GeneBe

OTC

protein-coding

ornithine transcarbamylase

Gene summary

This nuclear gene encodes a mitochondrial matrix enzyme. The encoded protein is involved in the urea cycle which functions to detoxify ammonia into urea for excretion. Mutations in this enzyme lead to ornithine transcarbamylase deficiency, which causes hyperammonemia. [provided by RefSeq, May 2022]

MANE transcript

NM_000531.6

Inheritance

XL, XLR

ClinVar variants

P:447U:193B:163

Top phenotype

Ornithine transcarbamylase deficiency

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chrX:38,327,598-38,422,908

External References & Databases

Ensembl (ENSG00000036473)NCBI Gene (5009)OMIM (300461)HGNC:8512GenCCUniProt (P00480)AlphaFoldClinVar (OTC)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~95.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ornithine carbamoyltransferase deficiencySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010703

Submitter: PanelApp Australia

ornithine carbamoyltransferase deficiencyDEFINITIVE

Inheritance Pattern: XLR

Disease ID:MONDO:0010703

Submitter: Natera

ornithine carbamoyltransferase deficiencySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010703

Submitter: Orphanet

ornithine carbamoyltransferase deficiencyDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010703

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

ornithine carbamoyltransferase deficiencySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010703

Submitter: Labcorp Genetics (formerly Invitae)

ornithine carbamoyltransferase deficiencyDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010703

Submitter: G2P

ornithine carbamoyltransferase deficiencyDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010703

Submitter: ClinGen

The relationship between OTC and ornithine carbamoyltransferase deficiency (X-linked) was evaluated using the ClinGen Clinical Validity Framework as of February, 2019. The OTC gene is located on the X chromosome and encodes a mitochondrial matrix enzyme that catalyzes the second step of the urea cycle. Most patients with OTC deficiency are hemizygous males, but female carriers can also be symptomatic. Variants in OTC were first reported in humans with this disease as early as 1985 (Rozen et al., PMID 2983225). More than 400 variants (missense, nonsense, frameshift, in-frame indels, and large deletions) have been reported in humans (Caldovic et al., 2015, PMID 26059767). Evidence supporting this gene-disease relationship includes case-level and experimental data. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is supported by biochemical assays, expression studies, and model systems. In summary, OTC is definitively associated with X-linked ornithine carbamoyltransferase deficiency . This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Clinical Genomic Database (CGD)

Ornithine transcarbamylase deficiencyXL

Manifestation: Biochemical; Gastrointestinal; Neurologic

Intervention: Biochemical; Pharmacogenomic

Rationale: Treatment to prevent and treat severe sequelae can be beneficial, including prompt recognition and management of acute decompensation (eg, with rapid measures to control hyperammonemia, such as with dialysis, nitrogen scavengers therapy, appropriate treatment related to catabolism and hydration, and replacement of citrulline/arginine); Long-term dietary measures (eg, decreasing the nitrogen load with low protein diet, use of nitrogen scavengers, and administration of arginine/citrulline) may be beneficial; Certain agents (eg, valproate, haloperidol, and systemic corticosteroids, as well as triggers such as fasting, and physical/psychological stress, with specific considerations during pregnancy to decrease the risk of catabolism) should be avoided due to the potential of adverse events; Hepatic transplant is considered in certain individuals with frequent hyperammonemic episodes, and has been described in infancy

Comments: While males are typically severely affected and may require liver transplant (therapy with modalities such as adult derived human liver stem/progenitor cells has also been described), the presentation in females may be more subtle

Refs: 13975632; 6112522; 7351973; 7078580; 7151305; 6427608; 3001312; 2983225; 3945292; 3826955; 3202644; 2843770; 3170748; 1671317; 2342525; 2298453; 1720458; 1549234; 8364586; 8778603; 8786061; 10946359; 11804205; 12063505; 18071043; 20142522; 20301396; 20458665; 20497355; 20817516; 21061009; 21585627; 21642786; 21884343; 21918856; 21926883; 21956151; 22138526; 22232626; 22264779; 22340867; 22507172; 22563224; 22583334; 22594780; 22727265; 22728053; 23209112; 23231960; 23278509; 23283608; 23430866; 23551631; 23568734; 23640148; 23790482; 24006547; 24073003; 24113687; 24142276; 25135652; 29396029; 31441224Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to OTC variants in ClinVar

