NDUFA6

protein-coding

NADH:ubiquinone oxidoreductase subunit A6, the group of NADH:ubiquinone oxidoreductase supernumerary subunits|LYR motif containing

Gene summary

This gene encodes a member of the LYR family of proteins that contain a highly conserved tripeptide (LYR) motif near the N-terminus. The encoded protein is an accessory subunit of NADH: ubiquinone oxidorerductase (Complex I), which is the largest enzyme of the mitochondrial membrane respiratory chain. Complex I functions in electron transfer from NADH to the respiratory chain. [provided by RefSeq, Oct 2016]

MANE transcript

NM_002490.6

Inheritance

ClinVar variants

P:8U:42B:16

Top phenotype

Medical treatment (eg, riboflavin, ubiquinol) may be beneficial; Individuals may have cardiac involvement

gnomAD constraint

pLI —, LoF o/e 0.93

Max pathogenic AF

—

Genomic locus

chr22:42,085,526-42,090,884

External References & Databases

Ensembl (ENSG00000184983)

Transcript & Mutation Effects

hg38 • Region Span ~5.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial complex I deficiency, nuclear type 33STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032636

Submitter: PanelApp Australia

mitochondrial complex I deficiency, nuclear type 33MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032636

Submitter: Ambry Genetics

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFA6* and *NDUFA6*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 29, 2024. The *NDUFA6* gene encodes the NADH:ubiquinone oxidoreductase (complex I) subunit A6, a complex I accessory protein required for complex I assembly and function within the mitochondria. Defects of this protein lead to complex I deficiency. The first and only report of *NDUFA6* in relation to autosomal recessive primary mitochondrial disease was in 2018 (PMID: 30245030). *NDUFA6* has been associated with a single disease entity to date; mitochondrial complex I deficiency, nuclear type 33 [OMIM# 618253]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *NDUFA6*-related primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six unique variants (one missense variant, one start loss variant, three frameshift variants, and one nonsense variant predicted to escape nonsense mediated decay) identified in four unrelated cases from one publication (PMIDs: 30245030). Age of onset ranges from the prenatal period to early childhood. Clinical features in affected individuals include small for gestational age, intrauterine growth restriction, oligohydramnios, developmental regression, seizures, dystonia, spasticity, feeding difficulty, optic atrophy, lactic acidosis, and hypoglycemia. White matter abnormalities and/or basal ganglia lesions have been seen on brain imaging. 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), NDUFA6 knock out in HEK293T cells (PMID: 27626371), and a *C.elegans* model (PMID: 38215760). In summary, there is moderate evidence to support the relationship between *NDUFA6* and autosomal recessive *NDUFA6*-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 April 29, 2024 (SOP Version 10).

mitochondrial complex I deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet

mitochondrial complex I deficiency, nuclear type 33STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032636

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial complex I deficiency, nuclear type 33STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032636

Submitter: G2P

Clinical Genomic Database (CGD)

Medical treatment (eg, riboflavin, ubiquinol) may be beneficial; Individuals may have cardiac involvementAR

Manifestation: Biochemical; 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, uniquinol) may be beneficial; Individuals may have cardiac involvement

Refs: 30245030

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NDUFA6 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 39

Inborn genetic diseasesTotal: 24

Mitochondrial complex I deficiency, nuclear type 33Total: 10

Mitochondrial diseaseTotal: 6

not specifiedTotal: 5

NDUFA6-related disorderTotal: 3

Fetal anomalies with a likely genetic causeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002490.6. 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			3 clinvar	13 clinvar		16
missense	1 clinvar		34 clinvar	3 clinvar		38
nonsense	1 clinvar		1 clinvar			2
start loss			2 clinvar			2
frameshift	2 clinvar	4 clinvar	1 clinvar			7
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	4	4	42	16	0	66

Highest pathogenic variant AF is 0.00008053914

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002490.6	RefSeq	NP_002481.3	3	MANE Select
ENST00000498737.8	Ensembl	ENSP00000418842.3	3	MANE Select
ENST00000470753.1	Ensembl	ENSP00000473478.1	2	Standard
ENST00000617763.1	Ensembl	ENSP00000482543.1	3	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
mitochondrial respiratory chain complex I assembly

Molecular Function

NADH dehydrogenase (ubiquinone) activity

Cellular Component

mitochondrial inner membrane
mitochondrial respiratory chain complex I
mitochondrial membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000498737
Coding exons: 3
Length: 5431
Individuals with no LoFs: 125688
Homozygous LoFs: 0
Heterozygous LoFs: 60
Defined: 125748
p: 0.000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.799	111	89.7	1.24	0.00000513	1016
Missense (PolyPhen)		30	28.806	1.0415		324
Synonymous	-2.70	53	33.2	1.60	0.00000176	301
Loss of Function	0.168	6	6.46	0.929	3.66e-7	67

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00032	0.00032	rare
South Asian	0.00029	0.00029	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed to be not 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: 0.336

Intolerance Scores

LoFtool: 0.825
RVIS EVS: 0.46
RVIS percentile EVS: 78.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.942

Gene Damage Prediction

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