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

Last Edited: Dec 13, 2024

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 61124 GenBank sequences with size greater than 15.4kbp and 80432 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 [VUS*]","0.000%
(0.000%)","0 (0)","3""MT-ND1","m.3460G>A",3460,"G-A","A52T","+/+","LHON","Cfrm [P]","0.051%
(0.000%)","31 (0)","229""MT-ND1","m.3481G>A",3481,"G-A","E59K","-/+","MELAS / Progressive Encephalomyopathy","Cfrm [LP]","0.000%
(0.000%)","0 (0)","5""MT-ND1","m.3571del",3571,"C-del","frameshift","nr/nr","Mitochondrial myopathy with reversible cytochrome C oxidase deficiency","Cfrm [LP]","0.000%
(0.000%)","0 (0)","2""MT-ND1","m.3635G>A",3635,"G-A","S110N","+/-","LHON","Cfrm [LP]","0.015%
(0.000%)","9 (0)","20""MT-ND1","m.3688G>A",3688,"G-A","A128T","+/-","Leigh Syndrome","Cfrm [LP]","0.000%
(0.000%)","0 (0)","4""MT-ND1","m.3697G>A",3697,"G-A","G131S","+/+","MELAS / Leigh Syndrome / LDYT / BSN","Cfrm [LP]","0.000%
(0.000%)","0 (0)","20""MT-ND1","m.3700G>A",3700,"G-A","A132T","+/-","LHON","Cfrm [VUS*]","0.005%
(0.000%)","3 (0)","6""MT-ND1","m.3733G>A",3733,"G-A","E143K","+/+","LHON","Cfrm [VUS*]","0.003%
(0.000%)","2 (0)","9""MT-ND1","m.3890G>A",3890,"G-A","R195Q","-/+","Progressive Encephalomyopathy / Leigh Syndrome / Optic Atrophy","Cfrm [LP]","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 [LP]","0.000%
(0.000%)","0 (0)","6""MT-ND1","m.3946G>A",3946,"G-A","E214K","+/+","MELAS","Cfrm [LP]","0.002%
(0.000%)","1 (0)","12""MT-ND1","m.4171C>A",4171,"C-A","L289M","+/+","LHON / Leigh-like phenotype","Cfrm [VUS*]","0.003%
(0.000%)","2 (0)","16""MT-ND2","m.4810G>A",4810,"G-A","W114Term","-/+","EXIT with myalgia & ophthalmoplegia","Cfrm [LP]","0.000%
(0.000%)","0 (0)","1""MT-CO1","m.5920G>A",5920,"G-A","W6Term","-/+","Myoglobinuria / EXIT","Cfrm [LP]","0.000%
(0.000%)","0 (0)","4""MT-CO1","m.6930G>A",6930,"G-A","G343Term","-/+","Multisystem Disorder","Cfrm [LP]","0.000%
(0.000%)","0 (0)","3""MT-CO1","m.7445A>G",7445,"A-G","Term514Term","+/+","SNHL","Cfrm [P]","0.002%
(0.000%)","1 (0)","45""MT-CO2","m.7587T>C",7587,"T-C","M1T","-/+","Mitochondrial Encephalomyopathy","Cfrm [LP]","0.000%
(0.000%)","0 (0)","2""MT-CO2","m.7896G>A",7896,"G-A","W104Term","-/+","Multisystem Disorder","Cfrm [P]","0.000%
(0.000%)","0 (0)","3""MT-CO2","m.8088del",8088,"T-del","frameshift","-/+","Mitochondrial myopathy with complex IV deficiency","Cfrm [LP]","0.000%
(0.000%)","0 (0)","1""MT-ATP8/6","m.8528T>C",8528,"T-C","ATP8:W55R ATP6:M1T","+/+","Infantile cardiomyopathy / hyperammonemia","Cfrm [LP]","0.000%
(0.000%)","0 (0)","9""MT-ATP6","m.8618_8619insT",8618,"T-TT","frameshift","-/+","NARP/cognitive decline+abnormal brain MRI+impaired kidney function","Cfrm [LP]","0.000%
(0.000%)","0 (0)","4""MT-ATP6","m.8851T>C",8851,"T-C","W109R","+/+","BSN / Leigh syndrome","Cfrm [VUS*]","0.007%
(0.000%)","4 (0)","9""MT-ATP6","m.8969G>A",8969,"G-A","S148N","-/+","Mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) / IgG nephropathy","Cfrm [LP]","0.002%
(0.000%)","1 (0)","7""MT-ATP6","m.8993T>C",8993,"T-C","L156P","-/+","NARP / Leigh Disease / MILS / other","Cfrm [P]","0.003%
