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Table 3.

Complex I variants

Disease/clinical features	Variant	Subunit	AA change	Age^a	% VAF				Complex I		Reference
Disease/clinical features	Variant	Subunit	AA change	Age^a	Muscle	Blood	Fibroblasts	Other	Residual activity, %	Protein levels	Reference
EXIT	3365T > C	MT-ND1	Leu20Pro		84				13, muscle	↓	(Gorman et al. 2015)
LHON/MELAS	3376G > A	MT-ND1	Glu24Lys	43 yr	98	18		67, urinary epithelium	36, muscle		(Blakely et al. 2005a)
MELAS	3380G > A	MT-ND1	Arg25Gln	63 yr	50			5, leukocytes	77, muscle		(Horváth et al. 2008)
LHON	3460G > A	MT-ND1	Ala52Thr				95		43, fibroblasts		(Cock et al. 1999)
Tumor progression	3460G > A	MT-ND1	Ala52Thr					100, cybrids	50, cybrids		(Iommarini et al. 2014)
LHON	3460G > A	MT-ND1	Ala52Thr					100, LCLs	33, LCLs		(Majander et al. 1991)
LHON	3460G > A	MT-ND1	Ala52Thr					100, LCLs	20, LCLs		(Majander et al. 1991)
MELAS	3481G > A	MT-ND1	Glu59Lys	8 yr	80		50	55, lymphocytes 80, urinary epithelium	8, muscle 67, fibroblasts	↓	(Malfatti et al. 2007)
Tumor progression	3571insC	MT-ND1	Frameshift					100, cybrids	<1, cybrids	↓	(Iommarini et al. 2014)
MELAS	3571insC	MT-ND1	Frameshift	4 yr	68	51	58	51, hair follicles 56, fingernails	19, muscle		(Lou et al. 2023)
LHON	3634A > G	MT-ND1	Ser110Gly					100, cybrids	36, cybrids	Similar levels to referent cells	(Carreño-Gago et al. 2017)
LHON	3697G > A	MT-ND1	Gly131Ser		>97	56			8, muscle		(Spruijt et al. 2007)
LHON with spastic dystonia	3697G > A	MT-ND1	Gly131Ser		<1	88			16, muscle		(Spruijt et al. 2007)
MELAS	3697G > A	MT-ND1	Gln131Ser	7 yr	80		79		60, muscle 35, fibroblasts	↓	(Kirby et al. 2004)
Dystonia	3796A > G	MT-ND1	Thr164Ala		100	87			22, muscle		(Simon et al. 2003)
MELAS	3946G > A	MT-ND1	Glu214Lys		60	37	45		2, muscle 34, fibroblasts	↓	(Kirby et al. 2004)
MELAS	3949T > C	MT-ND1	Tyr251His		93	45	88		19, muscle 24, fibroblasts	↓	(Kirby et al. 2004)
EXIT	4175G > A	MT-ND1	Trp290X		83	<1	<1	<1, urinary/buccal epithelium	<1, muscle	↓	(Gorman et al. 2015)
Leigh syndrome	10134C > A	MT-ND3	Gln26Lys	4.5 yr	98	99	98	98, liver	17, muscle 50, liver	↓ in muscle; similar levels to referent in liver	(Miller et al. 2014)
Leigh syndrome	10158T > C	MT-ND3	Ser34Pro	<1 yr	83	48			23, muscle		(Crimi et al. 2004)
Leigh syndrome	10158T > C	MT-ND3	Ser34Pro	<1 yr	85				27, muscle^b		(Lebon et al. 2003)
Leigh syndrome	10158T > C	MT-ND3	Ser34Pro	<1 yr	85				15, muscle		(Lebon et al. 2003)
Leigh syndrome	10158T > C	MT-ND3	Ser34Pro				30		98, fibroblasts		(Bakare et al. 2021)
Progressive MELAS, bilateral optic atrophy, cognitive decline	10191T > C	MT-ND3	Ser45Pro	42 yr	77	14			40, muscle		(Taylor et al. 2001)
