ClinVar Miner

Submissions for variant NM_054012.4(ASS1):c.1087C>T (p.Arg363Trp) (rs121908640)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000185787 SCV000202201 pathogenic not provided 2018-04-25 criteria provided, single submitter clinical testing
Counsyl RCV000006700 SCV000220168 likely pathogenic Citrullinemia type I 2014-03-16 criteria provided, single submitter literature only
GeneDx RCV000185787 SCV000238723 pathogenic not provided 2017-10-31 criteria provided, single submitter clinical testing The R363W pathogenic variant in the ASS1 gene has been reported multiple times in association with classic citrullinemia (Kobayashi et al. 1990; Gao et al. 2003; Faghfoury et al. 2011; Xie et al. 2014). The R363W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Furthermore, R363W 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, and this substitution occurs at a position that is conserved across species. Therefore, we interpret R363W to be a pathogenic variant.
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 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 363 of the ASS1 protein (p.Arg363Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant is one of the relatively common ASS1 mutations which has been reported in multiple individuals and families from different ethnic groups affected with citrullinemia type 1 (PMID: 16124451, 28111830, 26117549, 2358466, 14680976, 12815590, 25537548). ClinVar contains an entry for this variant (Variation ID: 6328). Experimental studies have shown that this missense change diminished ASS1 enzyme activity in vitro (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
OMIM RCV000006700 SCV000026891 pathogenic Citrullinemia type I 2013-04-04 no assertion criteria provided literature only

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