ClinVar Miner

Submissions for variant NM_054012.4(ASS1):c.535T>C (p.Trp179Arg)

gnomAD frequency: 0.00007  dbSNP: rs121908646
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000291508 SCV000329824 pathogenic not provided 2017-08-07 criteria provided, single submitter clinical testing The W179R missense change in the ASS1 gene has been reported multiple times in individuals with argininosuccinate synthetase deficiency and is described as being associated with a mild clinical course with patients often being identified by newborn screening programs (Häberle et al. 2002; Häberle et al. 2003; Gao et al. 2003; Dimmock et al. 2008). Expression of W179R in E.coli found that this variant is associated with intermediate (~6%) residual enzyme activity compared to wild-type (Berning et al. 2008). W179R was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The W179R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret this variant as pathogenic.
Invitae RCV001376556 SCV000834604 pathogenic Citrullinemia 2023-12-05 criteria provided, single submitter clinical testing This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 179 of the ASS1 protein (p.Trp179Arg). This variant is present in population databases (rs121908646, gnomAD 0.01%). This missense change has been observed in individual(s) with citrullinemia (PMID: 11941481, 12815590, 14680976, 18925679). ClinVar contains an entry for this variant (Variation ID: 6335). 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 ASS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ASS1 function (PMID: 18473344). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000256312 SCV001163226 pathogenic Citrullinemia type I criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000291508 SCV001747006 pathogenic not provided 2021-06-01 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000256312 SCV001810274 pathogenic Citrullinemia type I 2021-07-22 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000256312 SCV002019989 pathogenic Citrullinemia type I 2021-09-28 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000256312 SCV002800243 pathogenic Citrullinemia type I 2022-01-06 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003914816 SCV004730070 pathogenic ASS1-related disorder 2023-10-26 criteria provided, single submitter clinical testing The ASS1 c.535T>C variant is predicted to result in the amino acid substitution p.Trp179Arg. This variant has been documented in patients with citrullinemia type I (e.g., Haberle et al. 2002. PubMed ID: 11941481; Gao et al. 2003. PubMed ID: 12815590; Berning et al. 2008. PubMed ID: 18473344; Dimmock et al. 2008. PubMed ID: 18925679; Table S1 in Diez-Fernandez et al. 2017. PubMed ID: 28111830), and the p.Trp179Arg substitution was found to reduce enzyme activity using in vitro studies (Haberle et al. 2002. PubMed ID: 11941481; Berning et al. 2008. PubMed ID: 18473344). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-133346260-T-C). It has been interpreted as likely pathogenic or pathogenic by multiple independent submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/6335). Based on the collective evidence, this variant is interpreted as pathogenic.
OMIM RCV000006707 SCV000026898 pathogenic Citrullinemia, mild 2002-04-01 no assertion criteria provided literature only
GeneReviews RCV000256312 SCV000323094 not provided Citrullinemia type I no assertion provided literature only
GenomeConnect, ClinGen RCV000256312 SCV000607233 not provided Citrullinemia type I no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Counsyl RCV000256312 SCV001132123 likely pathogenic Citrullinemia type I 2018-01-19 no assertion criteria provided clinical testing
Natera, Inc. RCV000256312 SCV001453084 pathogenic Citrullinemia type I 2020-09-16 no assertion criteria provided clinical testing

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