CPS1

protein-coding

carbamoyl-phosphate synthase 1, the group of Glutamine amidotransferase class 1 domain containing

Gene summary

The mitochondrial enzyme encoded by this gene catalyzes synthesis of carbamoyl phosphate from ammonia and bicarbonate. This reaction is the first committed step of the urea cycle, which is important in the removal of excess urea from cells. The encoded protein may also represent a core mitochondrial nucleoid protein. Three transcript variants encoding different isoforms have been found for this gene. The shortest isoform may not be localized to the mitochondrion. Mutations in this gene have been associated with carbamoyl phosphate synthetase deficiency, susceptibility to persistent pulmonary hypertension, and susceptibility to venoocclusive disease after bone marrow transplantation.[provided by RefSeq, May 2010]

MANE transcript

NM_001875.5

Inheritance

ClinVar variants

P:456U:470B:681

Top phenotype

Carbamoylphosphate synthetase I deficiency

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr2:210,477,682-210,679,107

External References & Databases

Ensembl (ENSG00000021826)

Transcript & Mutation Effects

hg38 • Region Span ~201.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

carbamoyl phosphate synthetase I deficiency diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009376

Submitter: ClinGen

The relationship between CPS1 and carbamoyl phosphate synthetase 1 deficiency (autosomal recessive inheritance) was evaluated using the ClinGen Clinical Validity Framework as of October 10th, 2018. Variants in CPS1 were first reported in humans with this disease as early as 1993 (Roshide et al., PMID 8486760). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in more than 20 probands in 8 publications (Hoshide et al, 1993, PMID 8486760; Haberle et al, 2003, PMID 12655559; Wakutani et al, 2004, PMID 15617192; Eeds et al, 2006, PMID 16737834; Klaus et al, 2009, PMID 19793055; Funghini et al, 2012, PMID 22173106; Yamaguchi et al, 2016, PMID 27150549; Choi et al, 2017, PMID 27834067). More evidence is available in the literature, but the maximum score for genetic evidence evidence (12 points) has been reached. The mechanism for the disease is loss of function. This gene-disease association is supported by the biochemical function of carbamoyl phosphate synthetase (which catalyzes the first step of the urea cycle) (Jackson et al, 1986, PMID 3545062), knock out and conditional knockout mouse models (Schofield et al, 1999, PMID 9862865; Khoja et al, 2018, PMID 29801986), and gene therapy rescue in mouse models (Khoja et al, 2018, PMID 29801986). In summary, CPS1 is definitively associated with autosomal recessive carbamoyl phosphate synthetase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

carbamoyl phosphate synthetase I deficiency diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009376

Submitter: Myriad Women's Health

carbamoyl phosphate synthetase I deficiency diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009376

Submitter: Labcorp Genetics (formerly Invitae)

carbamoyl phosphate synthetase I deficiency diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009376

Submitter: G2P

carbamoyl phosphate synthetase I deficiency diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009376

Submitter: Natera

carbamoyl phosphate synthetase I deficiency diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009376

Submitter: Orphanet

Clinical Genomic Database (CGD)

Carbamoylphosphate synthetase I deficiencyAR

Manifestation: Biochemical; Neurologic

Intervention: Biochemical; Pharmacogenomic

Rationale: Specific urgent and long-term medical management (eg, dietary measures, arginine, sodium benzoate, sodium phenylbutyrate), as well as measures such as dialysis when necessary, may be beneficial to reduce morbidity and mortality; Avoidance of certain agents (eg, valproate), as well as special considerations in situations such as peregnancy, are warranted due to potential adverse events

Refs: 5356974; 5471650; 4111816; 4811018; 7078580; 6427608; 3759432; 3792387; 1414247; 8486760; 8273985; 9711878; 21120950; 16708072; 17310273; 19793055; 21120950; 22173106; 25135652; 25410056

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CPS1 variants in ClinVar

10 Conditions Cataloged

Congenital hyperammonemia, type ITotal: 1927

Pulmonary hypertension, neonatal, susceptibility toTotal: 172

not providedTotal: 170

Inborn genetic diseasesTotal: 167

not specifiedTotal: 156

CPS1-related disorderTotal: 53

Hereditary breast ovarian cancer syndromeTotal: 1

Neonatal encephalopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001875.5. 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			18 clinvar	588 clinvar	5 clinvar	611
missense	9 clinvar	81 clinvar	443 clinvar	80 clinvar	8 clinvar	621
nonsense	39 clinvar	78 clinvar	1 clinvar			118
start loss		1 clinvar	2 clinvar			3
frameshift	76 clinvar	84 clinvar				160
splice donor/acceptor (+/-2bp)	7 clinvar	81 clinvar	6 clinvar			94
Total	131	325	470	668	13	1607

