COX6A1

protein-coding

cytochrome c oxidase subunit 6A1, 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 the electron transfer and the nuclear-encoded subunits may function in the regulation and assembly of the complex. This nuclear gene encodes polypeptide 1 (liver isoform) of subunit VIa, and polypeptide 1 is found in all non-muscle tissues. Polypeptide 2 (heart/muscle isoform) of subunit VIa is encoded by a different gene, and is present only in striated muscles. These two polypeptides share 66% amino acid sequence identity. It has been reported that there may be several pseudogenes on chromosomes 1, 6, 7q21, 7q31-32 and 12. However, only one pseudogene (COX6A1P) on chromosome 1p31.1 has been documented. [provided by RefSeq, Jul 2008]

Previous symbols:

COX6A

MANE transcript

NM_004373.4

Inheritance

ClinVar variants

U:57B:37

Top phenotype

Charcot-Marie-Tooth disease, recessive intermediate D

gnomAD constraint

pLI —, LoF o/e 0.88

Max pathogenic AF

—

Genomic locus

chr12:120,438,090-120,440,737

External References & Databases

Ensembl (ENSG00000111775)

Transcript & Mutation Effects

hg38 • Region Span ~2.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Charcot-Marie-Tooth disease recessive intermediate DSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014467

Submitter: Orphanet

Charcot-Marie-Tooth disease recessive intermediate DSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014467

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *COX6A1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 18, 2024. The *COX6A1* gene encodes an isoform of a subunit of cytochrome *c* oxidase (COX). *COX6A1* was first reported in relation to autosomal recessive primary mitochondrial disease in 2014 (PMID: 25152455), in two Japanese probands with early childhood onset peripheral neuropathy. A third case with similar clinical features was reported in 2016 (PMID: 26302975). While various names have been given to the constellation of features seen in those with *COX6A1*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *COX6A1* 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 homozygous five base pair intronic deletion resulting in aberrant splicing and loss of function in all reported cases. The mechanism of disease is loss of function. This gene-disease association is also supported by the known biochemical function of COX6A1 as a subunit of complex IV, functional alteration in non-patient cells (PMID: 20307258), and a mouse model that recapitulates the clinical and biochemical phenotype seen in affected individuals (PMID: 25152455) In summary, there is strong evidence to support the relationship between *COX6A1* and autosomal recessive primary mitochondrial disease. While the three publications related to this gene-disease curation covered a span of six years (2010-2016), this Expert Panel elected to classify this association as strong given that a single variant only has been reported in the three unrelated probands, and two of these probands were from consanguineous families, raising the possibility other genetic etiologies could be present. We will re-evaluate this gene-disease relationship in the future to determine if an upgraded classification of Definitive is warranted. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 18, 2024 (SOP Version 10).

Charcot-Marie-Tooth disease recessive intermediate DLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014467

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Charcot-Marie-Tooth disease, recessive intermediate DAR

Manifestation: Musculoskeletal; Neurologic

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: 25152455

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COX6A1 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 95

not specifiedTotal: 31

COX6A1-related disorderTotal: 6

Charcot-Marie-Tooth disease recessive intermediate DTotal: 2

Peripheral neuropathyTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004373.4. 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				34 clinvar		34
missense			50 clinvar	3 clinvar		53
nonsense			1 clinvar			1
start loss			2 clinvar			2
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	57	37	0	94

Highest pathogenic variant AF is 0.000042320033

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004373.4	RefSeq	NP_004364.2	3	MANE Select
ENST00000229379.3	Ensembl	ENSP00000229379.2	3	MANE Select
ENST00000932192.1	Ensembl	ENSP00000602251.1	3	Standard
ENST00000932192.2	Ensembl	ENSP00000602251.1	3	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

generation of precursor metabolites and energy
mitochondrial electron transport, cytochrome c to oxygen
aerobic respiration
regulation of catalytic activity
proton transmembrane transport

Molecular Function

cytochrome-c oxidase activity
enzyme regulator activity

Cellular Component

mitochondrion
mitochondrial inner membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000229379
Coding exons: 3
Length: 2653
Individuals with no LoFs: 125725
Homozygous LoFs: 0
Heterozygous LoFs: 22
Defined: 125747
p: 0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.42	99	66.5	1.49	0.00000312	696
Missense (PolyPhen)		22	16.847	1.3059		220
Synonymous	-1.93	41	28.0	1.46	0.00000139	233
Loss of Function	0.247	4	4.57	0.875	1.96e-7	48

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00014	0.00014	rare
South Asian	0.000098	0.000098	rare
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.;
Disease: DISEASE: Charcot-Marie-Tooth disease, recessive, intermediate type, D (CMTRID) [MIM:616039]: A form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Recessive intermediate forms of Charcot-Marie-Tooth disease are characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec. {ECO:0000269|PubMed:25152455}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0899

Intolerance Scores

LoFtool: 0.356
RVIS EVS: -0.32
RVIS percentile EVS: 31.46

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.575

Gene Damage Prediction

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