NDUFAF2

protein-coding

NADH:ubiquinone oxidoreductase complex assembly factor 2, the group of Mitochondrial respiratory chain complex assembly factors

Gene summary

NADH:ubiquinone oxidoreductase (complex I) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. This gene encodes a complex I assembly factor. Mutations in this gene cause progressive encephalopathy resulting from mitochondrial complex I deficiency. [provided by RefSeq, Jul 2008]

Previous symbols:

NDUFA12L

MANE transcript

NM_174889.5

Inheritance

ClinVar variants

P:24U:38B:52

Top phenotype

Mitochondrial complex I deficiency, nuclear type 10; Leigh syndrome

gnomAD constraint

pLI —, LoF o/e 0.93

Max pathogenic AF

—

Genomic locus

chr5:60,945,177-61,154,531

External References & Databases

Ensembl (ENSG00000164182)

Transcript & Mutation Effects

hg38 • Region Span ~209.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Leigh syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NDUFAF2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of April 20, 2020. The NDUFAF2 gene encodes NADH:ubiquinone oxidoreductase (complex I) assembly factor 2. Defects of this protein lead to a complex I deficiency. The NDUFAF2 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2005 (PMID: 16200211). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six unique variants identified in seven cases from five publications (PMIDs: 16200211, 18180188, 19384974, 20571988, 20818383). 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, expression data, and cell culture models (PMIDs: 27977873, 16200211, 25613900, 23702311). 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 on April 20, 2020 (SOP Version 7).

Leigh syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: G2P

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFAF2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 18, 2023. The *NDUFAF2* gene (previously known as *B17.2L* and *NDUFA12L*) encodes the NADH:ubiquinone oxidoreductase (complex I) assembly factor 2. Defects of this protein lead to complex I deficiency. *NDUFAF2* was first reported in relation to autosomal recessive primary mitochondrial disease in 2005 (PMID: 16200211). While various names have been given to the constellation of features seen in those with *NDUFAF2*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *NDUFAF2* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *NDUFAF2* was first curated by this GCEP for its association with Leigh syndrome spectrum (LSS) on November 23, 2020 (SOP v7), with a final classification of Definitive. The scope of this current curation encompassed cases of primary mitochondrial disease, which includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six variants (three unique nonsense variants, one start-loss variant, two frameshift variants expected to result in protein truncation) in four probands from four publications (PMIDs: 19384974, 20818383, 26795593, 37938061). Affected individuals had Leigh syndrome spectrum, progressive encephalopathy, and Leber Hereditary Optic Neuropathy. Complex I deficiency was noted in affected individuals in various tissues. Additional cases are reported in the literature, but maximum case scoring was reached. The mechanism of disease is loss of function. This gene-disease association is also supported by its known biochemical function in mitochondrial complex I shared by more than 10 other genes also associated with primary mitochondrial disease, electron transport chain deficiencies in knockdown cell lines, and rescue studies in patient cells (PMIDs: 28797839, 23702311, 16200211). In summary, there is definitive evidence to support the relationship between *NDUFAF2* 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 December 18, 2023 (SOP Version 10).

mitochondrial complex I deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet

mitochondrial complex I deficiency, nuclear type 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032616

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial complex I deficiency, nuclear type 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032616

Submitter: PanelApp Australia

mitochondrial complex I deficiency, nuclear type 10MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032616

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Mitochondrial complex I deficiency, nuclear type 10; 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; 16200211; 20571988; 20818383

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NDUFAF2 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 108

Inborn genetic diseasesTotal: 26

Mitochondrial complex I deficiency, nuclear type 10Total: 21

not specifiedTotal: 17

Leigh syndromeTotal: 16

Mitochondrial complex I deficiency, nuclear type 1Total: 14

Cockayne syndrome type 1Total: 4

NDUFAF2-related disorderTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_174889.5. 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	43 clinvar		44
missense			35 clinvar	7 clinvar	1 clinvar	43
nonsense	1 clinvar	7 clinvar	1 clinvar			9
start loss		1 clinvar				1
frameshift	7 clinvar	7 clinvar	1 clinvar	1 clinvar		16
splice donor/acceptor (+/-2bp)		1 clinvar				1
Total	8	16	38	51	1	114

Highest pathogenic variant AF is 0.000116473435

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_174889.5	RefSeq	NP_777549.1	4	MANE Select
ENST00000296597.10	Ensembl	ENSP00000296597.5	4	MANE Select
ENST00000502658.1	Ensembl	ENSP00000426149.1	3	Standard
ENST00000511107.1	Ensembl	ENSP00000423377.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Thermogenesis - Homo sapiens (human)
Respiratory electron transport
The citric acid (TCA) cycle and respiratory electron transport
Metabolism
Complex I biogenesis

Biological Process

respiratory electron transport chain
mitochondrial respiratory chain complex I assembly
cellular respiration
negative regulation of insulin secretion involved in cellular response to glucose stimulus
reactive oxygen species metabolic process

Molecular Function

NADH dehydrogenase (ubiquinone) activity
electron transfer activity

Cellular Component

mitochondrion
mitochondrial inner membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000296597
Coding exons: 4
Length: 207898
Individuals with no LoFs: 125694
Homozygous LoFs: 0
Heterozygous LoFs: 54
Defined: 125748
p: 0.000215

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0661	82	80.3	1.02	0.00000360	1103
Missense (PolyPhen)		24	22.649	1.0596		296
Synonymous	-0.645	32	27.7	1.16	0.00000130	291
Loss of Function	0.189	9	9.63	0.934	4.77e-7	119

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00033	0.00031	rare
Latino/Admixed American	0.00021	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00049	0.00049	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00021	0.00020	rare
South Asian	0.00031	0.00026	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as a molecular chaperone for mitochondrial complex I assembly (PubMed:16200211). 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 (PubMed:16200211, PubMed:27626371). {ECO:0000269|PubMed:16200211, 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:16200211}. Note=The disease is caused by mutations affecting the gene represented in this entry.; 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:20571988}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0524

Intolerance Scores

LoFtool: 0.762
RVIS EVS: 0.08
RVIS percentile EVS: 59.76

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.307

Gene Damage Prediction

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