ASS1

protein-coding

argininosuccinate synthase 1

Gene summary

The protein encoded by this gene catalyzes the penultimate step of the arginine biosynthetic pathway. There are approximately 10 to 14 copies of this gene including the pseudogenes scattered across the human genome, among which the one located on chromosome 9 appears to be the only functional gene for argininosuccinate synthetase. Mutations in the chromosome 9 copy of this gene cause citrullinemia. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2012]

Previous symbols:

MANE transcript

NM_054012.4

Inheritance

ClinVar variants

P:253U:179B:213

Top phenotype

Citrullinemia

gnomAD constraint

pLI —, LoF o/e 0.66

Max pathogenic AF

—

Genomic locus

chr9:130,444,961-130,501,274

External References & Databases

Ensembl (ENSG00000130707)

Transcript & Mutation Effects

hg38 • Region Span ~56.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

citrullinemia type ISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008988

Submitter: PanelApp Australia

citrullinemia type ISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008988

Submitter: Labcorp Genetics (formerly Invitae)

citrullinemia type IDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008988

Submitter: G2P

citrullinemia type IDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008988

Submitter: Myriad Women's Health

adult-onset citrullinemia type ISUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016601

Submitter: Orphanet

citrullinemia type IDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008988

Submitter: ClinGen

Autosomal recessive citrullinemia type I has a long history as a well-known metabolic disorder with the first clinical reports published in the 1960s. Identification and dysfunction of the enzyme product of ASS1, argininosuccinate synthetase, in a citrullinemia patient cell line was first observed in 1967 (PMID 16591537). This same publication asserted that citrullinemia was a genetic inborn error of metabolism, although the ASS1 gene was not mapped until 1977 (PMID 852520) and cloned in 1982 (PMID 6194510). Causative variation in ASS1 was first molecularly confirmed in patient cell-lines (generated at an earlier date) in reports from 1990 (Kobayashi et al. PMID: 2358466, Su et al. PMID: 2246255). At least 130 unique variants (including missense, nonsense, frameshift, splice site, deletions and complex rearrangements) have been reported in humans (PMID: 28111830). Three variants (p.Arg304Trp, c.421-2A>G, and p.Gly390Arg) that are associated with severe disease account for the majority of citrullinemia type I (PMID 12815590). Additionally, at least 8 variants have been associated with mild disease, non-classic presentation of disease, or no clinical symptoms in patients with varying genotypes (PMID 2030163). Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene were curated in 8 cases (PMIDs 28111830, 23246278, 19006241, 16475226, 2246255, 2030163). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism for disease is loss of function. This gene-disease relationship is supported by the biochemical function of argininosuccinate synthase (Walsner, 1982, PMID 676334; Jackson 1986, PMID 3545062). Argininosuccinate synthetase catalyzes the conversion of citrulline and aspartate into argininosuccinate, the third step in the urea cycle. Together with ASL it is responsible for the biosynthesis of arginine in most body tissues. Consistent with this role, deficiency of argininosuccinate synthetase results in accumulation of citrulline and ammonia, leading to hyperammonemic encephalopathy, and deficiency of arginine. The gene-disease relationship is also supported by the biochemical and clinical features observed in murine and bovine animal models (Patejunas et al, 1993, PMID 8197477; (Harper et al, 1999, PMID 2596577) and rescue of these phenotypes in animal models by gene therapy (Lee et al, 1999, PMID 10097149; Ye et al, 2000, PMID 11083500; Chandler et al, 2013, PMID 24131980). More experimental evidence to support the gene-disease relationship is available in the literature but the maximum score for experimental evidence has been reached. In summary, ASS1 is definitively associated with citrullinemia type I (autosomal recessive). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on December 27th, 2018.

acute neonatal citrullinemia type ISUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016600

Submitter: Orphanet

citrullinemia type IDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008988

Submitter: Natera

Clinical Genomic Database (CGD)

CitrullinemiaAR

Manifestation: Biochemical; Gastrointestinal; Neurologic

Intervention: Biochemical; Pharmacogenomic

Rationale: To prevent decompensation, medical therapy (eg, with sodium phenylbutyrate, L-carnitine) and dietary management (including avoidance of excess protein) can be beneficial, especially in high-risk states such as during infectious episodes; In the acute state, control of hyperammonemia (eg, with sodium benzoate/phenylacetate or emergent hemodialysis, with dietary measures to prevent catabolism) with steps to prevent increased intracranial pressure can be beneficial; Avoidance of certain agents (eg, valproate) is warranted due to potential adverse events

