NM_000048.4(ASL):c.857A>C (p.Gln286Pro) AND Argininosuccinate lyase deficiency

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 29, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003499799.2

Allele description [Variation Report for NM_000048.4(ASL):c.857A>C (p.Gln286Pro)]

NM_000048.4(ASL):c.857A>C (p.Gln286Pro)

Gene:

ASL:argininosuccinate lyase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q11.21

Genomic location:

Preferred name:

NM_000048.4(ASL):c.857A>C (p.Gln286Pro)

HGVS:

NC_000007.14:g.66089114A>C
NG_009288.1:g.18326A>C
NM_000048.4:c.857A>CMANE SELECT
NM_001024943.2:c.857A>C
NM_001024944.2:c.857A>C
NM_001024946.2:c.779A>C
NP_000039.2:p.Gln286Pro
NP_001020114.1:p.Gln286Pro
NP_001020115.1:p.Gln286Pro
NP_001020117.1:p.Gln260Pro
NC_000007.13:g.65554101A>C

Protein change:

Q260P

Molecular consequence:

NM_000048.4:c.857A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001024943.2:c.857A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001024944.2:c.857A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001024946.2:c.779A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Argininosuccinate lyase deficiency
Synonyms:: Arginino succinase deficiency; Inborn error of urea synthesis, arginino succinic type; Urea cycle disorder, arginino succinase type; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008815; MedGen: C0268547; Orphanet: 23; OMIM: 207900; Human Phenotype Ontology: HP:0025630

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004353653	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 29, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12408190, 19703900, 21667091, 23430928, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004353653

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 29, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical, enzymatic, and molecular genetic characterization of a biochemical variant type of argininosuccinic aciduria: prenatal and postnatal diagnosis in five unrelated families.

Kleijer WJ, Garritsen VH, Linnebank M, Mooyer P, Huijmans JG, Mustonen A, Simola KO, Arslan-Kirchner M, Battini R, Briones P, Cardo E, Mandel H, Tschiedel E, Wanders RJ, Koch HG.

J Inherit Metab Dis. 2002 Sep;25(5):399-410.

PubMed [citation]

PMID:: 12408190

Functional complementation in yeast allows molecular characterization of missense argininosuccinate lyase mutations.

Trevisson E, Burlina A, Doimo M, Pertegato V, Casarin A, Cesaro L, Navas P, Basso G, Sartori G, Salviati L.

J Biol Chem. 2009 Oct 16;284(42):28926-34. doi: 10.1074/jbc.M109.050195. Epub 2009 Aug 24.

PubMed [citation]

PMID:: 19703900
PMCID:: PMC2781438

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004353653.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gln286 amino acid residue in ASL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12408190, 19703900, 21667091, 23430928). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ASL protein function. This variant has not been reported in the literature in individuals affected with ASL-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 286 of the ASL protein (p.Gln286Pro).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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