ASL

protein-coding

argininosuccinate lyase

Gene summary

This gene encodes a member of the lyase 1 family. The encoded protein forms a cytosolic homotetramer and primarily catalyzes the reversible hydrolytic cleavage of argininosuccinate into arginine and fumarate, an essential step in the liver in detoxifying ammonia via the urea cycle. Mutations in this gene result in the autosomal recessive disorder argininosuccinic aciduria, or argininosuccinic acid lyase deficiency. A nontranscribed pseudogene is also located on the long arm of chromosome 22. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000048.4

Inheritance

ClinVar variants

P:283U:152B:248

Top phenotype

Argininosuccinic aciduria

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr7:66,075,800-66,094,697

External References & Databases

Ensembl (ENSG00000126522)

Transcript & Mutation Effects

hg38 • Region Span ~18.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

argininosuccinic aciduriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008815

Submitter: G2P

argininosuccinic aciduriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008815

Submitter: ClinGen

The relationship between ASL and argininosuccinic aciduria (autosomal recessive inheritance) was evaluated using the ClinGen Clinical Validity Framework as of August 28, 2018. Variants in ASL were first reported in humans with this disease as early as 1990 (Walker et al., PMID 2263616) At least 100 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, splice site, etc) have been reported in humans. Supporting evidence includes case-level data (12 points) and experimental data (6 points). Variants in this gene were curated from 3 publications (Walker et al. 1990, PMID 2263616; Trevisson et al. 2007, PMID 17326097; Trevisson et al, 2009; PMID 19703900). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism for disease is biallelic loss of function. This gene-disease relationship is supported by the biochemical function of the gene product, argininosuccinate lyase (PMIDs 4732887, 21312326, 22081021, 31110235), and by the clinical and biochemical features observed in a null and hypomorphic mouse models (PMIDs 12559843, 22081021). In summary, ASL is definitively associated with argininosuccinate lyase deficiency. This classification was approved by the ClinGen Aminoacidopathy Expert Panel on September 5th, 2018.

argininosuccinic aciduriaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008815

Submitter: Orphanet

argininosuccinic aciduriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008815

Submitter: Natera

argininosuccinic aciduriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008815

Submitter: Myriad Women's Health

argininosuccinic aciduriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008815

Submitter: Ambry Genetics

argininosuccinic aciduriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008815

Submitter: PanelApp Australia

argininosuccinic aciduriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008815

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Argininosuccinic aciduriaAR

Manifestation: Biochemical; Dermatologic; Neurologic

Intervention: Biochemical; Pharmacogenomic

Rationale: Dietary and medical therapy (eg, with low-protein diet supplemented with arginine), may be beneficial, and special care to prevent/treat acute metabolic decompensation (eg, with IV glucose and ammonia-reducing agents) may be effective; Certain agents (such as enflurane, an anesthetic agent) should be avoided due to reports of adverse reactions

Refs: 13503250; 5836520; 84150; 2263616; 1897577; 1594374; 9504797; 12408190; 12384776; 17326097; 22541557; 20236848; 19635676; 22541557; 22841516; 23040521; 25135652

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ASL variants in ClinVar

9 Conditions Cataloged

Argininosuccinate lyase deficiencyTotal: 859

not providedTotal: 99

not specifiedTotal: 71

Inborn genetic diseasesTotal: 38

ASL-related disorderTotal: 35

Neurodevelopmental disorderTotal: 3

AutismTotal: 1

Congenital myasthenic syndrome 4CTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000048.4. 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			13 clinvar	236 clinvar	2 clinvar	251
missense	11 clinvar	126 clinvar	133 clinvar	9 clinvar	1 clinvar	280
nonsense	16 clinvar	16 clinvar	2 clinvar			34
start loss		1 clinvar				1
frameshift	29 clinvar	35 clinvar				64
splice donor/acceptor (+/-2bp)	14 clinvar	35 clinvar	4 clinvar			53
Total	70	213	152	245	3	683

Highest pathogenic variant AF is 0.0018317379

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 137 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000048.4	RefSeq	NP_000039.2	16	MANE Select
ENST00000304874.14	Ensembl	ENSP00000307188.9	16	MANE Select
NM_001024943.2	RefSeq	NP_001020114.1	16	Standard
NM_001024944.2	RefSeq	NP_001020115.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Alanine, aspartate and glutamate metabolism - Homo sapiens (human)
Arginine biosynthesis - Homo sapiens (human)
Argininemia
Hyperornithinemia with gyrate atrophy (HOGA)
Creatine deficiency, guanidinoacetate methyltransferase deficiency

Biological Process

urea cycle
locomotory behavior
post-embryonic development
ammonia assimilation cycle
arginine biosynthetic process via ornithine

Molecular Function

argininosuccinate lyase activity
protein binding
identical protein binding

Cellular Component

cytoplasm
cytosol
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000304874
Coding exons: 16
Length: 17761
Individuals with no LoFs: 125678
Homozygous LoFs: 0
Heterozygous LoFs: 66
Defined: 125744
p: 0.000262

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.749	247	282	0.875	0.0000195	3011
Missense (PolyPhen)		78	107.79	0.72365		1152
Synonymous	-1.37	134	115	1.16	0.00000822	908
Loss of Function	1.83	19	29.8	0.638	0.00000168	303

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000088	0.000087	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00038	0.00038	rare
Finnish	0.00020	0.00018	rare
European (Non-Finnish)	0.00036	0.00035	rare
South Asian	0.00026	0.00026	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Argininosuccinic aciduria (ARGINSA) [MIM:207900]: An autosomal recessive disorder of the urea cycle. The disease is characterized by mental and physical retardation, liver enlargement, skin lesions, dry and brittle hair showing trichorrhexis nodosa microscopically and fluorescing red, convulsions, and episodic unconsciousness. {ECO:0000269|PubMed:12408190, ECO:0000269|PubMed:1705937, ECO:0000269|PubMed:17326097, ECO:0000269|PubMed:19703900, ECO:0000269|PubMed:2263616, ECO:0000269|PubMed:24166829}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.454

Intolerance Scores

LoFtool: 0.0497
RVIS EVS: -0.98
RVIS percentile EVS: 8.85

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.964

Gene Damage Prediction

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