NM_000048.4(ASL):c.925G>A (p.Gly309Arg) AND Argininosuccinate lyase deficiency

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Feb 20, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV003230904.3

Allele description [Variation Report for NM_000048.4(ASL):c.925G>A (p.Gly309Arg)]

NM_000048.4(ASL):c.925G>A (p.Gly309Arg)

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.925G>A (p.Gly309Arg)

HGVS:

NC_000007.14:g.66089282G>A
NG_009288.1:g.18494G>A
NM_000048.3:c.925G>A
NM_000048.4:c.925G>AMANE SELECT
NM_001024943.2:c.925G>A
NM_001024944.2:c.918+107G>A
NM_001024946.2:c.847G>A
NP_000039.2:p.Gly309Arg
NP_001020114.1:p.Gly309Arg
NP_001020117.1:p.Gly283Arg
NC_000007.13:g.65554269G>A
NM_000048.4:c.925G>A

Protein change:

G283R

Links:

dbSNP: rs769506424

NCBI 1000 Genomes Browser:

rs769506424

Molecular consequence:

NM_001024944.2:c.918+107G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000048.4:c.925G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001024943.2:c.925G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001024946.2:c.847G>A - 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
SCV003928931	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 26, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12384776, 32778825, 27604308 Citation Link,
SCV004203016	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 20, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003928931

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Apr 26, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV004203016

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 20, 2024)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene.

Linnebank M, Tschiedel E, Häberle J, Linnebank A, Willenbring H, Kleijer WJ, Koch HG.

Hum Genet. 2002 Oct;111(4-5):350-9. Epub 2002 Aug 14.

PubMed [citation]

PMID:: 12384776

The role of exome sequencing in newborn screening for inborn errors of metabolism.

Adhikari AN, Gallagher RC, Wang Y, Currier RJ, Amatuni G, Bassaganyas L, Chen F, Kundu K, Kvale M, Mooney SD, Nussbaum RL, Randi SS, Sanford J, Shieh JT, Srinivasan R, Sunderam U, Tang H, Vaka D, Zou Y, Koenig BA, Kwok PY, Risch N, et al.

Nat Med. 2020 Sep;26(9):1392-1397. doi: 10.1038/s41591-020-0966-5. Epub 2020 Aug 10.

PubMed [citation]

PMID:: 32778825
PMCID:: PMC8800147

See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003928931.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: ASL c.925G>A (p.Gly309Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 242008 control chromosomes (gnomAD). c.925G>A has been reported in the literature in individuals affected with Argininosuccinic Aciduria (e.g. Linnebank_2002, Reid_2016, Adhikari_2020). These data indicate that the variant is likely to be associated with disease. Experimental evidence demonstrated the variant affects enzyme activity (Linnebank_2002). The following publications have been ascertained in the context of this evaluation (PMID: 32778825, 12384776, 27604308). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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

From Baylor Genetics, SCV004203016.2

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

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

Last Updated: Jun 17, 2024

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