A systematic review on the biochemical threshold of mitochondrial genetic variants

Table 3.

Complex I variants

Disease/clinical features Variant Subunit AA change Agea % VAF Complex I Reference
Muscle Blood Fibroblasts Other Residual activity, % Protein levels
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, muscleb (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)

  • aAge of the patient at which the VAF and complex I activity were measured.

  • bNot normalized to citrate synthase.

  • (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.

This Article

  1. Published in Advance April 16, 2024, doi: 10.1101/gr.278200.123 Genome Res. 34: 341-365

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