Refs: 934749; 6807193; 3459354; 2358466; 3148074; 2246861; 7977368; 7557970; 11571557; 11804205; 11941481; 15334737; 15266621; 19006241; 20142522; 20301631; 22494546; 22594780; 22768672; 23099195; 23246278; 23430935; 23611581; 25135652

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ASS1 variants in ClinVar

12 Conditions Cataloged

CitrullinemiaTotal: 643

Citrullinemia type ITotal: 350

not providedTotal: 119

not specifiedTotal: 81

Inborn genetic diseasesTotal: 47

ASS1-related disorderTotal: 43

See casesTotal: 4

Fetal anomalies with a likely genetic causeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_054012.4. 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			8 clinvar	202 clinvar		210
missense	19 clinvar	77 clinvar	164 clinvar	10 clinvar		270
nonsense	21 clinvar	19 clinvar				40
start loss		2 clinvar				2
frameshift	31 clinvar	34 clinvar				65
splice donor/acceptor (+/-2bp)	9 clinvar	41 clinvar	7 clinvar	1 clinvar		58
Total	80	173	179	213	0	645

Highest pathogenic variant AF is 0.00031605523

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 136 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_054012.4	RefSeq	NP_446464.1	14	MANE Select
ENST00000352480.10	Ensembl	ENSP00000253004.6	14	MANE Select
NM_000050.4	RefSeq	NP_000041.2	14	Standard
ENST00000372393.7	Ensembl	ENSP00000361469.2	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Alanine, aspartate and glutamate metabolism - Homo sapiens (human)
Fluid shear stress and atherosclerosis - Homo sapiens (human)
Arginine biosynthesis - Homo sapiens (human)
Argininemia
Hyperornithinemia with gyrate atrophy (HOGA)

Biological Process

urea cycle
citrulline metabolic process
argininosuccinate metabolic process
kidney development
liver development

Molecular Function

RNA binding
argininosuccinate synthase activity
protein binding
ATP binding
toxic substance binding

Cellular Component

nucleus
cytoplasm
mitochondrial outer membrane
lysosome
endoplasmic reticulum

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000372394
Coding exons: 14
Length: 56346
Individuals with no LoFs: 125706
Homozygous LoFs: 0
Heterozygous LoFs: 42
Defined: 125748
p: 0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.758	211	244	0.864	0.0000165	2700
Missense (PolyPhen)		48	74.302	0.64601		957
Synonymous	-1.11	112	98.1	1.14	0.00000716	764
Loss of Function	1.62	18	27.1	0.663	0.00000146	299

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00033	0.00033	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00018	0.00018	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: One of the enzymes of the urea cycle, the metabolic pathway transforming neurotoxic amonia produced by protein catabolism into inocuous urea in the liver of ureotelic animals. Catalyzes the formation of arginosuccinate from aspartate, citrulline and ATP and together with ASL it is responsible for the biosynthesis of arginine in most body tissues. {ECO:0000305|PubMed:18473344, ECO:0000305|PubMed:27287393, ECO:0000305|PubMed:8792870}.;
Disease: DISEASE: Citrullinemia 1 (CTLN1) [MIM:215700]: The classic form of citrullinemia, an autosomal recessive disease characterized primarily by elevated serum and urine citrulline levels. Ammonia intoxication is another manifestation. It is a disorder of the urea cycle, usually manifesting in the first few days of life. Affected infants appear normal at birth, but as ammonia builds up in the body they present symptoms such as lethargy, poor feeding, vomiting, seizures and loss of consciousness. Less commonly, a milder form can develop later in childhood or adulthood. {ECO:0000269|PubMed:11708871, ECO:0000269|PubMed:11941481, ECO:0000269|PubMed:12815590, ECO:0000269|PubMed:14680976, ECO:0000269|PubMed:15863597, ECO:0000269|PubMed:16475226, ECO:0000269|PubMed:18473344, ECO:0000269|PubMed:19006241, ECO:0000269|PubMed:1943692, ECO:0000269|PubMed:2358466, ECO:0000269|PubMed:23611581, ECO:0000269|PubMed:24889030, ECO:0000269|PubMed:25179242, ECO:0000269|PubMed:27287393, ECO:0000269|PubMed:28111830, ECO:0000269|PubMed:7977368}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.808

Intolerance Scores

LoFtool: 0.0989
RVIS EVS: -0.51
RVIS percentile EVS: 21.65

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.971

Gene Damage Prediction

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