COX7B

protein-coding

cytochrome c oxidase subunit 7B, the group of Mitochondrial complex IV: cytochrome c oxidase subunits

Gene summary

Cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. This component 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 function in the regulation and assembly of the complex. This nuclear gene encodes subunit VIIb, which is highly similar to bovine COX VIIb protein and is found in all tissues. This gene may have several pseudogenes on chromosomes 1, 2, 20 and 22. [provided by RefSeq, Jun 2011]

MANE transcript

NM_001866.3

Inheritance

ClinVar variants

P:3U:19B:10

Top phenotype

Linear skin defects with multiple congenital anomalies 2

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:77,899,440-77,907,376

External References & Databases

Ensembl (ENSG00000131174)

Transcript & Mutation Effects

hg38 • Region Span ~7.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

linear skin defects with multiple congenital anomaliesSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010672

Submitter: Orphanet

linear skin defects with multiple congenital anomalies 2DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010474

Submitter: G2P

mitochondrial diseaseLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *COX7B* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of September 30, 2024. The *COX7B* gene encodes the cytochrome *c* oxidase (complex IV) subunit 7B. The first and only report of the *COX7B* gene in relation to X-linked primary mitochondrial disease was in 2012 (PMID: 23122588). *COX7B* has been associated with a single disease entity to date; linear skin defects with multiple congenital anomalies 2 [OMIM# 300887]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and is considered a primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three variants (one nonsense, one frameshift, one splice acceptor) identified in three unrelated female probands from one publication (PMIDs: 23122588). All three probands had microcephaly, linear skin lesions on the face and neck, and poor growth. The mother of one proband also had the variant and presented at birth with linear skin defects. Additional features seen in the probands include intellectual disability, learning disability, and short stature. 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), functional studies in HeLa cells (PMID: 23122588), and a medaka fish model (PMID: 23122588). In summary, there is moderate evidence to support the relationship between *COX7B* and X-linked primary mitochondrial disease. However, this Expert Panel elected to downgrade the classification to limited as biochemistry was not performed in the probands, and because almost all of the evidence comes from one publication. 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 September 30, 2024 (SOP Version 10).

linear skin defects with multiple congenital anomalies 2STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010474

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Linear skin defects with multiple congenital anomalies 2XL

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 9747372; 23122588

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COX7B variants in ClinVar

5 Conditions Cataloged

not providedTotal: 23

Inborn genetic diseasesTotal: 7

Linear skin defects with multiple congenital anomalies 2Total: 6

not specifiedTotal: 3

COX7B-related disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001866.3. 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			2 clinvar	4 clinvar		6
missense			13 clinvar	5 clinvar	1 clinvar	19
nonsense	1 clinvar		1 clinvar			2
start loss			1 clinvar			1
frameshift	1 clinvar					1
splice donor/acceptor (+/-2bp)	1 clinvar		2 clinvar			3
Total	3	0	19	9	1	32

Loading ClinVar variants...

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_001866.3	RefSeq	NP_001857.1	3	MANE Select
ENST00000650309.2	Ensembl	ENSP00000497474.1	3	MANE Select
ENST00000373335.4	Ensembl	ENSP00000496880.1	2	Standard
ENST00000373335.5	Ensembl	ENSP00000496880.1	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

central nervous system development
electron transport chain
proton transmembrane transport

Molecular Function

cytochrome-c oxidase activity

Cellular Component

mitochondrial inner membrane
mitochondrial respirasome
integral component of membrane
respiratory chain complex IV

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000481445
Coding exons: 3
Length: 7936
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	0.424	25	31.7	0.788	0.00000240	521
Missense (PolyPhen)		2	6.7873	0.29467		159
Synonymous	-0.763	14	10.8	1.30	8.27e-7	149
Loss of Function	1.77	0	3.66	0.00	2.87e-7	49

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: This protein is one of the nuclear-coded polypeptide chains of cytochrome c oxidase, the terminal oxidase in mitochondrial electron transport. Plays a role in proper central nervous system (CNS) development in vertebrates. {ECO:0000269|PubMed:23122588}.;
Disease: DISEASE: Linear skin defects with multiple congenital anomalies 2 (LSDMCA2) [MIM:300887]: A distinct form of aplasia cutis congenita presenting as multiple linear skin defects on the face and neck associated with poor growth, microcephaly, and facial dysmorphism. Additional features include intellectual disability, nail dystrophy, short stature and cardiac abnormalities. {ECO:0000269|PubMed:23122588}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0840

Intolerance Scores

RVIS EVS: 0.28
RVIS percentile EVS: 70.87

Essentials

Essential (CRISPR): N
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.819

Gene Damage Prediction

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