ClinVar Genomic variation as it relates to human health

The E283K 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (R279Q, G280R, T284I) have been reported in the Human Gene Mutation Database in association with citrullinemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

The ASS1 c.847G>A; p.Glu283Lys variant (rs765338121) is reported in the literature in the homozygous or compound heterozygous state in several individuals affected with citrullinemia (Diez-Fernandez 2017, Gao 2003, Kleijer 2006). This variant is reported in ClinVar (Variation ID: 430139), and is only observed on six alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glutamic acid at codon 283 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely 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. Gao HZ et al. Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients. Hum Mutat. 2003 Jul;22(1):24-34. Kleijer WJ et al. Prenatal diagnosis of citrullinemia and argininosuccinic aciduria: evidence for a transmission ratio distortion in citrullinemia. Prenat Diagn. 2006 Mar;26(3):242-7.

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 283 of the ASS1 protein (p.Glu283Lys). This variant is present in population databases (rs765338121, gnomAD 0.004%). This missense change has been observed in individual(s) with citrullinemia type (PMID: 12815590, 16475226, 23611581, 28111830; Invitae). ClinVar contains an entry for this variant (Variation ID: 430139). 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%. For these reasons, this variant has been classified as Pathogenic.