ARG1

protein-coding

arginase 1

Gene summary

Arginase catalyzes the hydrolysis of arginine to ornithine and urea. At least two isoforms of mammalian arginase exist (types I and II) which differ in their tissue distribution, subcellular localization, immunologic crossreactivity and physiologic function. The type I isoform encoded by this gene, is a cytosolic enzyme and expressed predominantly in the liver as a component of the urea cycle. Inherited deficiency of this enzyme results in argininemia, an autosomal recessive disorder characterized by hyperammonemia. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

MANE transcript

NM_000045.4

Inheritance

ClinVar variants

P:154U:136B:164

Top phenotype

Hyperargininemia

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr6:131,470,832-131,584,332

External References & Databases

Ensembl (ENSG00000118520)

Transcript & Mutation Effects

hg38 • Region Span ~113.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

arginase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008814

Submitter: Myriad Women's Health

arginase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008814

Submitter: Ambry Genetics

arginase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008814

Submitter: Orphanet

arginase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008814

Submitter: G2P

arginase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008814

Submitter: PanelApp Australia

arginase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008814

Submitter: Labcorp Genetics (formerly Invitae)

arginase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008814

Submitter: ClinGen

ARG1 was first reported in relation to autosomal recessive inheritance of hyperargininemia in 1990 (Haraguchi et al., 1990, PMID: 2365823). At least 43 unique variants (including many missense and nonsense, as well as some in-frame indel, frameshift, large deletion, complex rearrangement, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in the gene have been reported in at least 11 probands in 5 publications (PMIDS: 23859858, 1463019, 1598908, 2365823, 29443755). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is homozygous loss of function. This gene-disease relationship is supported by the biochemical function of ARG1, catalyzing the final step of the urea cycle (PMID: 16747805), and two knockout mouse models which share the biochemical manifestations of hyperammonemia and hyperargininemia while lacking the clinical phenotypes of humans (PMIDs: 12052859, 23920045). In summary, ARG1 is definitively associated with autosomal recessive inheritance of hyperargininemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Clinical Genomic Database (CGD)

HyperargininemiaAR

Manifestation: Biochemical; Neurologic

Intervention: Biochemical; Pharmacogenomic

Rationale: Dietary and medical therapy (eg, with low-protein, arginine restricted diet, sodium benzoate, as well as with enzyme replacement), may be beneficial; Individuals with more severe and earlier presentations (similar to that of other urea cycle disorders) have been reported, and may benefit from similar care to prevent and acute sequelae; Individuals with urea cycle disorders may demonstrate sensitivity to certain agents, such as valproate

Refs: 1124944; 839368; 624188; 6422160; 3104676; 2913054; 2311630; 2365823; 2246859; 2291040; 8474825; 7649538; 9762606; 12640389; 16963300; 19052914; 19381865; 21229317; 21802329; 21310339; 22959135; 22928720; 22633632; 25135652; 29726057; 36049366

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ARG1 variants in ClinVar

5 Conditions Cataloged

Arginase deficiencyTotal: 545

not providedTotal: 63

not specifiedTotal: 25

Inborn genetic diseasesTotal: 24

ARG1-related disorderTotal: 14

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000045.4. 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				156 clinvar	1 clinvar	157
missense	11 clinvar	21 clinvar	133 clinvar	7 clinvar		172
nonsense	11 clinvar	8 clinvar				19
start loss	2 clinvar	1 clinvar				3
frameshift	42 clinvar	27 clinvar	2 clinvar			71
splice donor/acceptor (+/-2bp)	9 clinvar	22 clinvar	1 clinvar			32
Total	75	79	136	163	1	454

Highest pathogenic variant AF is 0.00003531476

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 37 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000045.4	RefSeq	NP_000036.2	8	MANE Select
ENST00000368087.8	Ensembl	ENSP00000357066.3	8	MANE Select
NM_001244438.2	RefSeq	NP_001231367.1	8	Standard
NM_001369020.1	RefSeq	NP_001355949.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Arginine and proline metabolism - Homo sapiens (human)
Amoebiasis - Homo sapiens (human)
Arginine biosynthesis - Homo sapiens (human)
Argininemia
Hyperornithinemia with gyrate atrophy (HOGA)

Biological Process

urea cycle
liver development
positive regulation of endothelial cell proliferation
adaptive immune response
arginine catabolic process

Molecular Function

arginase activity
protein binding
manganese ion binding

Cellular Component

extracellular region
extracellular space
nucleus
cytoplasm
mitochondrial outer membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000356962
Coding exons: 8
Length: 11189
Individuals with no LoFs: 125691
Homozygous LoFs: 0
Heterozygous LoFs: 53
Defined: 125744
p: 0.000211

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0560	176	178	0.988	0.00000862	2125
Missense (PolyPhen)		74	77.994	0.94879		913
Synonymous	0.0143	67	67.1	0.998	0.00000355	685
Loss of Function	1.81	8	15.7	0.508	8.27e-7	194

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00056	0.00055	rare
Latino/Admixed American	0.00075	0.00072	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Key element of the urea cycle converting L-arginine to urea and L-ornithine, which is further metabolized into metabolites proline and polyamides that drive collagen synthesis and bioenergetic pathways critical for cell proliferation, respectively; the urea cycle takes place primarily in the liver and, to a lesser extent, in the kidneys. {ECO:0000305}.;
Disease: DISEASE: Argininemia (ARGIN) [MIM:207800]: A rare autosomal recessive disorder of the urea cycle. Arginine is elevated in the blood and cerebrospinal fluid, and periodic hyperammonemia occurs. Clinical manifestations include developmental delay, seizures, mental retardation, hypotonia, ataxia and progressive spastic quadriplegia. {ECO:0000269|PubMed:1463019, ECO:0000269|PubMed:22959135, ECO:0000269|PubMed:23859858, ECO:0000269|PubMed:7649538}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.431

Intolerance Scores

LoFtool: 0.321
RVIS EVS: -0.25
RVIS percentile EVS: 35.75

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.984

Gene Damage Prediction

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