OTC

ornithine transcarbamylase

Basic information

Region (hg38): X:38327598-38422908

Links

ENSG00000036473 ∙ NCBI:5009 ∙ OMIM:300461 ∙ HGNC:8512 ∙ Uniprot:P00480 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• ornithine carbamoyltransferase deficiency (Definitive), mode of inheritance: XLR
• ornithine carbamoyltransferase deficiency (Supportive), mode of inheritance: XL
• ornithine carbamoyltransferase deficiency (Definitive), mode of inheritance: XL
• ornithine carbamoyltransferase deficiency (Definitive), mode of inheritance: XL
• ornithine carbamoyltransferase deficiency (Strong), mode of inheritance: XL
• ornithine carbamoyltransferase deficiency (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Ornithine transcarbamylase deficiency	XL	Biochemical; Pharmacogenomic	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	Biochemical; Gastrointestinal; Neurologic	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; 31441224
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

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the OTC gene.

• Ornithine carbamoyltransferase deficiency (88 variants)
• not provided (70 variants)
• Inborn genetic diseases (3 variants)
• not specified (1 variants)
• OTC-related disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the OTC gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	122	2	125
missense	48	71	110	11	4	244
nonsense	16	5				21
start loss	2					2
frameshift	14	9				23
inframe indel	2	3	3			8
splice donor/acceptor (+/-2bp)	18	5		1		24
splice region	1	3	8	24	7	43
non coding	1	1	6	73	32	113
Total	101	94	120	207	38

Highest pathogenic variant AF is 0.00000894

Variants in OTC

This is a list of pathogenic ClinVar variants found in the OTC region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
X-38352036-C-T			Benign (Jun 14, 2018)
X-38352051-G-A			Benign (Jun 14, 2018)
X-38352177-CTTCT-C			Benign (Oct 09, 2018)
X-38352256-A-G		not specified • OTC-related disorder	Benign (Feb 12, 2018)
X-38352260-T-C		OTC-related disorder	Uncertain significance (Dec 05, 2023)
X-38352331-A-G		not specified • Ornithine carbamoyltransferase deficiency • OTC-related disorder	Benign/Likely benign (Dec 06, 2023)
X-38352332-G-A		not specified • Ornithine carbamoyltransferase deficiency	Benign (Dec 02, 2015)
X-38352338-G-A		not specified • Ornithine carbamoyltransferase deficiency	Benign (Feb 12, 2018)
X-38352403-G-A			Likely benign (Jul 10, 2018)
X-38352540-T-G		Ornithine carbamoyltransferase deficiency	Likely pathogenic (Dec 12, 2017)
X-38352554-T-C		Ornithine carbamoyltransferase deficiency	Uncertain significance (May 16, 2023)
X-38352555-G-A		Ornithine carbamoyltransferase deficiency	Likely pathogenic (Feb 06, 2019)
X-38352558-A-G		Ornithine carbamoyltransferase deficiency	Likely pathogenic (Dec 12, 2017)
X-38352581-C-T		Ornithine carbamoyltransferase deficiency	Uncertain significance (Jul 06, 2023)
X-38352582-C-T		Ornithine carbamoyltransferase deficiency	Likely pathogenic (Dec 12, 2017)
X-38352591-C-A		Ornithine carbamoyltransferase deficiency	Pathogenic (May 14, 2024)
X-38352649-G-T		Ornithine carbamoyltransferase deficiency	Benign/Likely benign (Feb 16, 2022)
X-38352692-A-C		Ornithine carbamoyltransferase deficiency	Uncertain significance (Dec 13, 2023)
X-38352693-G-A			Likely benign (Apr 08, 2021)
X-38352697-A-G			Pathogenic (-)
X-38352697-A-T			Pathogenic (-)
X-38352698-T-C		Ornithine carbamoyltransferase deficiency	Pathogenic (Dec 03, 2021)
X-38352699-G-A		Ornithine carbamoyltransferase deficiency	Pathogenic (Jul 19, 2022)
X-38352700-C-T		Ornithine carbamoyltransferase deficiency	Likely benign (May 14, 2022)
X-38352702-G-A		Ornithine carbamoyltransferase deficiency	Likely benign (Jan 18, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
OTC	protein_coding	protein_coding	ENST00000039007	10	68906

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.873	0.127	125533	0	2	125535	0.00000797

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.33	89	132	0.675	0.00000989	2310
Missense in Polyphen		19	49.712	0.3822		840
Synonymous	0.192	50	51.8	0.966	0.00000398	675
Loss of Function	3.18	2	15.5	0.129	0.00000121	247

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000248	0.0000176
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: Arginine biosynthesis - Homo sapiens (human);Argininemia;Hyperornithinemia with gyrate atrophy (HOGA);Creatine deficiency, guanidinoacetate methyltransferase deficiency;L-arginine:glycine amidinotransferase deficiency;Hyperornithinemia-hyperammonemia-homocitrullinuria [HHH-syndrome];Guanidinoacetate Methyltransferase Deficiency (GAMT Deficiency);Citrullinemia Type I;Carbamoyl Phosphate Synthetase Deficiency;Argininosuccinic Aciduria;Urea Cycle;Prolinemia Type II;Prolidase Deficiency (PD);Ornithine Transcarbamylase Deficiency (OTC Deficiency);Arginine and Proline Metabolism;Hyperprolinemia Type I;Hyperprolinemia Type II;Ornithine Aminotransferase Deficiency (OAT Deficiency);Arginine: Glycine Amidinotransferase Deficiency (AGAT Deficiency);Amino Acid metabolism;Urea cycle and metabolism of amino groups;Metabolism of proteins;Metabolism of polyamines;Metabolism of amino acids and derivatives;Metabolism;Urea cycle and metabolism of arginine, proline, glutamate, aspartate and asparagine;urea cycle;Arginine Proline metabolism;Mitochondrial protein import;Urea cycle (Consensus)

Recessive Scores

• pRec: 0.857

Intolerance Scores

• rvis_EVS: 0.08
• rvis_percentile_EVS: 60.09

Haploinsufficiency Scores

• pHI: 0.223
• hipred: Y
• hipred_score: 0.580

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.937

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Otc
• Phenotype: endocrine/exocrine gland phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); homeostasis/metabolism phenotype; cellular phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); pigmentation phenotype; hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; renal/urinary system phenotype; immune system phenotype

Gene ontology

• Biological process: urea cycle;liver development;ornithine catabolic process;midgut development;response to zinc ion;citrulline biosynthetic process;response to insulin;arginine biosynthetic process via ornithine;anion homeostasis;protein homotrimerization;response to biotin;ammonia homeostasis
• Cellular component: mitochondrion;mitochondrial inner membrane;mitochondrial matrix
• Molecular function: ornithine carbamoyltransferase activity;phospholipid binding;amino acid binding;phosphate ion binding