NDUFA12

protein-coding

NADH:ubiquinone oxidoreductase subunit A12, the group of NADH:ubiquinone oxidoreductase supernumerary subunits

Gene summary

This gene encodes a protein which is part of mitochondrial complex 1, part of the oxidative phosphorylation system in mitochondria. Complex 1 transfers electrons to ubiquinone from NADH which establishes a proton gradient for the generation of ATP. Mutations in this gene are associated with Leigh syndrome due to mitochondrial complex 1 deficiency. Pseudogenes of this gene are located on chromosomes 5 and 13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2012]

MANE transcript

NM_018838.5

Inheritance

ClinVar variants

P:15U:44B:19

Top phenotype

Mitochondrial complex I deficiency, nuclear type 23; Leigh syndrome

gnomAD constraint

pLI —, LoF o/e 0.8

Max pathogenic AF

—

Genomic locus

chr12:94,895,297-95,003,748

External References & Databases

Ensembl (ENSG00000184752)

Transcript & Mutation Effects

hg38 • Region Span ~108.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Leigh syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NDUFA12 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of August 21, 2019. The NDUFA12 gene encodes the NADH:ubiquinone oxidoreductase (complex I) subunit A12, a non-catalytic complex I accessory protein which plays a role in complex I assembly and function within the mitochondria. Defects of this protein lead to complex I deficiency. The NDUFA12 gene has been reported in relation to autosomal recessive Leigh syndrome spectrum in a single publication in 2011 (PMID: 21617257). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one homozygous variant identified in one case in one publication (PMID: 21617257). 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 functional alteration in non-patient cells (PMIDs: 24717771, 27509854). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, 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 August 21, 2019 (SOP Version 7).

mitochondrial complex I deficiency, nuclear type 23MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032627

Submitter: Ambry Genetics

mitochondrial complex I deficiency, nuclear type 23DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032627

Submitter: G2P

mitochondrial complex I deficiency, nuclear type 23STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032627

Submitter: PanelApp Australia

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFA12* and *NDUFA12*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 18, 2024. The *NDUFA12* gene encodes NADH-ubiquinone oxidoreductase subunit A12, a non-catalytic complex I accessory protein which plays a role in complex I assembly and function. The *NDUFA12* gene was first reported in relation to autosomal recessive *NDUFA12*-related primary mitochondrial disease in 2011 (PMID: 21617257). *NDUFA12* has been associated with a single disease entity to date; mitochondrial complex I deficiency, nuclear type 23 [OMIM# 618244]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *NDUFA12*-related primary mitochondrial disease. Of note, *NDUFA12* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on August 21, 2019 (SOP v7), with a final classification of Limited. This current curation for the association with *NDUFA12*-related primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six unique variants (one missense, two frameshift, three nonsense) identified in six unrelated cases from three publications (PMIDs: 21617257, 29093663, 33715266). Of note, the maximum case level data score was reached, but there are an additional nine cases from six kindreds that have been reported (PMID: 35141356). Age of onset varied from early in life to childhood and most reported individuals were living at the time of report. Clinical features in affected individuals include Leigh syndrome spectrum disorder and optic atrophy. Muscle biopsies showed complex I deficiency when performed. Elevated blood lactate was seen. 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 by functional alteration studies in non-patient cells (PMIDs: 27626371, 24717771). In summary, there is definitive evidence to support the relationship between *NDUFA12* and autosomal recessive *NDUFA12*-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 January 18, 2024 (SOP Version 10).

mitochondrial complex I deficiency, nuclear type 23STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032627

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Mitochondrial complex I deficiency, nuclear type 23; 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: 21617257; 33715266; 35141356

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NDUFA12 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 61

Inborn genetic diseasesTotal: 23

Mitochondrial complex I deficiency, nuclear type 23Total: 13

not specifiedTotal: 8

NDUFA12-related disorderTotal: 4

Leigh syndromeTotal: 3

SLC35A2-congenital disorder of glycosylationTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018838.5. 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			2 clinvar	15 clinvar	1 clinvar	18
missense	1 clinvar		38 clinvar	3 clinvar		42
nonsense	3 clinvar	3 clinvar				6
start loss		1 clinvar				1
frameshift	4 clinvar	2 clinvar	3 clinvar			9
splice donor/acceptor (+/-2bp)		1 clinvar	1 clinvar			2
Total	8	7	44	18	1	78

Highest pathogenic variant AF is 0.000045854107

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018838.5	RefSeq	NP_061326.1	4	MANE Select
ENST00000327772.7	Ensembl	ENSP00000330737.2	4	MANE Select
NM_001258338.2	RefSeq	NP_001245267.1	3	Standard
ENST00000546788.1	Ensembl	ENSP00000448545.1	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

response to oxidative stress
respiratory gaseous exchange
mitochondrial respiratory chain complex I assembly
mitochondrial ATP synthesis coupled electron transport

Molecular Function

NADH dehydrogenase (ubiquinone) activity
electron transfer activity

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: ENST00000327772
Coding exons: 4
Length: 106716
Individuals with no LoFs: 125721
Homozygous LoFs: 0
Heterozygous LoFs: 26
Defined: 125747
p: 0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.00353	83	83.1	0.999	0.00000456	947
Missense (PolyPhen)		22	27.002	0.81475		363
Synonymous	-0.921	36	29.6	1.22	0.00000155	273
Loss of Function	0.536	7	8.71	0.804	4.62e-7	88

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.00032	0.00032	rare
European (Non-Finnish)	0.000053	0.000053	rare
South Asian	0.000098	0.000098	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}.;
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:21617257}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.112

Intolerance Scores

LoFtool: 0.759
RVIS EVS: -0.1
RVIS percentile EVS: 46.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.845

Gene Damage Prediction

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