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

gnomAD frequency: 0.00007  dbSNP: rs121908646

Total submissions: 15

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001376556	SCV000834604	pathogenic	Citrullinemia	2024-03-04	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	2024-02-20	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	2024-02-28	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000256312	SCV005052011	pathogenic	Citrullinemia type I	2024-02-01	criteria provided, single submitter	curation
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001376556	SCV005420855	pathogenic	Citrullinemia	2024-10-04	criteria provided, single submitter	research	PS3,PM3 (strong), PP3,PM2
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
PreventionGenetics, part of Exact Sciences	RCV003914816	SCV004730070	pathogenic	ASS1-related disorder	2024-07-10	no assertion criteria provided	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. It has been interpreted as 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.