ClinVar Miner

Submissions for variant NM_000050.4(ASS1):c.535T>C (p.Trp179Arg) (rs121908646)

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Total submissions: 5
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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.
GeneReviews RCV000256312 SCV000323094 pathogenic Citrullinemia type I 2016-09-01 no assertion criteria 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.
Invitae RCV000256312 SCV000834604 pathogenic Citrullinemia type I 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 179 of the ASS1 protein (p.Trp179Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is present in population databases (rs121908646, ExAC 0.02%). This variant has been reported in several families and individuals affected with citrullinemia (PMID: 11941481, 14680976, 12815590, 18925679). This variant has been identified as homozygous in individuals with mild citrullinemia type I manifesting mild or no clinical symptoms (PMID: 11941481, 18925679). ClinVar contains an entry for this variant (Variation ID: 6335). Experimental studies have shown that this missense change abrogates ASS1 enzyme activity (PMID: 18473344). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000006707 SCV000026898 pathogenic Citrullinemia, mild 2002-04-01 no assertion criteria provided literature only

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