(0.000%)","2 (0)","51""MT-ATP6","m.8993T>G",8993,"T-G","L156R","+/+","NARP / Leigh Disease / MILS / other","Cfrm [P]","0.010%
(0.000%)","6 (0)","165""MT-ATP6","m.8993TG>CA",8993,"TG-CA","L156P","+/+","Developmental delay & myopathy","Cfrm [LP]","0.000%
(0.000%)","0 (0)","1""MT-ATP6","m.9035T>C",9035,"T-C","L170P","+/+","Ataxia syndromes","Cfrm [LP]","0.000%
(0.000%)","0 (0)","7""MT-ATP6","m.9155A>G",9155,"A-G","Q210R","-/+","MIDD, renal insufficiency","Cfrm [LP]","0.000%
(0.000%)","0 (0)","4""MT-ATP6","m.9176T>C",9176,"T-C","L217P","+/+","FBSN / Leigh Disease / Spinocerebellar Ataxia","Cfrm [P]","0.005%
(0.000%)","3 (0)","37""MT-ATP6","m.9176T>G",9176,"T-G","L217R","+/+","Leigh Disease / Spastic Paraplegia / Spinocerebellar Ataxia","Cfrm [LP]","0.002%
(0.000%)","1 (0)","12""MT-ATP6","m.9185T>C",9185,"T-C","L220P","+/+","Leigh Disease / Ataxia syndromes / NARP-like disease / Episodic weakness and Charcot-Marie-Tooth","Cfrm [P]","0.005%
(0.000%)","3 (0)","37""MT-ATP6","m.9191T>C",9191,"T-C","L222P","-/+","Leigh Disease","Cfrm [LP]","0.000%
(0.000%)","0 (0)","5""MT-ATP6","m.9205_9206del",9205,"TA-del","Term-M","+/-","Encephalopathy / Seizures / Lacticacidemia","Cfrm [LP]","0.000%
(0.000%)","0 (0)","10""MT-CO3","m.9480_9494del",9480,"TTTTTCTTCGCAGGA-del","FFFAG-del","-/+","Myoglobinuria","Cfrm [LP], alt locus at 9487del15","0.000%
(0.000%)","0 (0)","5""MT-CO3","m.9537_9538insC",9537,"C-CC","frameshift","+/-","Leigh Disease","Cfrm [LP]","0.000%
(0.000%)","0 (0)","2""MT-CO3","m.9952G>A",9952,"G-A","W249Term","-/+","Mitochondrial Encephalopathy","Cfrm [LP]","0.000%
(0.000%)","0 (0)","1""MT-ND3","m.10158T>C",10158,"T-C","S34P","+/+","Leigh Disease / MELAS","Cfrm [P]","0.000%
(0.000%)","0 (0)","35""MT-ND3","m.10191T>C",10191,"T-C","S45P","-/+","Leigh Disease / ESOC","Cfrm [P]","0.000%
(0.000%)","0 (0)","34""MT-ND3","m.10197G>A",10197,"G-A","A47T","+/+","Leigh Disease / Dystonia / Stroke / LDYT","Cfrm [P]","0.005%
(0.000%)","3 (0)","26""MT-ND3","m.10254G>A",10254,"G-A","D66N","-/+","Leigh Disease","Cfrm [LP]","0.000%
(0.000%)","0 (0)","1""MT-ND4L","m.10663T>C",10663,"T-C","V65A","+/-","LHON","Cfrm [LP]","0.003%
(0.000%)","2 (0)","16""MT-ND4","m.11777C>A",11777,"C-A","R340S","-/+","Leigh Disease","Cfrm [LP]","0.000%
(0.000%)","0 (0)","13""MT-ND4","m.11778G>A",11778,"G-A","R340H","+/+","LHON / Progressive Dystonia","Cfrm [P]","0.311%
(0.000%)","190 (0)","425""MT-ND5","m.12425del",12425,"A-del","frameshift","-/+","Mitochondrial myopathy & renal failure","Cfrm [LP]","0.003%
(0.000%)","2 (0)","1""MT-ND5","m.12706T>C",12706,"T-C","F124L","-/+","Leigh Disease","Cfrm [LP]","0.000%
(0.000%)","0 (0)","13""MT-ND5","m.13042G>A",13042,"G-A","A236T","-/+","Optic neuropathy/ retinopathy/ LD","Cfrm [LP]","0.003%
(0.000%)","2 (0)","9""MT-ND5","m.13046T>C",13046,"T-C","M237T","-/+","LHON/MELAS overlap syndrome","Cfrm [LP]","0.000%
(0.000%)","0 (0)","5""MT-ND5","m.13051G>A",13051,"G-A","G239S","+/-","LHON","Cfrm [VUS*]","0.000%
(0.000%)","0 (0)","5""MT-ND5","m.13094T>C",13094,"T-C","V253A","+/+","Ataxia+PEO / MELAS, LD, LHON, myoclonus, fatigue","Cfrm [P]","0.002%
