ClinVar Miner

Submissions for variant NM_000048.4(ASL):c.1153C>T (p.Arg385Cys) (rs28940286)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,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 2020-09-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 385 of the ASL protein (p.Arg385Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs28940286, ExAC 0.03%). This variant has been observed as homozygous in several individuals affected with argininosuccinate lyase deficiency (PMID: 12408190, 18616627, 12384776). ClinVar contains an entry for this variant (Variation ID: 2401). Experimental studies have shown that this missense change abrogates argininosuccinate lyase enzymatic activity (PMID: 21667091, 25778938, 26745957). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000002502 SCV001163192 pathogenic Argininosuccinate lyase deficiency 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 pathologic Argininosuccinate lyase deficiency 2011-02-03 no assertion criteria provided curation Converted during submission to Pathogenic.
Natera, Inc. RCV000002502 SCV001459679 pathogenic Argininosuccinate lyase deficiency 2020-09-16 no assertion criteria provided clinical testing

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