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

Last Edited: Jun 03, 2022

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 56895 GenBank sequences with size greater than 15.4kbp and 78504 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
MT-ND1 m.3376G>A 3376 G-A E24K +/+ LHON MELAS overlap Cfrm 0.000%
(0.000%) 		0 (0) 4
MT-ND1 m.3460G>A 3460 G-A A52T +/+ LHON Cfrm 0.054%
(0.000%) 		31 (0) 206
MT-ND1 m.3635G>A 3635 G-A S110N +/- LHON Cfrm 0.016%
(0.000%) 		9 (0) 16
MT-ND1 m.3890G>A 3890 G-A R195Q -/+ Progressive Encephalomyopathy / Leigh Syndrome / Optic Atrophy Cfrm 0.002%
(0.000%) 		1 (0) 8
MT-ND1 m.3902_3908inv 3902 ACCTTGC-GCAAGGT DLA-GKV -/+ EXIT+myalgia / severe LA+cardiac / 3-MGA aciduria / nephropathy+deafness+diabetes Cfrm 0.000%
(0.000%) 		0 (0) 6
MT-ND1 m.4171C>A 4171 C-A L289M +/+ LHON / Leigh-like phenotype Cfrm 0.004%
(0.000%) 		2 (0) 17
MT-CO1 m.7445A>G 7445 A-G term514term +/+ SNHL Cfrm 0.002%
(0.000%) 		1 (0) 34
MT-ATP8/6 m.8528T>C 8528 T-C ATP8:W55R ATP6:M1T +/+ Infantile cardiomyopathy / hyperammonemia Cfrm 0.000%
(0.000%) 		0 (0) 8
MT-ATP6 m.8969G>A 8969 G-A S148N -/+ Mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) / IgG nephropathy Cfrm 0.002%
(0.000%) 		1 (0) 5
MT-ATP6 m.9035T>C 9035 T-C L170P +/+ Ataxia syndromes Cfrm 0.000%
(0.000%) 		0 (0) 5
MT-ATP6 m.9155A>G 9155 A-G Q210R -/+ MIDD, renal insufficiency Cfrm 0.000%
(0.000%) 		0 (0) 4
MT-ATP6 m.9176T>G 9176 T-G L217R +/+ Leigh Disease / Spastic Paraplegia / Spinocerebellar Ataxia Cfrm 0.002%
(0.000%) 		1 (0) 11
MT-ATP6 m.9185T>C 9185 T-C L220P +/+ Leigh Disease / Ataxia syndromes / NARP-like disease / Episodic weakness and Charcot-Marie-Tooth Cfrm 0.005%
(0.000%) 		3 (0) 34
MT-ATP6 m.9205_9206del 9205 TA-del Ter-M +/- Encephalopathy / Seizures / Lacticacidemia Cfrm 0.000%
(0.000%) 		0 (0) 9
MT-ND3 m.10191T>C 10191 T-C S45P -/+ Leigh Disease / Leigh-like Disease / ESOC Cfrm 0.000%
(0.000%) 		0 (0) 27
MT-ND3 m.10197G>A 10197 G-A A47T +/+ Leigh Disease / Dystonia / Stroke / LDYT Cfrm 0.007%
(0.000%) 		4 (0) 23
MT-ND4L m.10663T>C 10663 T-C V65A +/- LHON Cfrm 0.004%
(0.000%) 		2 (0) 16
MT-ND4 m.11777C>A 11777 C-A R340S -/+ Leigh Disease Cfrm 0.000%
(0.000%) 		0 (0) 12
MT-ND4 m.11778G>A 11778 G-A R340H +/+ LHON / Progressive Dystonia Cfrm 0.329%
(0.000%) 		187 (0) 395
MT-ND5 m.12706T>C 12706 T-C F124L -/+ Leigh Disease Cfrm 0.000%
(0.000%) 		0 (0) 13
MT-ND5 m.13042G>A 13042 G-A A236T -/+ Optic neuropathy/ retinopathy/ LD Cfrm 0.002%
(0.000%) 		1 (0) 8
MT-ND5 m.13051G>A 13051 G-A G239S +/- LHON Cfrm 0.000%
(0.000%) 		0 (0) 4
MT-ND5 m.13094T>C 13094 T-C V253A +/+ Ataxia+PEO / MELAS, LD, LHON, myoclonus, fatigue Cfrm 0.002%
(0.000%) 		1 (0) 11
MT-ND5 m.13379A>G 13379 A-G H348R +/- LHON Cfrm 0.000%
(0.000%) 		0 (0) 2
MT-ND5 m.13514A>G 13514 A-G D393G -/+ Leigh Disease / MELAS / Ca2+ downregulation Cfrm 0.000%
(0.000%) 		0 (0) 16
MT-ND6 m.14453G>A 14453 G-A A74V -/+ MELAS / Leigh Disease Cfrm 0.000%
(0.000%) 		0 (0) 10
MT-ND6 m.14482C>A 14482 C-A M64I +/+ LHON Cfrm 0.004%
(0.000%) 		2 (0) 14
MT-ND6 m.14482C>G 14482 C-G M64I +/+ LHON Cfrm 0.000%
(0.000%) 		0 (0) 8
MT-ND6 m.14484T>C 14484 T-C M64V +/+ LHON Cfrm 0.112%
(0.000%) 		64 (0) 217
MT-ND6 m.14487T>C 14487 T-C M63V -/+ Dystonia / Leigh Disease / ataxia / ptosis / epilepsy Cfrm 0.000%
(0.000%) 		0 (0) 34
MT-ND6 m.14495A>G 14495 A-G L60S -/+ LHON Cfrm 0.004%
(0.000%) 		2 (0) 12
MT-ND6 m.14568C>T 14568 C-T G36S +/- LHON Cfrm 0.011%
(0.000%) 		6 (0) 11
MT-CYB m.14849T>C 14849 T-C S35P -/+ EXIT / Septo-Optic Dysplasia Cfrm 0.000%
(0.000%) 		0 (0) 3
MT-CYB m.15579A>G 15579 A-G Y278C -/+ Multisystem Disorder, EXIT Cfrm 0.000%
(0.000%) 		0 (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.
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Topic revision: r386 - 10 Jun 2022, ShipingZhang
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