OXCT1

protein-coding

3-oxoacid CoA-transferase 1

Gene summary

This gene encodes a member of the 3-oxoacid CoA-transferase gene family. The encoded protein is a homodimeric mitochondrial matrix enzyme that plays a central role in extrahepatic ketone body catabolism by catalyzing the reversible transfer of coenzyme A from succinyl-CoA to acetoacetate. Mutations in this gene are associated with succinyl CoA:3-oxoacid CoA transferase deficiency. [provided by RefSeq, Jul 2008]

Previous symbols:

OXCT

MANE transcript

NM_000436.4

Inheritance

ClinVar variants

P:21U:92B:51

Top phenotype

Succinyl CoA:3-oxoacid CoA transferase deficiency

gnomAD constraint

pLI —, LoF o/e 0.32

Max pathogenic AF

—

Genomic locus

chr5:41,730,065-41,870,425

External References & Databases

Ensembl (ENSG00000083720)

Transcript & Mutation Effects

hg38 • Region Span ~140.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

succinyl-CoA:3-ketoacid CoA transferase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009492

Submitter: PanelApp Australia

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *OXCT1* and *OXCT1*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 15, 2024. *OXCT1*, also known as *SCOT* (succinyl CoA: 3-oxoacid-CoA transferase), catalyzes the reversible transfer of CoA from succinyl-CoA to acetoacetate, the first step of ketone body utilization. The *OXCT1* gene was first reported in relation to autosomal recessive *OXCT1*-related primary mitochondrial disease in 1996 (PMID: 8751852). *OXCT1* has been associated with a single disease entity to date; Succinyl CoA:3-oxoacid CoA transferase deficiency [OMIM#245050]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *OXCT1*-related primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five unique variants (two nonsense, two missense, one splicing) identified in five unrelated cases from five publications (PMIDs: 8751852, 21296660, 34765403, 23281106, 37091464), although there have been at least 44 cases from 39 families reported to date (PMID: 33596448). Affected individuals have episodes of ketoacidosis, often triggered by metabolic stressors, with persistent ketonuria. This gene-disease association is supported by functional alteration in patient cells (PMID: 11757586, 15669687, 10964512), and by rescue studies performed in patient fibroblasts (PMID: 21296660). In summary, there is definitive evidence to support the relationship between *OXCT1* and autosomal recessive *OXCT1*-related primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on July 15, 2024 (SOP Version 10).

succinyl-CoA:3-ketoacid CoA transferase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009492

Submitter: G2P

succinyl-CoA:3-ketoacid CoA transferase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009492

Submitter: Labcorp Genetics (formerly Invitae)

succinyl-CoA:3-ketoacid CoA transferase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009492

Submitter: Orphanet

succinyl-CoA:3-ketoacid CoA transferase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009492

Submitter: Ambry Genetics

succinyl-CoA:3-ketoacid CoA transferase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009492

Submitter: Illumina

Clinical Genomic Database (CGD)

Succinyl CoA:3-oxoacid CoA transferase deficiencyAR

Manifestation: Biochemical

Intervention: Biochemical

Rationale: Diagnosis may allow prompt recognition and treatment of ketoacidotic episodes (eg, with IV glucose and sodium bicarbonate), which may be beneficial to reduce morbidity and mortality

Refs: 4258782; 1405472; 8751852; 9521962; 10964512; 11286388; 11757586; 20652411

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to OXCT1 variants in ClinVar

5 Conditions Cataloged

Succinyl-CoA acetoacetate transferase deficiencyTotal: 164

Inborn genetic diseasesTotal: 35

not providedTotal: 27

OXCT1-related disorderTotal: 15

not specifiedTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000436.4. 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			4 clinvar	44 clinvar	2 clinvar	50
missense	5 clinvar	3 clinvar	81 clinvar	4 clinvar	1 clinvar	94
nonsense	2 clinvar	2 clinvar	2 clinvar			6
start loss						0
frameshift		4 clinvar	1 clinvar			5
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar	4 clinvar			9
Total	9	12	92	48	3	164

Highest pathogenic variant AF is 0.000042202002

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 58 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000436.4	RefSeq	NP_000427.1	17	MANE Select
ENST00000196371.10	Ensembl	ENSP00000196371.5	17	MANE Select
NM_001364299.2	RefSeq	NP_001351228.1	18	Standard
NM_001364300.2	RefSeq	NP_001351229.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Butanoate metabolism - Homo sapiens (human)
Synthesis and degradation of ketone bodies - Homo sapiens (human)
Valine, leucine and isoleucine degradation - Homo sapiens (human)
3-Methylglutaconic Aciduria Type I
Valine, Leucine and Isoleucine Degradation

Biological Process

brain development
heart development
response to nutrient
response to hormone
response to activity

Molecular Function

3-oxoacid CoA-transferase activity
protein homodimerization activity

Cellular Component

nucleoplasm
mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000196371
Coding exons: 17
Length: 140455
Individuals with no LoFs: 125723
Homozygous LoFs: 0
Heterozygous LoFs: 25
Defined: 125748
p: 0.0000994

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.57	169	293	0.578	0.0000153	3390
Missense (PolyPhen)		24	94.938	0.2528		1158
Synonymous	-0.841	111	100	1.11	0.00000546	1004
Loss of Function	3.53	10	31.3	0.319	0.00000172	372

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Key enzyme for ketone body catabolism. Transfers the CoA moiety from succinate to acetoacetate. Formation of the enzyme-CoA intermediate proceeds via an unstable anhydride species formed between the carboxylate groups of the enzyme and substrate.;

Intolerance Scores

LoFtool: 0.212
RVIS EVS: -0.2
RVIS percentile EVS: 38.82

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.375

Gene Damage Prediction

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