NDUFA11

protein-coding

NADH:ubiquinone oxidoreductase subunit A11, the group of NADH:ubiquinone oxidoreductase supernumerary subunits|Tim17 family

Gene summary

This gene encodes a subunit of the membrane-bound mitochondrial complex I. Complex I is composed of numerous subunits and functions as the NADH-ubiquinol reductase of the mitochondrial electron transport chain. Mutations in this gene are associated with severe mitochondrial complex I deficiency. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2010]

MANE transcript

NM_175614.5

Inheritance

ClinVar variants

P:4U:42B:18

Top phenotype

Mitochondrial complex I deficiency, nuclear type 14

gnomAD constraint

pLI —, LoF o/e 0.62

Max pathogenic AF

—

Genomic locus

chr19:5,891,207-5,904,006

External References & Databases

Ensembl (ENSG00000174886)

Transcript & Mutation Effects

hg38 • Region Span ~12.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial complex I deficiency, nuclear type 14MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032619

Submitter: PanelApp Australia

mitochondrial diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFA11* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 17, 2022. The *NDUFA11* gene encodes a subunit of complex I of the mitochondrial respiratory chain. The *NDUFA11* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2008 (PMID: 18306244). While various names have been given to the constellation of features seen in those with *NDUFA11*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *NDUFA11* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one splice region variant that was reported in a homozygous state in three consanguineous Israeli Bedouin families from one publication (PMID: 18306244). RT-PCR from cDNA from patients’ fibroblasts demonstrated a shorter transcript as well as the wild-type transcript, and enzymatic studies from isolated muscle mitochondria showed reduced complex I activity in the three probands (PMID: 18306244). Affected individuals from two families had a fatal infantile lactic acidosis while individuals in the third family had developmental delay, microcephaly, optic atrophy, and seizures. No segregation data were available. This gene-disease association is also supported by known functional alterations in non-patient cells and a Caenorhabditis elegans model organism (PMIDs: 24191001, 27626371, 30531981, 34106255). In summary, there is limited 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/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 17, 2022 (SOP Version 8).

mitochondrial complex I deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet

mitochondrial complex I deficiency, nuclear type 14STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032619

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Mitochondrial complex I deficiency, nuclear type 14AR

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; 18306244

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NDUFA11 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 69

not specifiedTotal: 25

Mitochondrial complex I deficiency, nuclear type 1Total: 10

NDUFA11-related disorderTotal: 6

Mitochondrial complex I deficiency, nuclear type 14Total: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_175614.5. 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	18 clinvar		19
missense		1 clinvar	40 clinvar			41
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar				3
Total	1	3	42	18	0	64

Highest pathogenic variant AF is 0.0000063483913

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_175614.5	RefSeq	NP_783313.1	4	MANE Select
ENST00000308961.5	Ensembl	ENSP00000311740.4	4	MANE Select
NM_001193375.3	RefSeq	NP_001180304.1	4	Standard
ENST00000418389.6	Ensembl	ENSP00000389160.1	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

mitochondrial respiratory chain complex I assembly
oxidation-reduction process

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial respiratory chain complex I
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000418389
Coding exons: 4
Length: 12731
Individuals with no LoFs: 125699
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125701
p: 0.00000796

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.541	117	135	0.869	0.00000802	1409
Missense (PolyPhen)		31	34.753	0.892		337
Synonymous	0.518	55	60.1	0.915	0.00000426	495
Loss of Function	0.769	3	4.82	0.622	2.04e-7	59

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
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)	0.0000088	0.0000088	rare
South Asian	0.000033	0.000033	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: 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:18306244}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0858

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.416

Gene Damage Prediction

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