Leigh syndrome	10191T > C	MT-ND3	Ser45Pro		90				17, muscle		(Lebon et al. 2003)
Leigh syndrome	10191T > C	MT-ND3	Ser45Pro		80				39, muscle		(Lebon et al. 2003)
EPC, optic atrophy	10191T > C	MT-ND3	Ser45Pro		95				23, muscle	↓	(Malfatti et al. 2007)
Leigh syndrome	10191T > C	MT-ND3	Ser45Pro	1 mo	100	100		50, hair roots	17, muscle	↓	(Leshinsky-Silver et al. 2005)
Leigh syndrome	10197G > A	MT-ND3	Ala47Thr		86				45, muscle		(Chae et al. 2007)
Leigh syndrome	10197G > A	MT-ND3	Ala47Thr		80				33, muscle		(Chae et al. 2007)
Leigh syndrome	10197G > A	MT-ND3	Ala47Thr	9 yr	98				55, muscle		(Chae et al. 2007)
Leigh syndrome	10197G > A	MT-ND3	Ala47Thr	<1 yr	100				9, muscle		(Sarzi et al. 2007)
Leigh syndrome	10197G > A	MT-ND3	Ala47Thr		100		100		<1, muscle 71, fibroblasts		(Sarzi et al. 2007)
Dystonia	10197G > A	MT-ND3	Ala47Thr		96			74, LCLs 97, cybrids	<1, muscle 41, LCLs 49, cybrids		(Sarzi et al. 2007)
Asymptomatic	10197G > A	MT-ND3	Ala47Thr					73, LCLs 69, cybrids	190, LCLs 33, cybrids		(Sarzi et al. 2007)
Leigh syndrome	10197G > A	MT-ND3	Ala47Thr	<1 yr	100			100, leukocytes 100, cybrids 100, lymphoblasts	6, muscle 19, cybrids 33, lymphoblasts		(Sarzi et al. 2007)
LHON	11778G > A	MT-ND4	Arg340His					100, LCLs	100, LCLs		(Majander et al. 1991)
LHON	12338T > C	MT-ND5	Met1Thr	32 yr				100, cybrids	62, cybrids	↓	(Zhang et al. 2018)
Bilateral ptosis & ophthalmoplegia	12706T > C	MT-ND5	Phe124Leu		60				10, muscle		(Lebon et al. 2003)
Leigh syndrome	12706T > C	MT-ND5	Phe124Leu		43		30		33, muscle 49, fibroblasts		(Taylor et al. 2002)
Severe neonatal lactic acidosis	12706T > C	MT-ND5	Phe124Leu				39		84, fibroblasts		(Bakare et al. 2021)
MELAS, MERRF	13042G > A	MT-ND5	Ala236Thr	25 yr	90	50			15, muscle		(Naini et al. 2005)
MELAS	13045A > G	MT-ND5	Met237Val	66 yr	50	<1			100, muscle		(Panadés-de Oliveira et al. 2020)
MELAS	13045A > G	MT-ND5	Met237Val	41 yr	84	<1		5, urinary sediment	36, muscle		(Panadés-de Oliveira et al. 2020)
Ataxia, excessive fragmentary hypnic myoclonus	13063G > A	MT-ND5	Val243Ile		80		70	25, lymphocytes	46, muscle 28, fibroblasts	Similar levels to referent	(Malfatti et al. 2007)
MELAS	13376T > C	MT-ND5	Ile347Thr	25 yr	>99			>99, hair	100, muscle		(Sasaki et al. 2020)
Leigh syndrome	13513G > A	MT-ND5	Asp393Asn	21 yr	64	26	25		31, muscle 85, fibroblasts		(Ruiter et al. 2007)
Leigh syndrome	13513G > A	MT-ND5	Asp393Asn		>90				12, muscle		(Chol et al. 2003)
Leigh syndrome	13513G > A	MT-ND5	Asp393Asn		>90				47, muscle		(Chol et al. 2003)
Leigh syndrome	13513G > A	MT-ND5	Asp393Asn		>90				22, Muscle		(Chol et al. 2003)
