Submissions for variant NM_054012.4(ASS1):c.1087C>T (p.Arg363Trp)

gnomAD frequency: 0.00004  dbSNP: rs121908640

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000185787	SCV000202201	pathogenic	not provided	2018-04-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000185787	SCV000238723	pathogenic	not provided	2022-07-15	criteria provided, single submitter	clinical testing	Observed multiple times with a pathogenic variant on the opposite allele (in trans) in individuals with classic citrillinemia (Kobayashi et al. 1990; Gao et al. 2003; Faghfoury et al. 2011; Xie et al. 2014); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 31208364, 14680976, 21227727, 26117549, 16124451, 28750687, 28111830, 28132756, 2358466, 25537548, 8792870, 12815590, 32778825, 31469252)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000185787	SCV000281021	pathogenic	not provided	2015-06-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000006700	SCV000602545	pathogenic	Citrullinemia type I	2019-10-04	criteria provided, single submitter	clinical testing	The ASS1 c.1087C>T, p.Arg363Trp variant (rs121908640) is reported in the literature in multiple individuals affected with citrullinemia, either in a homozygous state or compound heterozygous with another pathogenic variant (Diez-Fernandez 2017, Faghfoury 2011, Gao 2003, Haberle 2003, Kobayashi 1990, Mohamed 2015, Wasant 2005). This variant is reported as pathogenic or likely pathogenic by multiple laboratories in ClinVar (Variation ID: 6328), and is only observed on 8 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 363 is moderately conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, arginine 363 is implicated in tetramer binding, which is critical for protein function (Diez-Fernandez 2017). Additionally, other amino acid substitutions at this codon (Gly, Leu, Gln) have been reported in individuals with citrullinemia (Gao 2003, Mohamed 2015). Based on available information, the p.Arg363Trp variant is considered to be pathogenic. References: Diez-Fernandez C et al. Mutations in the Human Argininosuccinate Synthetase (ASS1) Gene, Impact on Patients, Common Changes, and Structural Considerations. Hum Mutat. 2017 May;38(5):471-484. Faghfoury H et al. Transient fulminant liver failure as an initial presentation in citrullinemia type I. Mol Genet Metab. 2011; 102(4):413-7. Gao H et al. Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients. Hum Mutat. 2003; 22(1):24-34. Haberle J et al. Mild citrullinemia in Caucasians is an allelic variant of argininosuccinate synthetase deficiency (citrullinemia type 1). Mol Genet Metab. 2003 Nov;80(3):302-6. Kobayashi K et al. Heterogeneity of mutations in argininosuccinate synthetase causing human citrullinemia. J Biol Chem. 1990; 265(19):11361-7. Mohamed S et al. Neurometabolic Disorders-Related Early Childhood Epilepsy: A Single-Center Experience in Saudi Arabia. Pediatr Neonatol. 2015 Dec;56(6):393-401. Wasant P et al. Argininosuccinate synthetase deficiency: mutation analysis in 3 Thai patients. Southeast Asian J Trop Med Public Health. 2005; 36(3):757-61.
Invitae	RCV001376637	SCV000630050	pathogenic	Citrullinemia	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 363 of the ASS1 protein (p.Arg363Trp). This variant is present in population databases (rs121908640, gnomAD 0.007%). This missense change has been observed in individual(s) with citrullinemia type 1 (PMID: 2358466, 12815590, 14680976, 16124451, 25537548, 26117549, 28111830). 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: 6328). 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: 8792870). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000006700	SCV000893800	pathogenic	Citrullinemia type I	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000006700	SCV001163603	pathogenic	Citrullinemia type I		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001376637	SCV002051420	pathogenic	Citrullinemia	2021-12-30	criteria provided, single submitter	clinical testing	Variant summary: ASS1 c.1087C>T (p.Arg363Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 250206 control chromosomes (gnomAD). c.1087C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Citrullinemia Type I (e.g. Haberle_2003, Wasant_2005, Zielonka_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated severely diminished activity compared to the wild type (Zielonka_2019). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV000006700	SCV002060326	likely pathogenic	Citrullinemia type I	2021-11-01	criteria provided, single submitter	clinical testing	NM_000050.4(ASS1):c.1087C>T(R363W) is a missense variant classified as likely pathogenic in the context of citrullinemia type 1. R363W has been observed in cases with relevant disease (PMID: 16124451, 26117549, 2358466, 14680976, 25537548, 31056765, 30904546). Functional assessments of this variant are available in the literature (PMID: 31469252). Internal structural analysis of the variant is supportive of pathogenicity. R363W has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, NM_000050.4(ASS1):c.1087C>T(R363W) is a missense variant that has both functional and internal structural support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Revvity Omics, Revvity	RCV000006700	SCV003817962	pathogenic	Citrullinemia type I	2022-09-26	criteria provided, single submitter	clinical testing
OMIM	RCV000006700	SCV000026891	pathogenic	Citrullinemia type I	2013-04-04	no assertion criteria provided	literature only
Natera, Inc.	RCV000006700	SCV002085112	pathogenic	Citrullinemia type I	2020-06-03	no assertion criteria provided	clinical testing