ClinVar Genomic variation as it relates to human health

Variant summary: The ASL c.857A>G (p.Gln286Arg) variant is indicated to located on the highly conserved and flexible loop C3 comprising residues 270-290 (called 280's loop) that has been proposed to be involved in entry of the substrate and exit of the product at the catalytic center (Balmer_2012) with 4/5 in silico tools predict a damaging outcome, which is further supported by functional studies, Trevisson_2009. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 9/120022 (1/13335), which does not exceed the estimated maximal expected allele frequency for a pathogenic ASL variant of 1/236. The variant of interest has been reported in multiple affected individuals, both as compound heterozygotes and homozygotes, via publications. In addition, multiple databases/clinical diagnostic laboratories have cited the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.

NM_001024943.1(ASL):c.857A>G(Q286R) is classified as pathogenic in the context of argininosuccinic aciduria. Sources cited for classification include the following: PMID 11747433, 24166829, 15273245, 9686346, 11747432, 19703900, 21667091 and 25778938. Classification of NM_001024943.1(ASL):c.857A>G(Q286R) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Across a selection of the available literature, the ASL c.857A>G (p.Gln286Arg) missense variant has been identified in a total of 18 individuals with argininosuccinate lyase deficiency, including in nine individuals in a homozygous state, in seven individuals in a compound heterozygous state and in two affected individuals in a heterozygous state in whom a second variant was not identified (Walker et al. 1997; Linnebank et al. 2002; Balmer et al. 2014). In two of the compound heterozygotes the second variant results is a frameshift leading to early termination of the protein and in the remaining four compound heterozygotes it is a missense variant. In the study by Balmer et al. (2014), four of the homozygotes and two of the compound heterozygotes were noted to have neonatal onset of the disease with one of the compound heterozygotes noted to have late onset of the disease. The age of onset for the remaining four homozygotes and four compound heterozygotes was unknown. The variant has been noted to be associated with a severe phenotype (Balmer et al. 2014). The p.Gln286Arg variant was absent from 20 controls (Walker et al. 1997) and is reported at a frequency of 0.00047 in the other population of the Exome Aggregation Consortium. Sampaleanu et al. (2001) note that the Gln286 residue is located in a highly conserved and flexible loop region of the protein that has been proposed to be involved in entry of the substrate and exit of the product at the catalytic center. Substitution of the glutamine at this residue to arginine changes the interactions of this loop and neighbouring residues that may impact catalysis. Expression of the variant p.Gln286Arg protein in COS-1 cells and HEK293T cells resulted in a similar level of protein expression of the correct size compared to wild type (Walker et al. 1997; Hu et al. 2015). However, the variant protein was shown to retain no significant residual enzymatic activity in either patient-derived red blood cells (less than 5%) or fibroblasts (less than 3%) or when expressed in E.coli, COS-1 cells (0.05%), or HEK293T cells (Walker et al. 1997; Balmer et al. 2014; Hu et al. 2015). Based on the collective evidence, the p.Gln286Arg variant is classified as pathogenic for argininosuccinate lyase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 286 of the ASL protein (p.Gln286Arg). This variant is present in population databases (rs28941472, gnomAD 0.02%). This missense change has been observed in individuals with argininosuccinate lyase deficiency (PMID: 12408190, 19703900, 21667091, 23430928). ClinVar contains an entry for this variant (Variation ID: 2399). 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 ASL protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ASL function (PMID: 9686346, 11747433, 19703900, 21667091). For these reasons, this variant has been classified as Pathogenic.

Reported many times in unrelated patients with argininosuccinic aciduria and has been identified on approximately 8% of ASL pathogenic alleles (PMID: 12384776); 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: 22231378, 12408190, 25778938, 11747433, 21667091, 24166829, 9686346, 30285816, 31943503, 17326097, 31980526, 34426522, 32778825, 31589614, 38198573, 36270249, 9045711, 12384776, 11747432)