rs267606898 — MT-ND5

Heteroplasmic missense variant in the mitochondrially encoded ND5 subunit of complex I, causing variable-penetrance mitochondrial disease including Leigh syndrome, MELAS, and Leber optic atrophy depending on mutation load.

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MT-ND5 m.13042G>A — A Mitochondrial Throttle Stuck in Low Gear

Every cell in your body runs on ATP — the molecular currency of energy — manufactured by the electron transport chain11 electron transport chain
a series of five protein complexes embedded in the inner mitochondrial membrane. Complex I (NADH:ubiquinone oxidoreductase) is the first and largest of these complexes, accepting electrons from cellular metabolism and using their energy to pump protons that ultimately drive ATP synthesis. MT-ND5 encodes one of the seven core subunits of complex I that are encoded in the mitochondrial genome itself rather than in the cell nucleus. The m.13042G>A variant substitutes alanine for threonine at a position (Ala236) that is conserved across vertebrates and sits within a functionally critical domain of the ND5 subunit.

Unlike nuclear DNA, where you have two copies (one from each parent), you carry hundreds to thousands of copies of mitochondrial DNA in every cell. This variant is heteroplasmic — meaning some copies carry the G>A mutation while others are normal. The ratio of mutant to normal copies (the heteroplasmy level) is the principal determinant of whether, and how severely, the variant causes disease. At low heteroplasmy levels (<50-60%), most individuals are asymptomatic or only mildly affected. Above 70-80%, complex I activity falls sufficiently to produce clinical disease. Heteroplasmy levels can differ substantially between tissues and between generations.

The Mechanism

The p.Ala236Thr substitution replaces a non-polar alanine with a larger, polar threonine at a position under strong evolutionary constraint in the ND5 protein. The consequence is reduced complex I assembly and/or catalytic efficiency. When mutant mtDNA exceeds the biochemical threshold in a tissue, that tissue cannot meet its ATP demand — and the most energy-intensive tissues (brain, skeletal muscle, heart, retina) fail first.

The phenotypic range is broad because heteroplasmy levels vary between individuals and tissues. In the first reported family, affected members presented with LHON-like optic neuropathy, retinopathy, cataracts, strokes, and early deaths — all tracing through the maternal line22 LHON-like optic neuropathy, retinopathy, cataracts, strokes, and early deaths — all tracing through the maternal line
Valentino ML et al. The 13042G>A/ND5 mutation in mtDNA is pathogenic and can be associated also with a prevalent ocular phenotype. J Med Genet, 2006. The original case report described a 25-year-old man with MELAS/MERRF overlap (strokes, seizures, myoclonus) and confirmed isolated complex I deficiency in muscle biopsy.

The Evidence

The pathogenicity of m.13042G>A is supported by multiple independent case series and by expert panel review. ClinVar VCV00000970333 ClinVar VCV000009703
ClinVar expert panel review — Likely Pathogenic, ★★★★ review status classifies the variant as Likely Pathogenic for mitochondrial disease, based on six unrelated individuals with disease onset from the first year of life to adulthood, variable phenotypes including CPEO, LHON, and Leigh-like syndrome, and demonstrated disease segregation within families. The criteria met include PS4_moderate (case enrichment), PP1_moderate (co-segregation), PP3 (computational evidence), and PM2_supporting (rare in population databases).

Naini et al.44 Naini et al.
Naini AB et al. A novel heteroplasmic point mutation in the mitochondrial tRNA gene. Arch Neurol, 2005 established the first clinical description and biochemically confirmed complex I deficiency in muscle. Blok et al.55 Blok et al.
Blok MJ et al. Mutations in the ND5 subunit of complex I of the mitochondrial DNA are a frequent cause of oxidative phosphorylation disease. J Med Genet, 2007 screened 116 complex I–deficient patients and identified m.13042G>A in a patient with Leigh-like syndrome, concluding that ND5 represents a diagnostic hot spot. Danhelovska et al.66 Danhelovska et al.
Danhelovska T et al. Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I. BMC Pediatrics, 2020 showed in a 13-patient MT-ND cohort that higher heteroplasmy correlates with worse clinical outcomes, though biochemical complex I activity does not reliably track mutation load — making heteroplasmy quantification more diagnostically informative than enzyme assay alone.

