ClinVar Genomic variation as it relates to human health

Variant summary: ASL c.436C>T (p.Arg146Trp) 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 2e-05 in 249972 control chromosomes (gnomAD). c.436C>T has been reported in the literature in individuals affected with Argininosuccinic Aciduria (examples: Balmer_2014, Silver-Ruiz_2019, and Ali_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Zielonka_2020). Two clinical diagnostic laboratories have submitted 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.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 146 of the ASL protein (p.Arg146Trp). This variant is present in population databases (rs199938613, gnomAD 0.006%). This missense change has been observed in individuals with argininosuccinate lyase deficiency (PMID: 24166829, 31709144). ClinVar contains an entry for this variant (Variation ID: 203626). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg146 amino acid residue in ASL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28251416; Invitae). 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.

The ASL c.436C>T variant is predicted to result in the amino acid substitution p.Arg146Trp. This variant has been reported in the homozygous or compound heterozygous state with a second ASL variant in several individuals with argininosuccinate lyase deficiency (Balmer et al. 2014. PubMed ID: 24166829; Ali et al. 2019. PubMed ID: 31709144; Silvera-Ruiz et al. 2019. PubMed ID: 31426867). In in vitro studies, the p.Arg146Trp substitution resulted in greatly decreased protein expression and argininosuccinate lyase enzyme activity (Zielonka et al. 2020. PubMed ID: 31943503). Different substitutions impacting the same amino acid (p.Arg146Gly, p.Arg146Gln) have also been reported in patients with argininosuccinate lyase deficiency (Baruteau et al. 2017. PubMed ID: 28251416). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-65548151-C-T). Taken together, this variant is interpreted as pathogenic.