NDUFB3

protein-coding

NADH:ubiquinone oxidoreductase subunit B3, the group of NADH:ubiquinone oxidoreductase supernumerary subunits

Gene summary

This gene encodes an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which is the first enzyme in the electron transport chain of mitochondria. This protein localizes to the inner membrane of the mitochondrion as a single-pass membrane protein. Mutations in this gene contribute to mitochondrial complex 1 deficiency. Alternative splicing results in multiple transcript variants encoding the same protein. Humans have multiple pseudogenes of this gene. [provided by RefSeq, Mar 2012]

MANE transcript

NM_002491.3

Inheritance

ClinVar variants

P:6U:25B:4

Top phenotype

Mitochondrial complex I deficiency, nuclear type 25

gnomAD constraint

pLI —, LoF o/e 1.61

Max pathogenic AF

—

Genomic locus

chr2:201,071,433-201,085,750

External References & Databases

Ensembl (ENSG00000119013)

Transcript & Mutation Effects

hg38 • Region Span ~14.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial complex I deficiency, nuclear type 25STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032629

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial complex I deficiency, nuclear type 25MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032629

Submitter: Ambry Genetics

mitochondrial complex I deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFB3* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 7, 2022. The *NDUFB3* gene encodes NADH:ubiquinone oxidoreductase (complex I) subunit B3, which is essential for complex I activity and assembly. Defects of this protein lead to complex I deficiency. The *NDUFB3* gene was first reported in relation to autosomal recessive mitochondrial disease in 2012 (PMID: 22277967). While various names have been given to the constellation of features seen in those with NDUFB3-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NDUFB3 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included two variants identified in eleven cases [10 cases had homozygous c.64T>C (p.Trp22Arg); the 11th case was compound heterozygous for c.64T>C (p.Trp22Arg) and c.208G>T (p.Gly70Ter)] in four publications (PMIDs: 22277967, 22499348, 27091925, 31000363). Features seen in these cases include intrauterine growth restriction, oligohydramnios, failure to thrive, short stature, metabolic acidosis, lactic acidosis, developmental delay, hypertrophic cardiomyopathy, arrhythmia (Wolff-Parkinson-White syndrome), pulmonary hypertension, liver disease, and dysmorphic features (prominent forehead, smooth philtrum, deep-set eyes, low-set ears). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, functional alteration in patient cells, functional alteration in non-patient cells, and rescue in patient cells (PMIDs: 22277967, 22499348, 27626371, 27509854). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 7, 2022 (SOP Version 8).

mitochondrial complex I deficiency, nuclear type 25DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032629

Submitter: G2P

mitochondrial complex I deficiency, nuclear type 25STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032629

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Mitochondrial complex I deficiency, nuclear type 25AR

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; 15534765; 22277967

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NDUFB3 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 30

Inborn genetic diseasesTotal: 14

Mitochondrial complex I deficiency, nuclear type 25Total: 4

not specifiedTotal: 4

NDUFB3-related disordersTotal: 2

NDUFB3-related conditionTotal: 2

Mitochondrial complex I deficiencyTotal: 1

Death in childhoodTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002491.3. 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				3 clinvar		3
missense		1 clinvar	24 clinvar	1 clinvar		26
nonsense		2 clinvar	1 clinvar			3
start loss						0
frameshift	2 clinvar	1 clinvar				3
splice donor/acceptor (+/-2bp)						0
Total	2	4	25	4	0	35

Highest pathogenic variant AF is 0.0016649372

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 52 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002491.3	RefSeq	NP_002482.1	2	MANE Select
ENST00000237889.9	Ensembl	ENSP00000237889.4	2	MANE Select
NM_001257102.2	RefSeq	NP_001244031.1	2	Standard
ENST00000433898.5	Ensembl	ENSP00000410600.1	2	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

mitochondrial inner membrane
mitochondrial respiratory chain complex I
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000237889
Coding exons: 2
Length: 14318
Individuals with no LoFs: 125540
Homozygous LoFs: 0
Heterozygous LoFs: 41
Defined: 125581
p: 0.000163

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.316	45	51.4	0.876	0.00000234	650
Missense (PolyPhen)		12	14.551	0.82471		176
Synonymous	0.982	12	17.2	0.699	7.42e-7	170
Loss of Function	-1.10	6	3.72	1.61	1.57e-7	47

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00022	0.00022	rare
South Asian	0.00014	0.00013	rare
Other	0.00016	0.00016	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: 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:22499348, ECO:0000269|PubMed:27091925}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.688
RVIS EVS: 0.21
RVIS percentile EVS: 67.72

Essentials

Essential (CRISPR): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.539

Gene Damage Prediction

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