Highest pathogenic variant AF is 0.000033496515

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001875.5	RefSeq	NP_001866.2	38	MANE Select
ENST00000233072.10	Ensembl	ENSP00000233072.5	38	MANE Select
NM_001122633.3	RefSeq	NP_001116105.2	38	Standard
NM_001369256.1	RefSeq	NP_001356185.1	39	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cps1	Danio rerio	Structure: urea cycle Quality: disrupted abnormal

Gene / Model

Organism

Observed Phenotype

cps1

Danio rerio

Structure: urea cycle

Quality: disrupted

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Alanine, aspartate and glutamate metabolism - Homo sapiens (human)
Nitrogen metabolism - Homo sapiens (human)
Arginine biosynthesis - Homo sapiens (human)
Argininemia
2-Hydroxyglutric Aciduria (D And L Form)

Biological Process

urea cycle
proteolysis
arginine biosynthetic process
nitrogen compound metabolic process
midgut development

Molecular Function

carbamoyl-phosphate synthase (ammonia) activity
endopeptidase activity
calcium ion binding
protein binding
ATP binding

Cellular Component

nucleolus
cytoplasm
mitochondrial inner membrane
mitochondrial matrix
protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000430249
Coding exons: 39
Length: 201426
Individuals with no LoFs: 125680
Homozygous LoFs: 0
Heterozygous LoFs: 68
Defined: 125748
p: 0.000270

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.46	681	797	0.854	0.0000417	9875
Missense (PolyPhen)		231	315.4	0.7324		3872
Synonymous	-1.29	309	281	1.10	0.0000146	2928
Loss of Function	5.08	30	78.7	0.381	0.00000388	981

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00044	0.00044	rare
Finnish	0.00032	0.00032	rare
European (Non-Finnish)	0.00034	0.00032	rare
South Asian	0.00020	0.00020	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the urea cycle of ureotelic animals where the enzyme plays an important role in removing excess ammonia from the cell.;
Disease: DISEASE: Carbamoyl phosphate synthetase 1 deficiency (CPS1D) [MIM:237300]: An autosomal recessive disorder of the urea cycle causing hyperammonemia. It can present as a devastating metabolic disease dominated by severe hyperammonemia in neonates or as a more insidious late-onset condition, generally manifesting as life-threatening hyperammonemic crises under catabolic situations. Clinical features include protein intolerance, intermittent ataxia, seizures, lethargy, developmental delay and mental retardation. {ECO:0000269|PubMed:11388595, ECO:0000269|PubMed:11474210, ECO:0000269|PubMed:12655559, ECO:0000269|PubMed:12955727, ECO:0000269|PubMed:15164414, ECO:0000269|PubMed:15617192, ECO:0000269|PubMed:16737834, ECO:0000269|PubMed:17310273, ECO:0000269|PubMed:20578160, ECO:0000269|PubMed:21120950, ECO:0000269|PubMed:22173106, ECO:0000269|PubMed:23649895, ECO:0000269|PubMed:24813853, ECO:0000269|PubMed:26440671, ECO:0000269|PubMed:9711878}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Pulmonary hypertension, neonatal (PHN) [MIM:615371]: A disease characterized by elevated pulmonary artery pressure. Pulmonary hypertension in the neonate is associated with multiple underlying problems such as respiratory distress syndrome, meconium aspiration syndrome, congenital diaphragmatic hernia, bronchopulmonary dysplasia, sepsis, or congenital heart disease. {ECO:0000269|PubMed:11407344}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. CPS1 variants influence the availability of precursors for nitric oxide (NO) synthesis and play a role in clinical situations where endogenous NO production is critically important, such as neonatal pulmonary hypertension, increased pulmonary artery pressure following surgical repair of congenital heart defects or hepatovenocclusive disease following bone marrow transplantation. Infants with neonatal pulmonary hypertension homozygous for Thr- 1406 have lower L-arginine concentrations than neonates homozygous for Asn-1406 (PubMed:11407344). {ECO:0000269|PubMed:11407344}.;

Recessive Scores

pRec: 0.264

Intolerance Scores

LoFtool: 0.0148
RVIS EVS: -0.63
RVIS percentile EVS: 16.81

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.980

Gene Damage Prediction

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