinopathy/ LD G13042A G-A A-T - + Cfrm 1 6
13051 MT-ND5 LHON G13051A G-A G-S + - Cfrm 0 2
13094 MT-ND5 Ataxia+PEO / MELAS, LD, LHON, myoclonus, fatigue T13094C T-C V-A + + Cfrm 1 6
13513 MT-ND5 Leigh Disease / MELAS / LHON-MELAS Overlap Syndrome / negative association w Carotid Atherosclerosis G13513A G-A D-N - + Cfrm 1 37
13514 MT-ND5 Leigh Disease / MELAS A13514G A-G D-G - + Cfrm 0 13
14459 MT-ND6 LDYT / Leigh Disease / dystonia / carotid atherosclerosis risk G14459A G-A A-V + + Cfrm 3 33
14482 MT-ND6 LHON C14482A C-A M-I + + Cfrm 2 11
14482 MT-ND6 LHON C14482G C-G M-I + + Cfrm 0 5
14484 MT-ND6 LHON T14484C T-C M-V + + Cfrm 56 162
14487 MT-ND6 Dystonia / Leigh Disease / ataxia / ptosis / epilepsy T14487C T-C M-V - + Cfrm 0 22
14495 MT-ND6 LHON A14495G A-G L-S - + Cfrm 2 7
14568 MT-ND6 LHON C14568T C-T G-S + - Cfrm 6 9
14849 MT-CYB EXIT / Septo-Optic Dysplasia T14849C T-C S-P - + Cfrm 0 3
14864 MT-CYB MELAS T14864C T-C C-R - + Cfrm 2 1
15579 MT-CYB Multisystem Disorder, EXIT A15579G A-G Y-C - + Cfrm 0 4


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.
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