(0.000%)","1 (0)","13""MT-ND5","m.13379A>G",13379,"A-G","H348R","+/-","LHON","Cfrm [VUS*]","0.000%
(0.000%)","0 (0)","2""MT-ND5","m.13513G>A",13513,"G-A","D393N","-/+","Leigh Disease / MELAS / LHON-MELAS Overlap Syndrome / negative association w Carotid Atherosclerosis","Cfrm [P]","0.002%
(0.000%)","1 (0)","62""MT-ND5","m.13514A>G",13514,"A-G","D393G","-/+","Leigh Disease / MELAS / Ca2+ downregulation","Cfrm [LP]","0.000%
(0.000%)","0 (0)","17""MT-ND6","m.14453G>A",14453,"G-A","A74V","-/+","MELAS / Leigh Disease","Cfrm [LP]","0.000%
(0.000%)","0 (0)","10""MT-ND6","m.14459G>A",14459,"G-A","A72V","+/+","LDYT / Leigh Disease / dystonia / carotid atherosclerosis risk","Cfrm [P]","0.005%
(0.000%)","3 (0)","47""MT-ND6","m.14482C>A",14482,"C-A","M64I","+/+","LHON","Cfrm [LP]","0.003%
(0.000%)","2 (0)","13""MT-ND6","m.14482C>G",14482,"C-G","M64I","+/+","LHON","Cfrm [LP]","0.000%
(0.000%)","0 (0)","8""MT-ND6","m.14484T>C",14484,"T-C","M64V","+/+","LHON","Cfrm [P]","0.113%
(0.000%)","69 (0)","270""MT-ND6","m.14487T>C",14487,"T-C","M63V","-/+","Dystonia / Leigh Disease / ataxia / ptosis / epilepsy","Cfrm [P]","0.000%
(0.000%)","0 (0)","40""MT-ND6","m.14495A>G",14495,"A-G","L60S","-/+","LHON","Cfrm [LP]","0.003%
(0.000%)","2 (0)","11""MT-ND6","m.14512_14513del",14512,"TA-del","frameshift","-/+","EXIT w mild myopathy & hyperCKaemia","Cfrm [LP]","0.000%
(0.000%)","0 (0)","1""MT-ND6","m.14568C>T",14568,"C-T","G36S","+/-","LHON","Cfrm [LP]","0.010%
(0.000%)","6 (0)","10""MT-ND6","m.14597A>G",14597,"A-G","I26T","-/+","LHON / LS","Cfrm [LP]","0.000%
(0.000%)","0 (0)","2""MT-CYB","m.14787_14790del",14787,"TTAA-del","frameshift","-/+","PD / MELAS","Cfrm [LP]","0.000%
(0.000%)","0 (0)","1""MT-CYB","m.14849T>C",14849,"T-C","S35P","-/+","EXIT / Septo-Optic Dysplasia","Cfrm [VUS*]","0.000%
(0.000%)","0 (0)","3""MT-CYB","m.15150G>A",15150,"G-A","W135Term","-/+","EXIT","Cfrm [LP]","0.000%
(0.000%)","0 (0)","1""MT-CYB","m.15242G>A",15242,"G-A","G166Term","-/+","Mitochondrial Encephalomyopathy","Cfrm [LP]","0.000%
(0.000%)","0 (0)","2""MT-CYB","m.15579A>G",15579,"A-G","Y278C","-/+","Multisystem Disorder, EXIT","Cfrm [VUS*]","0.000%
(0.000%)","0 (0)","5"
♣ ClinGen Pathogenicity Rating NEW

As a member of the mtDNA Variant Curation Expert Panel for ClinGen, we are adding the calculated ClinGen pathogenicity ratings after VCEP curation. This will be shown in brackets in the Status column, for example, "Reported [VUS]", "Cfrm [LP]", etc., as the ClinGen scoring becomes available. The ClinGen VCEP may update this scoring from time to time if additional supporting evidence is published. The following abbreviations are used: B, Benign; LB, Likely Benign; VUS, Variant of Uncertain Significance; LP, Likely Pathogenic; P, Pathogenic. The criteria used in the ClinGen curations may be found in McCormick et al, 2020, DOI: 10.1002/humu.24107. Note that the ClinGen scoring gives fewer points than Mitomap does for many types of evidence, e.g., cybrid & other functional studies, in-silico tools, absence in large databases, heteroplasmy, de-novo requirements, and case numbers.


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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