Submissions for variant NM_000048.4(ASL):c.1153C>T (p.Arg385Cys)

gnomAD frequency: 0.00007  dbSNP: rs28940286

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000002502	SCV000469783	likely pathogenic	Argininosuccinate lyase deficiency	2017-04-28	criteria provided, single submitter	clinical testing	The ASL c.1153C>T (p.Arg385Cys) missense variant has been reported in at least five studies and is found in a total of 15 individuals with argininosuccinate lyase deficiency, including five who carried the variant in a homozygous state, two with the variant in a compound heterozygous state, and an additional eight individuals where zygosity is unclear (Kleijer et al. 2002; Keskinen et al. 2008; Balmer et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in E.coli, HEK 293T cells and cultured patient fibroblasts show that the variant results in reduced enzyme activity of 0-12% compared to wild type (Kleijer et al. 2002; Engel et al. 2012; Hu et al. 2015). The Arg385 residue is located near the active site and interacts with a glycine residue for stabilization of the protein (Balmer et al. 2014). Based on the evidence, the p.Arg385Cys variant is classified as pathogenic for argininosuccinate lyase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Counsyl	RCV000002502	SCV000485615	likely pathogenic	Argininosuccinate lyase deficiency	2016-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000002502	SCV000694149	pathogenic	Argininosuccinate lyase deficiency	2017-02-02	criteria provided, single submitter	clinical testing	Variant summary: The ASL c.1153C>T (p.Arg385Cys) variant involves the alteration of a conserved nucleotide indicated to be "located near the active site and interacts with glu389 for with glu389 for stabilization of the carboxy terminus helix bundle and its mutation may impact glu399, which has been proposed as part of active site (via Balmer_2014)." In silico tools, 5/5, predict a damaging outcome, which is supported by mulitple functional studies (Kleijer_2002). The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 8/118832 (1/14858), which does not exceed the estimated maximal expected allele frequency for a pathogenic ASL variant of 1/236. Multiple publications cite the variant in affected individuals, who are homozygous and compound heterozygous, along with authors stating the variant may cause mild to severe phenotypes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
SIB Swiss Institute of Bioinformatics	RCV000002502	SCV000803479	likely pathogenic	Argininosuccinate lyase deficiency	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Likely Pathogenic, for Argininosuccinic aciduria, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:25778938) (PMID:21667091). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.
Invitae	RCV000002502	SCV000953087	pathogenic	Argininosuccinate lyase deficiency	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 385 of the ASL protein (p.Arg385Cys). This variant is present in population databases (rs28940286, gnomAD 0.07%). This missense change has been observed in individuals with argininosuccinate lyase deficiency (PMID: 12384776, 12408190, 18616627). ClinVar contains an entry for this variant (Variation ID: 2401). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ASL function (PMID: 21667091, 25778938, 26745957). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000002502	SCV001163192	pathogenic	Argininosuccinate lyase deficiency	2023-05-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000002502	SCV002019518	pathogenic	Argininosuccinate lyase deficiency	2021-08-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000002502	SCV002795041	pathogenic	Argininosuccinate lyase deficiency	2022-05-05	criteria provided, single submitter	clinical testing
OMIM	RCV000002502	SCV000022660	pathogenic	Argininosuccinate lyase deficiency	2002-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000002502	SCV000040816	not provided	Argininosuccinate lyase deficiency		no assertion provided	literature only
Natera, Inc.	RCV000002502	SCV001459679	pathogenic	Argininosuccinate lyase deficiency	2020-09-16	no assertion criteria provided	clinical testing