NDUFB11

protein-coding

NADH:ubiquinone oxidoreductase subunit B11, the group of NADH:ubiquinone oxidoreductase supernumerary subunits

Gene summary

The protein encoded by this gene is a subunit of the multisubunit NADH:ubiquinone oxidoreductase (complex I). Mammalian complex I is located at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to ubiquinone. Mutations in the human gene are associated with linear skin defects with multiple congenital anomalies 3 and mitochondrial complex I deficiency. [provided by RefSeq, Dec 2016]

MANE transcript

NM_001135998.3

Inheritance

ClinVar variants

P:9U:44B:23

Top phenotype

Linear skin defects with multiple congenital anomalies 3

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:47,142,071-47,145,466

External References & Databases

Ensembl (ENSG00000147123)

Transcript & Mutation Effects

hg38 • Region Span ~3.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial complex I deficiency, nuclear type 30STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0026721

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFB11* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 20, 2022. *NDUFB11* encodes an accessory subunit of complex I of the mitochondrial respiratory chain. *NDUFB11* was first reported in relation to X-linked mitochondrial disease in 2015 (PMID: 25772934). While various names have been given to the constellation of features seen in those with *NDUFB11*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *NDUFB11* 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 eight unique variants, comprising four nonsense and frameshift variants, three missense variants, and one in-frame deletion, in 13 probands across seven publications (PMIDs: 25772934, 25921236, 26741492, 27488349, 28050600, 27102574, 30423443). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Of note, *NDUFB11* pathogenic variants were initially reported in individuals with linear skin defects, failure to thrive, developmental delay, and histiocytoid cardiomyopathy. Subsequent publications have shown expansion of the phenotypic spectrum, ranging from isolated cardiomyopathy to multisystemic disorders including cardiomyopathy, optic atrophy, myopathy, short stature, and hearing impairment. The recurrent in-frame deletion, c.276_278del (p.Phe93del) has been reported in at least five probands (PMIDs: 27488349, 27102574) with a unique presentation of sideroblastic anemia with or without some of the multisystemic features described above. Loss-of-function is implicated as the mechanism of disease. This gene-disease association is also supported by the known biochemical function, rescue in a cell culture model, and animal models (PMIDs: 27509854, 25921236, 26741492, 27488349, 27102574). More evidence is available in the literature, but the maximum score for experimental evidence (6 points) has been reached. In summary, *NDUFB11* is definitively associated with X-linked mitochondrial disease. This has been repeatedly demonstrated and has been upheld over time. 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 January 20, 2022 (SOP Version 8).

linear skin defects with multiple congenital anomalies 3STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010494

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial complex I deficiency, nuclear type 30STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0026721

Submitter: PanelApp Australia

linear skin defects with multiple congenital anomaliesSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010672

Submitter: Orphanet

Clinical Genomic Database (CGD)

Linear skin defects with multiple congenital anomalies 3XL

Manifestation: Biochemical; Cardiovascular; Dermatologic; Neurologic

Intervention: Cardiovascular

Rationale: Among other findings, individuals have been described with early-onset cardiomyopathy, and awareness may allow prompt awareness and management

Comments: Cardiac transplantation has been described

Refs: 25772934; 26741492

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NDUFB11 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 61

not specifiedTotal: 21

Inborn genetic diseasesTotal: 15

Linear skin defects with multiple congenital anomalies 3Total: 10

NDUFB11-related disordersTotal: 9

Mitochondrial complex I deficiency, nuclear type 30Total: 7

Linear skin defects with multiple congenital anomalies 1Total: 2

Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001135998.3. 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	15 clinvar		16
missense		2 clinvar	40 clinvar	6 clinvar	1 clinvar	49
nonsense	1 clinvar	1 clinvar				2
start loss			1 clinvar			1
frameshift	1 clinvar	3 clinvar	1 clinvar			5
splice donor/acceptor (+/-2bp)		1 clinvar	1 clinvar	1 clinvar		3
Total	2	7	44	22	1	76

Highest pathogenic variant AF is 0.000015485304

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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_001135998.3	RefSeq	NP_001129470.1	3	MANE Select
ENST00000377811.4	Ensembl	ENSP00000367042.3	3	MANE Select
NM_019056.7	RefSeq	NP_061929.2	3	Standard
ENST00000276062.10	Ensembl	ENSP00000276062.9	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ndufb11	Danio rerio	Structure: trunk vasculature Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

ndufb11

Danio rerio

Structure: trunk vasculature

Quality: morphology

abnormal

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

Molecular Function

protein binding

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: ENST00000276062
Coding exons: 3
Length: 3289
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.513	54	65.7	0.822	0.00000506	1046
Missense (PolyPhen)		14	23.13	0.60527		388
Synonymous	-0.292	30	28.0	1.07	0.00000227	333
Loss of Function	2.15	0	5.39	0.00	4.86e-7	71

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	0.0	absent
South Asian	0	0.0	absent
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:26741492}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.335

Intolerance Scores

RVIS EVS: -0.05
RVIS percentile EVS: 49.39

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.613

Gene Damage Prediction

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