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

Last Edited: Nov 30, 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 56910 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.

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 [VUS*]	Pathogenic	0.000% (0.000%)	0 (0)	5
616	MT-TF	Maternally inherited epilepsy / mito tubulointerstitial kidney disease (MITKD) / Gitelman-like syndrome	T616C	tRNA Phe	+	+	Cfrm [LP]	Pathogenic	0.002% (0.000%)	1 (0)	6
1494	MT-RNR1	DEAF	C1494T	12S rRNA	+	-	Cfrm [LP]	N/A	0.007% (0.000%)	4 (0)	31
1555	MT-RNR1	DEAF; autism spectrum intellectual disability; possibly antiatherosclerotic	A1555G	12S rRNA	+	+	Cfrm	N/A	0.141% (0.000%)	80 (0)	152
1606	MT-TV	AMDF	G1606A	tRNA Val	-	+	Cfrm [VUS*]	Pathogenic	0.000% (0.000%)	0 (0)	5
1630	MT-TV	MNGIE-like disease / MELAS	A1630G	tRNA Val	-	+	Cfrm	Pathogenic	0.000% (0.000%)	0 (0)	9
1644	MT-TV	Leigh Syndrome / HCM / MELAS	G1644A	tRNA Val	-	+	Cfrm [LP]	Pathogenic	0.000% (0.000%)	0 (0)	6
3243	MT-TL1	MELAS / Leigh Syndrome / DMDF / MIDD / SNHL / CPEO / MM / FSGS / ASD / Cardiac+multi-organ dysfunction	A3243G	tRNA Leu (UUR)	-	+	Cfrm [P]	Pathogenic	0.018% (0.000%)	10 (0)	445
3243	MT-TL1	MM / MELAS / SNHL / CPEO	A3243T	tRNA Leu (UUR)	-	+	Cfrm [LP]	Pathogenic	0.000% (0.000%)	0 (0)	12
3256	MT-TL1	MELAS; possible atherosclerosis risk	C3256T	tRNA Leu (UUR)	-	+	Cfrm [P]	Pathogenic	0.000% (0.000%)	0 (0)	20
3258	MT-TL1	MELAS / Myopathy	T3258C	tRNA Leu (UUR)	-	+	Cfrm [LP]	Pathogenic	0.002% (0.000%)	1 (0)	5
3260	MT-TL1	MMC / MELAS	A3260G	tRNA Leu (UUR)	-	+	Cfrm	Pathogenic	0.000% (0.000%)	0 (0)	13
3271	MT-TL1	MELAS / DM	T3271C	tRNA Leu (UUR)	-	+	Cfrm	Pathogenic	0.000% (0.000%)	0 (0)	28
3273	MT-TL1	PEM / retinal dystrophy in MELAS	T3273del	tRNA Leu (UUR)	-	+	Cfrm	Pathogenic	0.000% (0.000%)	0 (0)	2
3280	MT-TL1	Myopathy	A3280G	tRNA Leu (UUR)	-	+	Cfrm [VUS*]	Pathogenic	0.000% (0.000%)	0 (0)	6
3291	MT-TL1	MELAS / Myopathy / Deafness+Cognitive Impairment	T3291C	tRNA Leu (UUR)	-	+	Cfrm [LP]	Pathogenic	0.000% (0.000%)	0 (0)	17
3302	MT-TL1	MM	A3302G	tRNA Leu (UUR)	-	+	Cfrm [P]	Pathogenic	0.000% (0.000%)	0 (0)	12
3303	MT-TL1	MMC	C3303T	tRNA Leu (UUR)	+	+	Cfrm	Pathogenic	0.000% (0.000%)	0 (0)	21
4298	MT-TI	CPEO / MS	G4298A	tRNA Ile	-	+	Cfrm	Pathogenic	0.000% (0.000%)	0 (0)	11
4300	MT-TI	MICM	A4300G	tRNA Ile	+	+	Cfrm [VUS*]	Pathogenic	0.000% (0.000%)	0 (0)	10
4308	MT-TI	CPEO	G4308A	tRNA Ile	-	+	Cfrm [VUS*]	Pathogenic	0.000% (0.000%)	0 (0)	3
4332	MT-TQ	Encephalopathy / MELAS	G4332A	tRNA Gln	-	+	Cfrm	Pathogenic	0.000% (0.000%)	0 (0)	4
4450	MT-TM	Myopathy / MELAS / Leigh Syndrome	G4450A	tRNA Met	-	+	Cfrm	Pathogenic	0.000% (0.000%)	0 (0)	4
5521	MT-TW	Mitochondrial myopathy	G5521A	tRNA Trp	-	+	Cfrm [LP]	Pathogenic	0.000% (0.000%)	0 (0)	7
5537	MT-TW	Leigh Syndrome	A5537insT	tRNA Trp	-	+	Cfrm	-	0.000% (0.000%)	0 (0)	6
