NDUFA10

protein-coding

NADH:ubiquinone oxidoreductase subunit A10, the group of NADH:ubiquinone oxidoreductase supernumerary subunits

Gene summary

The protein encoded by this gene is a component of 42 kDa complex I, the first enzyme complex in the electron transport chain of mitochondria. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. A mutation in this gene was found in an individual with Leigh syndrome. [provided by RefSeq, Apr 2016]

MANE transcript

NM_004544.4

Inheritance

ClinVar variants

P:11U:109B:48

Top phenotype

Mitochondrial complex I deficiency, nuclear type 22; Leigh syndrome

gnomAD constraint

pLI —, LoF o/e 0.7

Max pathogenic AF

—

Genomic locus

chr2:239,892,450-240,025,743

External References & Databases

Ensembl (ENSG00000130414)

Transcript & Mutation Effects

hg38 • Region Span ~133.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Leigh syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NDUFA10 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of June 10, 2019. The NDUFA10 gene encodes the NADH:ubiquinone oxidoreductase (complex I) subunit A10, a non-catalytic complex I accessory protein required for complex I assembly and function within the mitochondria. Defects of this protein lead to complex I deficiency. The NDUFA10 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2011 (PMID: 21150889). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three unique variants identified in three cases from three publications (PMIDs: 22200994, 28247337, 21150889). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known protein interactions and functional alterations observed in patient cells and in non-patient cells (PMIDs: 21150889, 27626371, 27509854). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on June 10, 2019 (SOP Version 6).

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFA10* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of November 6, 2023. *NDUFA10* encodes NADH:ubiquinone oxidoreductase (complex I) subunit A10, a non-catalytic complex I accessory protein required for complex I assembly and function within the mitochondria. Defects of this protein lead to complex I deficiency. *NDUFA10* was first reported in relation to primary mitochondrial disease in 2011 (PMID: 21150889), in a boy with a confirmed neuropathological diagnosis of Leigh syndrome. While various names could be given to the constellation of features seen in those with *NDUFA10*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *NDUFA10* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *NDUFA10* was previously curated by this GCEP on June 10, 2019 (SOP V6) as having a Limited association with Leigh Syndrome Spectrum (LSS). The scope of this current curation encompassed cases of primary mitochondrial disease, which includes LSS. Evidence supporting the gene-disease relationship between *NDUFA10* and primary mitochondrial disease includes case-level data and experimental data. This curation includes nine variants (five missense, two deletions, one insertion, one frameshift) in seven probands from seven publications (PMIDs: 21150889; 22200994; 28247337; 26741492; 36270260; 35379322; 35094435). Affected individuals present with a broad phenotypic spectrum of disease which includes LSS. The age of onset ranges from birth to early childhood. Additional features seen include developmental delay, ataxia, spastic tetraparesis, seizures, hypertrophic cardiomyopathy, pulmonary hypertension, and feeding difficulty. Elevated blood and cerebrospinal fluid lactates are seen. Muscle biopsies showed a complex I deficiency. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function and functional alteration in patient fibroblasts and in a *C. elegans* model system (PMIDs: 27509854; 27626371, 21150889, 19672299). In summary, there is moderate evidence to support the relationship between *NDUFA10* and primary mitochondrial disease. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on November 6, 2023 (SOP Version 9).

mitochondrial complex I deficiency, nuclear type 22STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032626

Submitter: G2P

mitochondrial complex I deficiency, nuclear type 22STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032626

Submitter: PanelApp Australia

mitochondrial complex I deficiency, nuclear type 22STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032626

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Mitochondrial complex I deficiency, nuclear type 22; Leigh syndromeAR

Manifestation: Biochemical; Cardiovascular; Gastrointestinal; 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: Medical treatment (eg, riboflavin, ubiquinol) may be beneficial; Individuals may have cardiac involvement

Refs: 11743516; 21150889

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NDUFA10 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 155

Inborn genetic diseasesTotal: 41

not specifiedTotal: 33

Leigh syndromeTotal: 27

Mitochondrial complex I deficiency, nuclear type 1Total: 25

Mitochondrial complex I deficiency, nuclear type 22Total: 22

NDUFA10-related disorderTotal: 12

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004544.4. 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			5 clinvar	35 clinvar	1 clinvar	41
missense	2 clinvar	3 clinvar	96 clinvar	12 clinvar		113
nonsense			1 clinvar			1
start loss		1 clinvar	1 clinvar			2
frameshift		3 clinvar	2 clinvar			5
splice donor/acceptor (+/-2bp)		2 clinvar	4 clinvar			6
Total	2	9	109	47	1	168

Highest pathogenic variant AF is 0.000042135893

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 92 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004544.4	RefSeq	NP_004535.1	10	MANE Select
ENST00000252711.7	Ensembl	ENSP00000252711.2	10	MANE Select
NM_001322019.2	RefSeq	NP_001308948.1	10	Standard
NM_001322020.2	RefSeq	NP_001308949.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Retrograde endocannabinoid signaling - Homo sapiens (human)
Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
Alzheimer,s disease - Homo sapiens (human)
Huntington,s disease - Homo sapiens (human)
Thermogenesis - Homo sapiens (human)

Biological Process

mitochondrial electron transport, NADH to ubiquinone
mitochondrial respiratory chain complex I assembly

Molecular Function

NADH dehydrogenase (ubiquinone) activity

Cellular Component

cytoplasm
mitochondrion
mitochondrial inner membrane
mitochondrial respiratory chain complex I
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000252711
Coding exons: 10
Length: 132953
Individuals with no LoFs: 125711
Homozygous LoFs: 0
Heterozygous LoFs: 37
Defined: 125748
p: 0.000147

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.362	206	192	1.07	0.0000116	2315
Missense (PolyPhen)		65	67.017	0.9699		793
Synonymous	0.142	73	74.6	0.979	0.00000478	651
Loss of Function	1.23	14	20.0	0.702	0.00000103	242

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00013	0.00012	rare
South Asian	0.00023	0.00023	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in 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. {ECO:0000269|PubMed:27626371}.;
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:21150889}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.110

Intolerance Scores

LoFtool: 0.262
RVIS EVS: 0.06
RVIS percentile EVS: 58.53

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.962

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium