ClinVar Genomic variation as it relates to human health

NM_001024943.1(ASL):c.707G>A(R236Q) is a missense variant classified as likely pathogenic in the context of argininosuccinic aciduria. R236Q has been observed in cases with relevant disease (PMID: 31056765, 24166829, Boulos_2021_(no PMID; abstract)). Functional assessments of this variant are available in the literature (PMID: 11698398). R236Q has been observed in population frequency databases (gnomAD: SAS 0.003%). In summary, NM_001024943.1(ASL):c.707G>A(R236Q) is a missense variant that 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.

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.99; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000555574 / PMID: 24166829). A different missense change at the same codon (p.Arg236Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000941054 / PMID: 17326097). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Not observed at 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: 24166829, 11698398, 19703900, 18677552, 17326097, 31056765, 21744316)

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 236 of the ASL protein (p.Arg236Gln). This variant is present in population databases (rs764602422, gnomAD 0.003%). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 24166829; Invitae). ClinVar contains an entry for this variant (Variation ID: 555574). 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%. This variant disrupts the p.Arg236 amino acid residue in ASL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17326097, 19703900, 24166829). 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.

This variant was previously reported in a compound heterozygous state in late-onset ASLD patient [PMID: 24166829]. In addition, another protein change at this position p.Arg236Trp (c.706C>T) was previously reported in an Italian patient with neonatal onset of ASLD, manifested with clinical features of lethargy, hyperammonemia, mild psychomotor retardation in the compound heterozygous state. A molecular modeling data revealed that Arg236 is highly conserved residue, located within the active site of the enzyme, and crucial for substrate interaction. Variations affecting this Arg236 residue are likely to have a severe impact on the catalytic function of the protein [PMID: 17326097]