ClinVar Genomic variation as it relates to human health

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. 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: 24166829; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ASL function (PMID: 19703900). 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. ClinVar contains an entry for this variant (Variation ID: 941054). This missense change has been observed in individual(s) with argininosuccinic aciduria (PMID: 17326097, 19703900, 24166829). This variant is present in population databases (rs761268464, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 236 of the ASL protein (p.Arg236Trp).

Variant summary: ASL c.706C>T (p.Arg236Trp) results in a non-conservative amino acid change located in the fumarate lyase, N-terminal domain (IPR022761) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251328 control chromosomes (gnomAD). c.706C>T has been reported in the literature as a biallelic genotype in individuals affected with Argininosuccinic Aciduria, primarily with an early onset of the disease (e.g. Trevisson_2007, Trevisson_2009, Balmer_2014, Zielonka_2020). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function and found the variant effect results in <10% of normal activity (Trevisson_2009, Zielonka_2020). The following publications have been ascertained in the context of this evaluation (PMID: 24166829, 17326097, 19703900, 31943503). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.