Leigh syndrome	13513G > A	MT-ND5	Asp393Asn	22 yr	63	42			33, muscle 100, fibroblasts		(Ruiter et al. 2007)
Leigh syndrome	13513G > A	MT-ND5	Asp393Asn	1 yr	50			50, lymphocytes	54, muscle		(Brecht et al. 2015)
Leigh syndrome	13513G > A	MT-ND5	Asp393Asn	<4 yr	31	29	46	41, liver	35, muscle 31, liver 28, fibroblasts	↓	(Kirby et al. 2003)
Leigh syndrome	13513G > A	MT-ND5	Asp393Asn	<24 yr			44		32, fibroblasts	↓	(Kirby et al. 2003)
Leigh syndrome	13513G > A	MT-ND5	Asp393Asn	35 yr	26	7		6, LCLs	8, muscle	↓	(Kirby et al. 2003)
MELAS/Leigh syndrome	13513G > A	MT-ND5	Asp393Asn	<2 yr	14	14			8, muscle		(Blok et al. 2007)
MELAS	13513G > A	MT-ND5	Asp393Asn	45 yr	51	10		34, kidney 25, liver 53, heart 57, cerebellum 54, cerebrum/frontal lobe	52, liver 46, brain tissue		(Santorelli et al. 1997)
MELAS	13513G > A	MT-ND5	Asp393Asn	10 yr	30			42, urinary epithelium	25, muscle		(Van Karnebeek et al. 2011)
MELAS	14453G > A	MT-ND6	Ala74Val		82	78			28, muscle		(Ravn et al. 2001)
MELAS/LHON	14459G > A	MT-ND6	Ala72Val		94	39		88, urinary epithelium 81, buccal mucosa	50, LCLs		(Yu et al. 2021)
Leigh syndrome	14459G > A	MT-ND6	Ala72Val	15 mo	>99	>99			36, muscle		(Ronchi et al. 2011)
Leigh syndrome	14459G > A	MT-ND6	Ala72Val	16 yr	87	69		91, urinary sediment 89, buccal mucosa	58, muscle		(Kurt et al. 2016)
Diffuse dystonia	14459G > A	MT-ND6	Ala72Val	12 yr	61	53	59		72, muscle		(Kurt et al. 2016)
Leigh syndrome	14487T > C	MT-ND6	Met63Val		80				60, muscle		(Lebon et al. 2003)
Leigh syndrome	14487T > C	MT-ND6	Met63Val	10 mo	95		85		15, muscle 42, fibroblasts	Similar levels as referent	(Malfatti et al. 2007)
Optic atrophy, ptosis, intractable myoclonic epilepsy	14487T > C	MT-ND6	Met63Val		84	15		75, urinary sediment 58, buccal mucosa 86, hair follicles	21, muscle		(Spyropoulos et al. 2013)
Optic atrophy, ataxia	14487T > C	MT-ND6	Met63Val		50			50, lymphocytes	28, muscle		(Malfatti et al. 2007)
Type 2 diabetes	14577T > C	MT-ND6	Ile33Val	69 yr				99, cybrids	36, cybrids		(Tawata et al. 2000)
Leigh syndrome	14600G > A	MT-ND6	Pro25Leu	3 mo	>99		>99		33, muscle	↓	(Malfatti et al. 2007)

[i] ^aAge of the patient at which the VAF and complex I activity were measured.

[ii] ^bNot normalized to citrate synthase.

[iii] (AA) Amino acid; (VAF) variant allele frequency; (ND) NADH dehydrogenase; (EXIT) exercise intolerance; (LHON) Leber's hereditary optic neuropathy; (MELAS) mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes; (EPC) epilepsia partialis continua; (MERRF) myoclonic epilepsy with ragged red fibers; and (LCLs) lymphoblastoid cell lines.