NDUFV1

protein-coding

NADH:ubiquinone oxidoreductase core subunit V1, the group of NADH:ubiquinone oxidoreductase core subunits

Gene summary

The mitochondrial respiratory chain provides energy to cells via oxidative phosphorylation and consists of four membrane-bound electron-transporting protein complexes (I-IV) and an ATP synthase (complex V). This gene encodes a 51 kDa subunit of the NADH:ubiquinone oxidoreductase complex I; a large complex with at least 45 nuclear and mitochondrial encoded subunits that liberates electrons from NADH and channels them to ubiquinone. This subunit carries the NADH-binding site as well as flavin mononucleotide (FMN)- and Fe-S-biding sites. Defects in complex I are a common cause of mitochondrial dysfunction; a syndrome that occurs in approximately 1 in 10,000 live births. Mitochondrial complex I deficiency is linked to myopathies, encephalomyopathies, and neurodegenerative disorders such as Parkinson's disease and Leigh syndrome. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Oct 2009]

MANE transcript

NM_007103.4

Inheritance

ClinVar variants

P:87U:177B:152

Top phenotype

Mitochondrial complex I deficiency, nuclear type 4

gnomAD constraint

pLI —, LoF o/e 0.82

Max pathogenic AF

—

Genomic locus

chr11:67,605,653-67,612,554

External References & Databases

Ensembl (ENSG00000167792)

Transcript & Mutation Effects

hg38 • Region Span ~6.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial complex I deficiency, nuclear type 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032609

Submitter: PanelApp Australia

mitochondrial complex I deficiency, nuclear type 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032609

Submitter: Labcorp Genetics (formerly Invitae)

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 *NDUFV1* and *NDUFV1*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 20, 2024. The *NDUFV1* gene encodes the NADH:ubiquinone oxidoreductase (complex I) flavoprotein 1, a core subunit of mitochondrial complex I. Defects of this protein lead to complex I deficiency. The *NDUFV1* gene was first reported in relation to autosomal recessive *NDUFV1*-related primary mitochondrial disease in 2011 (PMID: 11349233). *NDUFV1* has been associated with one disease entity to date; mitochondrial complex I deficiency, nuclear type 4 [OMIM# 618225]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *NDUFV1*-related primary mitochondrial disease. Of note, *NDUFV1* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on November 20, 2019 (SOP v6), with a final classification of Definitive. This current curation for the association with *NDUFV1*-related primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 13 unique variants (10 missense, one nonsense, one frameshift, and one splice site) identified in 12 unrelated cases from 10 publications (PMIDs: 11349233, 2169386, 23266820, 23334465, 27344648, 29976978, 30090137, 10080174, 15576045, 256154419). Clinical features in affected individuals include LSS, myoclonic epilepsy, leukodystrophy, and optic atrophy. 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: 27509854), functional alteration in patient cells (PMID: 11349233), and studies in *Drosophila melanogaster* (PMID: 30972103), and *Caenorhabditis elegans* (PMID: 19672299). In summary, there is definitive evidence to support the relationship between *NDUFV1* and autosomal recessive *NDUFV1*-related 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 May 20, 2024 (SOP Version 10).

mitochondrial complex I deficiency, nuclear type 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032609

Submitter: Ambry Genetics

Leigh syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NDUFV1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of November 20, 2019. The NDUFV1 gene encodes the NADH:ubiquinone oxidoreductase (complex I) flavoprotein 1, a core subunit of mitochondrial complex I. Defects of this protein lead to complex I deficiency. The NDUFV1 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2001 (PMID: 11349233). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included nine unique variants identified in nine cases from seven publications (PMIDs: 23266820, 29976978, 11349233, 27344648, 30090137, 23334465, 21696386). 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, animal models, and functional alterations in patient cells (PMIDs: 11349233, 30972103, 19672299, 27509854). 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 November 20, 2019 (SOP Version 7).

mitochondrial complex I deficiency, nuclear type 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032609

Submitter: G2P

Clinical Genomic Database (CGD)

Mitochondrial complex I deficiency, nuclear type 4AR

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: 10080174; 11743516; 18991197; 21696386

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NDUFV1 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 447

not specifiedTotal: 78

Inborn genetic diseasesTotal: 74

Mitochondrial complex I deficiency, nuclear type 4Total: 67

Leigh syndromeTotal: 51

Mitochondrial complex I deficiency, nuclear type 1Total: 51

NDUFV1-related disorderTotal: 36

Mitochondrial complex I deficiencyTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007103.4. 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	5 clinvar	139 clinvar	3 clinvar	148
missense	5 clinvar	29 clinvar	168 clinvar	9 clinvar		211
nonsense	7 clinvar	5 clinvar	1 clinvar			13
start loss		3 clinvar				3
frameshift	12 clinvar	14 clinvar		1 clinvar		27
splice donor/acceptor (+/-2bp)	1 clinvar	10 clinvar	3 clinvar			14
Total	25	62	177	149	3	416

Highest pathogenic variant AF is 0.00016170523

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 57 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007103.4	RefSeq	NP_009034.2	10	MANE Select
ENST00000322776.11	Ensembl	ENSP00000322450.6	10	MANE Select
NM_001166102.2	RefSeq	NP_001159574.1	10	Standard
ENST00000415352.6	Ensembl	ENSP00000395368.2	10	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
mitochondrial ATP synthesis coupled electron transport
cellular respiration

Molecular Function

NADH dehydrogenase activity
NADH dehydrogenase (ubiquinone) activity
FMN binding
metal ion binding
NAD binding

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial respiratory chain complex I
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000322776
Coding exons: 10
Length: 5684
Individuals with no LoFs: 125689
Homozygous LoFs: 0
Heterozygous LoFs: 59
Defined: 125748
p: 0.000235

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.282	281	295	0.954	0.0000212	2980
Missense (PolyPhen)		120	143.35	0.83713		1402
Synonymous	0.142	120	122	0.984	0.00000905	968
Loss of Function	0.799	18	22.0	0.816	0.00000121	241

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00014	0.00012	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0	0.0	absent
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.00027	0.00026	rare
South Asian	0.00039	0.00039	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). {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:10080174}. 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:10080174, ECO:0000269|PubMed:11349233}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.260

Intolerance Scores

LoFtool: 0.102
RVIS EVS: -1.49
RVIS percentile EVS: 3.63

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.860

Gene Damage Prediction

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