OXA1L

protein-coding

OXA1L mitochondrial inner membrane protein, the group of Mitochondrial respiratory chain complex assembly factors

Gene summary

This gene encodes an evolutionarily conserved protein that is localized to the inner mitochondrial membrane. The encoded protein is essential for the translocation of the N-terminal tail of subunit 2 of cytochrome c oxidase, and is involved in the assembly of the cytochrome c oxidase and ATPase complexes of the mitochondrial respiratory chain. [provided by RefSeq, Jul 2016]

MANE transcript

NM_005015.5

Inheritance

ClinVar variants

P:2U:83B:8

Top phenotype

OXA1L-related disorder

gnomAD constraint

pLI —, LoF o/e 0.71

Max pathogenic AF

—

Genomic locus

chr14:22,766,522-22,773,042

External References & Databases

Ensembl (ENSG00000155463)

Transcript & Mutation Effects

hg38 • Region Span ~6.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *OXA1L* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 26, 2024. The *OXA1L* gene encodes a mitochondrial membrane insertase that mediates the cotranslational insertion of integral membrane proteins into the mitochondrial inner membrane, and functions in the assembly of mitochondrial respiratory chain complexes IV and V. The first and only report of *OXA1L* in relation to autosomal recessive primary mitochondrial disease was in 2018 (PMID: 30201738). *OXA1L* has been associated with a single disease entity to date; severe, childhood‐onset mitochondrial encephalopathy and combined respiratory chain deficiency (PMID: 30201738). 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 two variants (one frameshift variant and one missense variant that leads to exon skipping and loss of function) identified in one case from one publication (PMID: 30201738). Clinical features in the single reported case include neonatal onset of hypotonia and developmental delay; he then developed a febrile illness at 5 years old and experienced rapid deterioration and onset of seizures and encephalopathy prior to cardiorespiratory arrest. Brain imaging showed dysgenesis of the corpus callosum. 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), rescue in patient cells (PMID: 30201738), *OXA1L* knockout *Drosophila melanogaster* model (PMID: 30201738), and *OXA1L* knockout in HEK293T cells (PMID: 30201738). 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 August 26, 2024 (SOP Version 10).

combined oxidative phosphorylation deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0000732

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to OXA1L variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 77

not providedTotal: 2

OXA1L-related disorderTotal: 2

Mitochondrial diseaseTotal: 2

Prostate cancerTotal: 1

Myoepithelial tumorTotal: 1

Lysinuric protein intoleranceTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005015.5. 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			2 clinvar			2
missense	1 clinvar		77 clinvar	7 clinvar	1 clinvar	86
nonsense						0
start loss						0
frameshift	1 clinvar					1
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	2	0	83	7	1	93

Highest pathogenic variant AF is 0.000001368107

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 37 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005015.5	RefSeq	NP_005006.4	10	MANE Select
ENST00000612549.6	Ensembl	ENSP00000483491.2	10	MANE Select
ENST00000285848.9	Ensembl	ENSP00000285848.5	10	Standard
ENST00000358043.5	Ensembl	ENSP00000350740.5	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Protein export - Homo sapiens (human)
Mitochondrial translation initiation
Translation
Metabolism of proteins
Mitochondrial translation elongation

Biological Process

aerobic respiration
protein transport
negative regulation of ATPase activity
protein insertion into mitochondrial inner membrane from matrix
mitochondrial respiratory chain complex I assembly

Molecular Function

protein binding
membrane insertase activity
protein homodimerization activity
mitochondrial ribosome binding

Cellular Component

mitochondrion
mitochondrial respirasome
mitochondrial matrix
integral component of mitochondrial inner membrane
mitochondrial membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000285848
Coding exons: 10
Length: 5277
Individuals with no LoFs: 125683
Homozygous LoFs: 0
Heterozygous LoFs: 64
Defined: 125747
p: 0.000255

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.956	332	286	1.16	0.0000152	3179
Missense (PolyPhen)		61	54.426	1.1208		569
Synonymous	-2.49	137	105	1.31	0.00000530	1034
Loss of Function	1.38	19	26.7	0.712	0.00000148	267

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00033	0.00033	rare
Finnish	0.00042	0.00042	rare
European (Non-Finnish)	0.00025	0.00025	rare
South Asian	0.00016	0.00016	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for the insertion of integral membrane proteins into the mitochondrial inner membrane. Essential for the activity and assembly of cytochrome oxidase. Required for the correct biogenesis of ATP synthase and complex I in mitochondria. {ECO:0000269|PubMed:17936786, ECO:0000269|PubMed:7991568}.;

Recessive Scores

pRec: 0.0905

Intolerance Scores

LoFtool: 0.903
RVIS EVS: 0.94
RVIS percentile EVS: 89.86

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.827

Gene Damage Prediction

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