5650	MT-TA	Myopathy	G5650A	tRNA Ala	-	+	Cfrm [LP]	Pathogenic	0.002% (0.000%)	1 (0)	10
5690	MT-TN	CPEO+ptosis+proximal myopathy	A5690G	tRNA Asn	-	+	Cfrm	Pathogenic	0.000% (0.000%)	0 (0)	3
5703	MT-TN	CPEO / MM	G5703A	tRNA Asn	-	+	Cfrm	Pathogenic	0.002% (0.000%)	1 (0)	9
5728	MT-TN	Multiorgan failure / myopathy	T5728C	tRNA Asn	-	+	Cfrm	Pathogenic	0.002% (0.000%)	1 (0)	4
7445	MT-TS1 precursor	SNHL	A7445G	tRNA Ser (UCN) precursor	+	+	Cfrm [P]	-	0.002% (0.000%)	1 (0)	43
7471	MT-TS1	PEM / AMDF / Motor neuron disease-like	C7471CC	tRNA Ser (UCN)	+	+	Cfrm [P]	-	0.012% (0.000%)	7 (0)	32
7497	MT-TS1	MM / EXIT	G7497A	tRNA Ser (UCN)	+	+	Cfrm	Pathogenic	0.002% (0.000%)	1 (0)	8
7510	MT-TS1	SNHL	T7510C	tRNA Ser (UCN)	-	+	Cfrm	Pathogenic	0.002% (0.000%)	1 (0)	14
7511	MT-TS1	SNHL/Deafness	T7511C	tRNA Ser (UCN)	+	+	Cfrm	Pathogenic	0.004% (0.000%)	2 (0)	24
8306	MT-TK	Severe adult-onset multisymptom myopathy / Myoclonic epilepsy	T8306C	tRNA Lys	-	+	Cfrm [VUS*]	Pathogenic	0.000% (0.000%)	0 (0)	3
8313	MT-TK	MNGIE / Progressive mito cytopathy	G8313A	tRNA Lys	-	+	Cfrm	Pathogenic	0.002% (0.000%)	1 (0)	7
8340	MT-TK	Myopathy / Exercise Intolerance / Eye disease+SNHL	G8340A	tRNA Lys	-	+	Cfrm	Pathogenic	0.000% (0.000%)	0 (0)	8
8344	MT-TK	MERRF; Other - LD / Depressive mood disorder / leukoencephalopathy / HiCM	A8344G	tRNA Lys	-	+	Cfrm [P]	Pathogenic	0.007% (0.000%)	4 (0)	137
8356	MT-TK	MERRF	T8356C	tRNA Lys	-	+	Cfrm	Pathogenic	0.000% (0.000%)	0 (0)	12
8363	MT-TK	MICM+DEAF / MERRF / Autism / Leigh Syndrome / Ataxia	G8363A	tRNA Lys	-	+	Cfrm	Pathogenic	0.000% (0.000%)	0 (0)	23
10010	MT-TG	PEM	T10010C	tRNA Gly	-	+	Cfrm [VUS*]	Pathogenic	0.000% (0.000%)	0 (0)	11
12147	MT-TH	MERRF-MELAS / Encephalopathy	G12147A	tRNA His	-	+	Cfrm	Pathogenic	0.000% (0.000%)	0 (0)	6
12201	MT-TH	Maternally inherited non-syndromic deafness	T12201C	tRNA His	-	+	Cfrm	Pathogenic	0.002% (0.000%)	1 (0)	8
12258	MT-TS2	DMDF / RP+SNHL	C12258A	tRNA Ser (AGY)	-	+	Cfrm	Pathogenic	0.002% (0.000%)	1 (0)	9
12276	MT-TL2	CPEO	G12276A	tRNA Leu (CUN)	-	+	Cfrm	Pathogenic	0.002% (0.000%)	1 (0)	4
12294	MT-TL2	CPEO / EXIT+Ophthalmoplegia	G12294A	tRNA Leu (CUN)	-	+	Cfrm [VUS*]	Pathogenic	0.000% (0.000%)	0 (0)	2
12315	MT-TL2	CPEO / KSS / possible carotid atherosclerosis risk, trend toward myocardial infarction risk	G12315A	tRNA Leu (CUN)	-	+	Cfrm	Pathogenic	0.000% (0.000%)	0 (0)	15
12316	MT-TL2	CPEO	G12316A	tRNA Leu (CUN)	-	+	Cfrm	Pathogenic	0.000% (0.000%)	0 (0)	2
14674	MT-TE	Reversible COX deficiency myopathy	T14674C	tRNA Glu	+	-	Cfrm	Pathogenic	0.018% (0.000%)	10 (0)	16
14709	MT-TE	MM+DMDF / Encephalomyopathy / Dementia+diabetes+ophthalmoplegia	T14709C	tRNA Glu	+	+	Cfrm	Pathogenic	0.002% (0.000%)	1 (0)	28
14710	MT-TE	Encephalomyopathy + Retinopathy	G14710A	tRNA Glu	-	+	Cfrm	Pathogenic	0.000% (0.000%)	0 (0)	6
15990	MT-TP	MM / PEO	C15990T	tRNA Pro	-	+	Cfrm	Pathogenic	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.