ADSL

protein-coding

adenylosuccinate lyase, the group of Purinosome

Gene summary

The protein encoded by this gene belongs to the lyase 1 family. It is an essential enzyme involved in purine metabolism, and catalyzes two non-sequential reactions in the de novo purine biosynthetic pathway: the conversion of succinylaminoimidazole carboxamide ribotide (SAICAR) to aminoimidazole carboxamide ribotide (AICAR) and the conversion of adenylosuccinate (S-AMP) to adenosine monophosphate (AMP). Mutations in this gene are associated with adenylosuccinase deficiency (ADSLD), a disorder marked with psychomotor retardation, epilepsy or autistic features. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

MANE transcript

NM_000026.4

Inheritance

ClinVar variants

P:91U:235B:123

Top phenotype

Adenylosuccinase deficiency

gnomAD constraint

pLI —, LoF o/e 0.74

Max pathogenic AF

—

Genomic locus

chr22:40,346,461-40,390,463

External References & Databases

Ensembl (ENSG00000239900)

Transcript & Mutation Effects

hg38 • Region Span ~44.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

adenylosuccinate lyase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007068

Submitter: Labcorp Genetics (formerly Invitae)

adenylosuccinate lyase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007068

Submitter: PanelApp Australia

adenylosuccinate lyase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007068

Submitter: Orphanet

adenylosuccinate lyase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007068

Submitter: ClinGen

*ADSL* was first reported in relation to autosomal recessive adenylosuccinate lyase (ADSL) deficiency in 1984 (PMID: 6150139). ADSL deficiency results in psychomotor retardation, seizures, hypotonia and autistic behaviors, and encompasses a wide phenotypic spectrum with three forms: neonatal fatal, severe (type I) and mild (type II) (PMIDs: 10888601, 18524658, 25112391). ADSL deficiency is diagnosed biochemically by the presence of two compounds, succinylaminoimidazole cardoxamide riboside (SAICAr) and succinyladenosine (S-Ado), that occur as a result of deficient ADSL enzyme function. At least 80 patients with ADSL deficiency have been reported to date with over 50 variants identified, including missense, nonsense, frameshift and in-frame indels (PMIDs: 10888601, 18524658, 25112391). Pathogenic *ADSL* variants result in decreased or impaired ADSL enzyme function, indicating homozygous loss-of-function as the mechanism of pathogenicity. This gene-disease relationship is also supported by biochemical function and functional assays (PMID: 20127976). In summary, there is definitive evidence supporting the relationship between *ADSL* and autosomal recessive ADSL deficiency. 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 Intellectual Disability and Autism Gene Curation Expert Panel on September 7, 2020 (SOP Version 7).

adenylosuccinate lyase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007068

Submitter: G2P

Clinical Genomic Database (CGD)

Adenylosuccinase deficiencyAR

Manifestation: Biochemical; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: As with many disorders involving seizures, appropriate interventions may be beneficial (eg, ketogenic diet has been reported as beneficial)

Refs: 6150139; 3234432; 1405483; 1302001; 9266401; 9266351; 10090474; 10888601; 11042421; 12070256; 12833398; 17188615; 18524658; 18649008; 18830228; 20177786; 20933180; 22883297; 23055421; 23504561

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ADSL variants in ClinVar

12 Conditions Cataloged

Adenylosuccinate lyase deficiencyTotal: 538

not providedTotal: 150

not specifiedTotal: 56

Inborn genetic diseasesTotal: 39

ADSL-related disorderTotal: 36

Inability to walkTotal: 2

Difficulty standingTotal: 2

Generalized myoclonic seizureTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000026.4. 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		1 clinvar	5 clinvar	108 clinvar	2 clinvar	116
missense	8 clinvar	46 clinvar	228 clinvar	12 clinvar	1 clinvar	295
nonsense	12 clinvar	5 clinvar				17
start loss						0
frameshift	8 clinvar		2 clinvar			10
splice donor/acceptor (+/-2bp)	2 clinvar	9 clinvar				11
Total	30	61	235	120	3	449

Highest pathogenic variant AF is 0.00026828854

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 111 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000026.4	RefSeq	NP_000017.1	13	MANE Select
ENST00000623063.3	Ensembl	ENSP00000485525.1	13	MANE Select
NM_001123378.3	RefSeq	NP_001116850.1	12	Standard
NM_001317923.2	RefSeq	NP_001304852.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Alanine, aspartate and glutamate metabolism - Homo sapiens (human)
Purine metabolism - Homo sapiens (human)
Purine Nucleoside Phosphorylase Deficiency
Mercaptopurine Action Pathway
Azathioprine Action Pathway

Biological Process

response to hypoxia
purine nucleotide biosynthetic process
AMP biosynthetic process
'de novo' IMP biosynthetic process
response to nutrient

Molecular Function

N6-(1,2-dicarboxyethyl)AMP AMP-lyase (fumarate-forming) activity
(S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido)succinate AMP-lyase (fumarate-forming) activity

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000216194
Coding exons: 13
Length: 43961
Individuals with no LoFs: 125713
Homozygous LoFs: 0
Heterozygous LoFs: 35
Defined: 125748
p: 0.000139

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.803	244	282	0.865	0.0000175	3171
Missense (PolyPhen)		96	116.9	0.82123		1330
Synonymous	1.05	87	100	0.867	0.00000536	936
Loss of Function	1.26	21	28.2	0.744	0.00000171	301

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000055	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes two non-sequential steps in de novo AMP synthesis: converts (S)-2-(5-amino-1-(5-phospho-D- ribosyl)imidazole-4-carboxamido)succinate (SAICAR) to fumarate plus 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide, and thereby also contributes to de novo IMP synthesis, and converts succinyladenosine monophosphate (SAMP) to AMP and fumarate. {ECO:0000269|PubMed:10888601}.;

Recessive Scores

pRec: 0.312

Intolerance Scores

LoFtool: 0.183
RVIS EVS: -0.6
RVIS percentile EVS: 18.06

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.958

Gene Damage Prediction

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