COX6B1

protein-coding

cytochrome c oxidase subunit 6B1, the group of Mitochondrial complex IV: cytochrome c oxidase subunits

Gene summary

Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. It is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may be involved in the regulation and assembly of the complex. This nuclear gene encodes subunit VIb. Mutations in this gene are associated with severe infantile encephalomyopathy. Three pseudogenes COX6BP-1, COX6BP-2 and COX6BP-3 have been found on chromosomes 7, 17 and 22q13.1-13.2, respectively. [provided by RefSeq, Jan 2010]

Previous symbols:

COX6B

MANE transcript

NM_001863.5

Inheritance

ClinVar variants

P:2U:27B:14

Top phenotype

Mitochondrial complex IV deficiency, nuclear type 7

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr19:35,648,323-35,658,782

External References & Databases

Ensembl (ENSG00000126267)

Transcript & Mutation Effects

hg38 • Region Span ~10.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *COX6B1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 21, 2022. The *COX6B1* gene encodes cytochrome c oxidase (complex IV) subunit 6B1. Defects of this protein lead to complex IV deficiency. The *COX6B1* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2008 (PMID: 18499082). While various names have been given to the constellation of features seen in those with *COX6B1*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *COX6B1* 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 three unique variants, each present in the homozygous state in three cases from three publications (PMIDs: 18499082, 22277967, 24781756). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, expression, functional alteration in non-patient cells, rescue in patient cells, and model systems (PMIDs: 18499082, 24781756, 34937540). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. This classification was approved by NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 21, 2022 (SOP Version 8).

cytochrome-c oxidase deficiency diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009068

Submitter: Orphanet

mitochondrial complex IV deficiency, nuclear type 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033637

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial complex IV deficiency, nuclear type 7DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0033637

Submitter: G2P

Clinical Genomic Database (CGD)

Mitochondrial complex IV deficiency, nuclear type 7AR

Manifestation: Biochemical; Musculoskeletal; 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

Refs: 18499082

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COX6B1 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 45

Mitochondrial complex IV deficiency, nuclear type 7Total: 12

Inborn genetic diseasesTotal: 11

not specifiedTotal: 7

Mitochondrial complex IV deficiency, nuclear type 1Total: 6

COX6B1-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001863.5. 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	12 clinvar		13
missense		2 clinvar	22 clinvar	2 clinvar		26
nonsense			1 clinvar			1
start loss			1 clinvar			1
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	2	27	14	0	43

Highest pathogenic variant AF is 0.0000054726374

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001863.5	RefSeq	NP_001854.1	3	MANE Select
ENST00000649813.2	Ensembl	ENSP00000497926.1	3	MANE Select
ENST00000392201.1	Ensembl	ENSP00000376037.2	3	Standard
ENST00000590618.1	Ensembl	ENSP00000467776.2	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cardiac muscle contraction - 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

substantia nigra development
electron transport chain
proton transmembrane transport

Molecular Function

cytochrome-c oxidase activity
protein binding

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial intermembrane space
respiratory chain complex IV

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000246554
Coding exons: 3
Length: 10639
Individuals with no LoFs: 125746
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125748
p: 0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.748	40	55.7	0.718	0.00000370	576
Missense (PolyPhen)		4	13.266	0.30152		183
Synonymous	0.756	16	20.3	0.787	0.00000142	140
Loss of Function	1.34	2	5.35	0.374	2.30e-7	56

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	0.000046	0.000046	rare
European (Non-Finnish)	0.000018	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Connects the two COX monomers into the physiological dimeric form. {ECO:0000250}.;
Disease: DISEASE: Mitochondrial complex IV deficiency (MT-C4D) [MIM:220110]: A disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Features include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development and mental retardation. Some affected individuals manifest a fatal hypertrophic cardiomyopathy resulting in neonatal death. A subset of patients manifest Leigh syndrome. {ECO:0000269|PubMed:18499082}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.142

Intolerance Scores

LoFtool: 0.433
RVIS EVS: -0.03
RVIS percentile EVS: 51.04

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.855

Gene Damage Prediction

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