MT-ND3
protein-codingmitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 3, the group of NADH:ubiquinone oxidoreductase core subunits|Mitochondrially encoded protein coding genes
Gene summary
Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone. Located in mitochondrial inner membrane. Part of respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and Parkinson's disease. [provided by Alliance of Genome Resources, Jul 2025]
- MTND3
MANE transcript
Inheritance
ClinVar variants
Top phenotype
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~0.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Mitochondrial
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *MT-ND3* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 6, 2023. *MT-ND3* is located at m.10059-10404 of the mitochondrial DNA (mtDNA) genome and encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit ND3. Defects of this protein lead to complex I deficiency. *MT-ND3* was first reported in relation to primary mitochondrial disease in 2001 (PMID: 11456298). While various names have been given to the constellation of features seen in those with *MT-ND3*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MT-ND3* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *MT-ND3* was previously curated by this panel for its association with Leigh syndrome spectrum (LSS) on March 24, 2021 (SOP v8), with a final classification of definitive. This current curation for the association with primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation includes five variants (m.10134C>A, m.10158T>C, m.10191T>C, m.10197G>A, m.10254G>A) in 18 probands from 11 publications (PMIDs: 1928099, 14705112, 14764913, 17152068, 20202874, 25118196, 25384404, 11456298, 19458970, 30199507, 29237403). All curated variants were missense and three were recurrent (m.10158T>C, m.10191T>C, m.10197G>A). Affected individuals present with a broad phenotypic spectrum of clinical features including LSS; Leber Hereditary Optic Neuropathy (LHON); mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); lactic acidosis, epilepsia partialis continua (EPC), epileptic encephalopathy, dystonia, and optic atrophy. The age of onset is also highly variable, ranging from infantile to adult. Metabolic labs revealed elevated lactate in blood and cerebrospinal fluid (CSF). Muscle biopsy showed and complex I deficiency. Heteroplasmy levels in affected individuals ranged from 76% - homoplasmic in muscle, 10% - homoplasmic in blood, as well as at >98% in various other tissues (fibroblasts, liver). Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known protein interaction and functional alteration in patient fibroblast cells (PMIDs: 27509854, 14705112). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 6, 2023 (SOP Version 9).
Inheritance Pattern: Mitochondrial
Disease ID:MONDO:0016814
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0100133
Submitter: Orphanet
Inheritance Pattern: Mitochondrial
Disease ID:MONDO:0020478
Submitter: Orphanet
Inheritance Pattern: Mitochondrial
Disease ID:MONDO:0009723
Submitter: ClinGen
The relationship between *MT-ND3* and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of March 24, 2021. The *MT-ND3* gene encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit ND3. Defects of this protein lead to complex I deficiency. The *MT-ND3* gene was first reported in relation to maternally inherited Leigh syndrome spectrum in 2003 (PMID: 14684687). Evidence supporting the gene-disease relationship between *MT-ND3* and Leigh syndrome spectrum includes case-level data and experimental data. This curation included 5 variants in 14 cases (1 with m.10134C>A, 5 with m.10158T>C, 3 with m.10191T>C, 4 with m.10197G>A, 1 with m.10254G>A) from 7 publications (PMIDs: 14684687, 14705112, 14764913, 17152068, 20202874, 25118196, 25384404). Of note, while Gene Curation SOP Version 8 maxes case level missense variant total score at 7, the Mitochondrial Disease Gene Curation Expert Panel agreed the maximum score would be 12 given that the majority of pathogenic mitochondrial DNA variants are missense variants (the total score for genetic level evidence in this curation was 19.5). Segregation information is scored as case level evidence according to the criteria established by the Mitochondrial Disease Gene Curation Expert Panel. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known protein interaction and functional alteration in patient cells (PMIDs: 27509854, 14705112). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 24, 2021 (SOP Version 8).
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Neurologic; Ophthalmologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
Comments: Mitochondrial variants may involve a variety of sequelae, including hearing impairment
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MT-ND3 variants in ClinVar
No annotated ClinVar phenotypes.
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript . Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 0 | |||||
| missense | 0 | |||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 0 | 0 | 0 | 0 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| Ensembl | ENSP00000355206.2 | 1 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Retrograde endocannabinoid signaling - Homo sapiens (human)
- Thermogenesis - Homo sapiens (human)
- Oxidative phosphorylation - Homo sapiens (human)
- Parkinson,s disease - Homo sapiens (human)
- Electron Transport Chain
Biological Process
- mitochondrial electron transport, NADH to ubiquinone
- response to oxidative stress
- response to light intensity
- mitochondrial respiratory chain complex I assembly
- cellular response to glucocorticoid stimulus
Molecular Function
- protein binding
- NADH dehydrogenase (ubiquinone) activity
Cellular Component
- mitochondrial inner membrane
- mitochondrial respiratory chain complex I
- integral component of membrane
- NADH dehydrogenase complex
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) that is believed to belong to the minimal assembly required for catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone (By similarity). {ECO:0000250}.;
- Disease
- DISEASE: Leigh syndrome (LS) [MIM:256000]: An early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, and dysphagia. {ECO:0000269|PubMed:17152068}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mitochondrial complex I deficiency (MT-C1D) [MIM:252010]: A disorder of the mitochondrial respiratory chain that causes a wide range of clinical manifestations from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. {ECO:0000269|PubMed:11456298, ECO:0000269|PubMed:14705112, ECO:0000269|PubMed:20818383}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Essentials
- Indispensability pred.
- E
- Indispensability score
- 0.613