NDUFS8

protein-coding

NADH:ubiquinone oxidoreductase core subunit S8, the group of NADH:ubiquinone oxidoreductase core subunits|MicroRNA protein coding host genes

Gene summary

This gene encodes a subunit of mitochondrial NADH:ubiquinone oxidoreductase, or Complex I, a multimeric enzyme of the respiratory chain responsible for NADH oxidation, ubiquinone reduction, and the ejection of protons from mitochondria. The encoded protein is involved in the binding of two of the six to eight iron-sulfur clusters of Complex I and, as such, is required in the electron transfer process. Mutations in this gene have been associated with Leigh syndrome. [provided by RefSeq, Mar 2010]

MANE transcript

NM_002496.4

Inheritance

ClinVar variants

P:22U:80B:39

Top phenotype

Mitochondrial complex I deficiency, nuclear type 2; Leigh syndrome

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr11:68,030,617-68,036,644

External References & Databases

Ensembl (ENSG00000110717)

Transcript & Mutation Effects

hg38 • Region Span ~6.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial complex I deficiency, nuclear type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032606

Submitter: G2P

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFS8* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of November 6, 2023. The *NDUFS8* gene encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit S8. Defects of this protein lead to complex I deficiency. *NDUFS8* was first reported in relation to primary mitochondrial disease in 1998 (PMID: 9837812). While various names have been given to the constellation of features seen in those with *NDUFS8*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *NDUFS8* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *NDUFS8* was previously curated by this GCEP on November 20, 2019 (SOP Version 7) as having a moderate association with autosomal recessive Leigh syndrome spectrum (LSS). The scope of this current curation encompassed cases of primary mitochondrial disease, which includes cases with LSS. Evidence supporting the relationship between *NDUFS8* and autosomal recessive primary mitochondrial disease includes case-level data and experimental data. This curation includes 10 variants identified in 10 unrelated probands from eight publications (PMIDs: 9837812, 15159508, 20818383, 22499348, 23430795, 19336460, 20819849, 36101822). All reported variants were missense. Affected individuals present with complex I deficiency and variable other features with a typically progressive disease course. Age of onset is typically in infancy or childhood. Clinical features may include LSS, lactic acidosis, developmental delay and regression, dystonia, seizures, hypertrophic cardiomyopathy, respiratory insufficiency, episodic apnea, progressive external ophthalmoplegia, and poor feeding. The mechanism of disease is loss of function. This gene-disease association is also supported by a biochemical function in mitochondrial complex I shared by more than 10 other genes also associated with primary mitochondrial disease as well as model systems (PMIDs: 33340416, 29285794, 19672299). In summary, there is definitive evidence to support the relationship between *NDUFS8* and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. 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 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet

mitochondrial complex I deficiency, nuclear type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032606

Submitter: Labcorp Genetics (formerly Invitae)

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NDUFS8 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of November 20, 2019. The NDUFS8 gene encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit S8. Defects of this protein lead to complex I deficiency. The NDUFS8 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 1998 (PMID: 9837812). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included seven unique variants identified in five cases from five publications (PMIDs: 9837812, 22200994, 15159508, 23430795, 20818383). 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 animal models (PMIDs: 21924235, 19672299, 29285794, 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 November 20, 2019 (SOP Version 7).

mitochondrial complex I deficiency, nuclear type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032606

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Mitochondrial complex I deficiency, nuclear type 2; 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: 9837812; 11743516; 15159508

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NDUFS8 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 116

Inborn genetic diseasesTotal: 28

not specifiedTotal: 26

Mitochondrial complex I deficiency, nuclear type 2Total: 25

Leigh syndromeTotal: 22

Mitochondrial complex I deficiency, nuclear type 1Total: 16

NDUFS8-related disorderTotal: 7

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002496.4. 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				35 clinvar		35
missense	3 clinvar	15 clinvar	71 clinvar	4 clinvar		93
nonsense		1 clinvar	1 clinvar			2
start loss			1 clinvar			1
frameshift		1 clinvar	3 clinvar			4
splice donor/acceptor (+/-2bp)		2 clinvar	4 clinvar			6
Total	3	19	80	39	0	141

Highest pathogenic variant AF is 0.000022954391

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 54 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002496.4	RefSeq	NP_002487.1	6	MANE Select
ENST00000313468.10	Ensembl	ENSP00000315774.5	6	MANE Select
ENST00000453471.6	Ensembl	ENSP00000403972.2	4	Standard
ENST00000524810.5	Ensembl	ENSP00000434283.1	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
response to oxidative stress
aerobic respiration
mitochondrial respiratory chain complex I assembly

Molecular Function

NADH dehydrogenase activity
NADH dehydrogenase (ubiquinone) activity
metal ion binding
4 iron, 4 sulfur cluster binding

Cellular Component

mitochondrion
mitochondrial respiratory chain complex I
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000313468
Coding exons: 6
Length: 6028
Individuals with no LoFs: 125722
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125730
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.744	119	144	0.826	0.0000107	1345
Missense (PolyPhen)		45	62.831	0.7162		569
Synonymous	-0.591	64	58.3	1.10	0.00000428	415
Loss of Function	2.15	3	10.5	0.286	5.38e-7	117

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
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)	0.000035	0.000035	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

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). May donate electrons to ubiquinone. {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:9837812}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.256

Intolerance Scores

LoFtool: 0.194
RVIS EVS: -0.21
RVIS percentile EVS: 38.58

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.801

Gene Damage Prediction

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