12 Conditions Cataloged
Ornithine carbamoyltransferase deficiencyTotal: 695
not providedTotal: 420
not specifiedTotal: 50
Inborn genetic diseasesTotal: 37
OTC-related disorderTotal: 16
HyperammonemiaTotal: 3
Likely inborn error of metabolismTotal: 3
Protein avoidanceTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000531.6. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
2
clinvar
7
clinvar
136
clinvar
2
clinvar
 149
missense
179
clinvar
114
clinvar
177
clinvar
23
clinvar
1
clinvar
 494
nonsense
40
clinvar
8
clinvar
1
clinvar
 49
start loss
3
clinvar
1
clinvar
 4
frameshift
37
clinvar
12
clinvar
1
clinvar
 50
splice donor/acceptor (+/-2bp)
41
clinvar
8
clinvar
7
clinvar
1
clinvar
 57
Total3021451931603803

Highest pathogenic variant AF is 0.000015634312

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000531.6RefSeqNP_000522.310MANE Select
ENST00000039007.5EnsemblENSP00000039007.410MANE Select
NM_001407092.1RefSeqNP_001394021.110Standard
ENST00000643344.1EnsemblENSP00000496606.14Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Arginine biosynthesis - Homo sapiens (human)
  • Argininemia
  • Hyperornithinemia with gyrate atrophy (HOGA)
  • Creatine deficiency, guanidinoacetate methyltransferase deficiency
  • L-arginine:glycine amidinotransferase deficiency

Biological Process

  • urea cycle
  • liver development
  • ornithine catabolic process
  • midgut development
  • response to zinc ion

Molecular Function

  • ornithine carbamoyltransferase activity
  • phospholipid binding
  • amino acid binding
  • phosphate ion binding

Cellular Component

  • mitochondrion
  • mitochondrial inner membrane
  • mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000039007
Coding exons
10
Length
68906
Individuals with no LoFs
125533
Homozygous LoFs
0
Heterozygous LoFs
2
Defined
125535
p
0.00000797
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.33891320.6750.000009892310
Missense (PolyPhen)1949.7120.3822840
Synonymous0.1925051.80.9660.00000398675
Loss of Function3.18215.50.1290.00000121247

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000250.000018rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Disease
DISEASE: Ornithine carbamoyltransferase deficiency (OTCD) [MIM:311250]: An X-linked disorder of the urea cycle which causes a form of hyperammonemia. Mutations with no residual enzyme activity are always expressed in hemizygote males by a very severe neonatal hyperammonemic coma that generally proves to be fatal. Heterozygous females are either asymptomatic or express orotic aciduria spontaneously or after protein intake. The disorder is treatable with supplemental dietary arginine and low protein diet. The arbitrary classification of patients into the 'neonatal' group (clinical hyperammonemia in the first few days of life) and 'late' onset (clinical presentation after the neonatal period) has been used to differentiate severe from mild forms. {ECO:0000269|PubMed:10070627, ECO:0000269|PubMed:10502831, ECO:0000269|PubMed:10737985, ECO:0000269|PubMed:11793483, ECO:0000269|PubMed:1480464, ECO:0000269|PubMed:1671317, ECO:0000269|PubMed:1721894, ECO:0000269|PubMed:2347583, ECO:0000269|PubMed:2474822, ECO:0000269|PubMed:2556444, ECO:0000269|PubMed:3170748, ECO:0000269|PubMed:7474905, ECO:0000269|PubMed:7951259, ECO:0000269|PubMed:8019569, ECO:0000269|PubMed:8081373, ECO:0000269|PubMed:8081398, ECO:0000269|PubMed:8099056, ECO:0000269|PubMed:8112735, ECO:0000269|PubMed:8530002, ECO:0000269|PubMed:8807340, ECO:0000269|PubMed:8830175, ECO:0000269|PubMed:8956038, ECO:0000269|PubMed:8956045, ECO:0000269|PubMed:9065786, ECO:0000269|PubMed:9143919, ECO:0000269|PubMed:9266388, ECO:0000269|PubMed:9286441, ECO:0000269|PubMed:9452024, ECO:0000269|PubMed:9452049, ECO:0000269|PubMed:9452065, ECO:0000269|Ref.32, ECO:0000269|Ref.43}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.857

Intolerance Scores

RVIS EVS
0.08
RVIS percentile EVS
60.09

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.937

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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