NDUFB8

protein-coding

NADH:ubiquinone oxidoreductase subunit B8, the group of NADH:ubiquinone oxidoreductase supernumerary subunits

Gene summary

Predicted to enable NADH dehydrogenase (ubiquinone) activity. Predicted to be involved in mitochondrial electron transport, NADH to ubiquinone and proton motive force-driven mitochondrial ATP synthesis. Located in mitochondrial inner membrane. Part of respiratory chain complex I. Implicated in nuclear type mitochondrial complex I deficiency 32. Biomarker of Alzheimer's disease and Parkinson's disease. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_005004.4

Inheritance

ClinVar variants

P:4U:54B:27

Top phenotype

Mitochondrial complex I deficiency, nuclear type 32

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr10:100,523,668-100,530,000

External References & Databases

Ensembl (ENSG00000166136)

Transcript & Mutation Effects

hg38 • Region Span ~6.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NDUFB8 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of November 23, 2020. The NDUFB8 gene encodes the NADH:ubiquinone oxidoreductase (complex I) subunit B8, which is essential for complex I activity and assembly. Defects of this protein lead to complex I deficiency. The NDUFB8 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2018 (PMID: 29429571). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four variants identified in two cases in one publication (PMID: 29429571). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function, functional alteration in non-patient cells, and animal models (PMIDs: 31127358, 27626371, 27509854). In summary, there is moderate evidence to support this gene-disease relationship. 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 U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on November 23, 2020 (SOP Version 7).

mitochondrial complex I deficiency, nuclear type 32STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032635

Submitter: G2P

mitochondrial complex I deficiency, nuclear type 32MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032635

Submitter: Ambry Genetics

mitochondrial complex I deficiency, nuclear type 32STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032635

Submitter: PanelApp Australia

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFB8* and *NDUFB8*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of November 18, 2024. The *NDUFB8* gene encodes mitochondrial NADH:ubiquinone oxidoreductase (complex I) subunit B8, which is essential for complex I activity and assembly. Defects of this protein lead to complex I deficiency. The *NDUFB8* gene was first reported in relation to autosomal recessive *NDUFB8*-related primary mitochondrial disease in 2018 (PMID: 29429571). *NDUFB8* has been associated with a single disease entity to date; mitochondrial complex I deficiency, nuclear type 32 [OMIM# 618252]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *NDUFB8*-related primary mitochondrial disease. Of note, *NDUFB8* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on November 23, 2020 (SOP v7), with a final classification of Moderate. This current curation for the association with *NDUFB8*-related primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five unique variants (four missense, one frameshift) identified in three unrelated cases from two publications (PMIDs: 29429571, 30770271). All three probands presented in the first year of life. There are limited details on the outcome of one case, one case died at age 15 months, and one case was alive but severely affected at age 5 years. Two cases had LSS and the third had cavitating leukoencephalopathy. Additional features include developmental delay, seizures, left ventricular hypertrophy, and respiratory failure. Complex I deficiency was noted in muscle biopsies and blood lactate was elevated. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416), and functional alteration studies in HEK293T cells (PMID: 27626371). In summary, there is moderate evidence to support the relationship between *NDUFB8* and autosomal recessive *NDUFB8*-related 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 18, 2024 (SOP Version 10).

mitochondrial complex I deficiency, nuclear type 32LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0032635

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Mitochondrial complex I deficiency, nuclear type 32AR

Manifestation: Biochemical; Cardiovascular; Neurologic

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

Refs: 29429571

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NDUFB8 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 72

Inborn genetic diseasesTotal: 30

NDUFB8-related disorderTotal: 11

Mitochondrial complex I deficiency, nuclear type 32Total: 9

not specifiedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005004.4. 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			1 clinvar	19 clinvar	2 clinvar	22
missense	3 clinvar		48 clinvar	3 clinvar	3 clinvar	57
nonsense			2 clinvar			2
start loss						0
frameshift		1 clinvar	2 clinvar			3
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	3	1	54	22	5	85

Highest pathogenic variant AF is 0.0000013710801

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 37 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005004.4	RefSeq	NP_004995.1	5	MANE Select
ENST00000299166.9	Ensembl	ENSP00000299166.4	5	MANE Select
NM_001284367.2	RefSeq	NP_001271296.1	5	Standard
NM_001284368.1	RefSeq	NP_001271297.1	4	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

mitochondrion
mitochondrial inner membrane
mitochondrial respiratory chain complex I
mitochondrial matrix
endoplasmic reticulum

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000299166
Coding exons: 5
Length: 22555
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 125746
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.113	121	118	1.03	0.00000611	1222
Missense (PolyPhen)		37	35.475	1.043		446
Synonymous	0.391	41	44.3	0.925	0.00000238	344
Loss of Function	1.61	5	10.7	0.467	4.57e-7	115

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000071	0.000070	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

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}.;

Recessive Scores

pRec: 0.127

Intolerance Scores

LoFtool: 0.334
RVIS EVS: -0.18
RVIS percentile EVS: 39.95

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.642

Gene Damage Prediction

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