Submissions for variant NM_054012.4(ASS1):c.1088G>A (p.Arg363Gln)

gnomAD frequency: 0.00001  dbSNP: rs771937610

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185788	SCV000238724	likely pathogenic	not provided	2021-02-24	criteria provided, single submitter	clinical testing	Reported in other individuals reported to have citrullinemia who either did not have a second variant identified in the ASS1 gene or for whom detailed clinical information was not provided (Haberle et al., 2010; Zielonka et al., 2019); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30285816, 24508627, 19006241, 12815590, 28111830, 31469252, 20005624)
Invitae	RCV000633525	SCV000754765	pathogenic	Citrullinemia	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 363 of the ASS1 protein (p.Arg363Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with citrullinemia type I (PMID: 30285816, 31469252; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203631). 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%. This variant disrupts the p.Arg363 amino acid residue in ASS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2358466, 12815590, 14680976, 16124451, 25537548, 26117549, 28111830). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000185788	SCV000854776	pathogenic	not provided	2018-08-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002500568	SCV002807301	likely pathogenic	Citrullinemia type I	2021-11-16	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV002500568	SCV004101491	likely pathogenic	Citrullinemia type I		criteria provided, single submitter	clinical testing	The missense variant p.R363Q in ASS1 (NM_054012.4) has been previously reported in an individual affected with ASS1-related conditins (Gao et al, 2003). The p.R363Q variant has a gnomAD frequency of 0.0003999 % and is novel (not in any individuals) in 1000 Genomes. There is a small physicochemical difference between arginine and glutamine, which is not likely to impact secondary protein structure as these residues share similar properties. The p.R363Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 363 of ASS1 is conserved in all mammalian species. The nucleotide c.1088 in ASS1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. The observed variant is also detected in the spouse.
Baylor Genetics	RCV002500568	SCV004202583	pathogenic	Citrullinemia type I	2023-09-20	criteria provided, single submitter	clinical testing