Practical Actions

Management of mitochondrial complex I disease focuses on supporting residual mitochondrial function, avoiding metabolic stressors, and monitoring affected organs. Supplementation with mitochondrial cofactors is standard practice in specialist centres, though robust RCT evidence is limited by disease rarity. The GeneReviews MELAS protocol recommends CoQ10 (adults 200–400 mg/day in 3 divided doses, children 5–10 mg/kg/day), L-carnitine (adults 3 g/day, children 100 mg/kg/day), and creatine for individuals with this class of mitochondrial disease. Energy demand from intercurrent illness, fasting, extreme exertion, and valproate can precipitate acute metabolic decompensation.

Heteroplasmy measurement — ideally in muscle or urine (more informative than blood) — guides prognosis and should be repeated at clinical reassessments. Organ-specific surveillance includes annual cardiac, ophthalmological, and audiological evaluation, given the multi-organ tropism of ND5 mutations.

Interactions

All mitochondrial disease variants share the same metabolic pathway (oxidative phosphorylation) and interact through the common mechanism of ATP depletion and reactive oxygen species excess. Combination of m.13042G>A with nuclear-encoded complex I subunit variants (NDUFS1, NDUFS2, NDUFV1, etc.) in the same individual is theoretically additive, though clinical documentation of such combinations is very limited given the rarity of the variant. The maternal inheritance pattern means that risk to relatives flows exclusively through the maternal lineage — all children of an affected or carrier mother are at risk.

Nutrient Interactions

coenzyme Q10 increased_need
L-carnitine increased_need
riboflavin increased_need
alpha-lipoic acid increased_need

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-Carrier Normal

No MT-ND5 m.13042G>A detected — normal mitochondrial complex I function

You do not carry the m.13042G>A variant in your mitochondrial DNA at detectable levels. Your ND5 subunit encodes the reference alanine at position 236, and mitochondrial complex I function is not affected by this variant. This is the most common result — the A allele is absent from large population databases (0/478 samples in ALFA), making it an ultra-rare pathogenic variant. Your mitochondrial complex I activity is not expected to be impaired by this specific mutation.

AG Heteroplasmic Carrier Carrier

Heteroplasmic for m.13042G>A — risk depends on mutation load in each tissue

Detection of this variant in blood or saliva (as in consumer genotyping) does not reliably predict clinical phenotype because heteroplasmy levels differ substantially between tissues. Blood-derived heteroplasmy is often lower than muscle or neuronal heteroplasmy — the clinically relevant tissues. A person with 20% heteroplasmy in blood might have 70% in muscle. Clinical evaluation should include quantification in muscle (via biopsy) or at minimum in urine epithelial cells, which approximate neural tissue more closely than blood.

Disease presentations linked to m.13042G>A span MELAS (mitochondrial encephalomyopathy, lactic acidosis, strokelike episodes), MERRF (myoclonic epilepsy with ragged-red fibers), Leigh-like syndrome, LHON-like optic neuropathy, retinopathy, cataracts, cardiomyopathy, sensorineural hearing loss, and multisystem involvement. Onset ranges from infancy to adulthood depending on tissue-specific heteroplasmy.

Maternal relatives should be offered cascade testing. All children of a heteroplasmic woman will inherit some mtDNA containing the variant, but the proportion passed to offspring is highly variable (mitotic segregation during oogenesis is stochastic), meaning children's heteroplasmy levels are unpredictable.

AA Homozygous Mutant Homozygous

Near-homoplasmic m.13042G>A — severe mitochondrial complex I deficiency expected

Homoplasmy or near-homoplasmy for a pathogenic complex I variant essentially eliminates residual enzyme activity in all tissues. Complex I contributes approximately 40% of the proton-motive force driving ATP synthase in neurons and cardiomyocytes — organs that cannot compensate for this loss with alternative metabolic pathways the way skeletal muscle can partially do through glycolysis.

At high mutant load, Leigh syndrome (bilateral symmetric lesions in the basal ganglia and brainstem on MRI) is the characteristic neurological presentation in children. In adolescents and adults with slower accumulation, MELAS-like strokes, optic atrophy, cardiomyopathy, or a multisystem picture predominates. Lactic acidosis — elevated blood and CSF lactate — reflects the shift from oxidative phosphorylation to anaerobic glycolysis throughout the body.

Note: consumer genotyping chips use low coverage and cannot reliably distinguish true homoplasmy from very high heteroplasmy. This result should be confirmed by deep-sequencing mtDNA in a clinical genetics laboratory before clinical decisions are made.