ClinVar Genomic variation as it relates to human health

Variant summary: ASL c.557G>A (p.Arg186Gln) results in a conservative amino acid change located in the Fumarate lyase, N-terminal domain (IPR022761) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 218826 control chromosomes (gnomAD). c.557G>A has been reported in the literature in individuals affected with Argininosuccinic Aciduria (e.g. Balmer_2014, Nagamani_2012, Trevisson_2007, Burrage_2020). These data indicate that the variant is likely to be associated with disease. Experimental evidence demonstrated the variant affects enzyme activity (e.g. Trevisson_2009). Additionally, another variant at the same residue, p.Arg186Trp, was found in individuals affected Argininosuccinic Aciduria (e.g.Balmer_2014) and has been classified as pathogenic at our laboratory, indicating the arginine residue is critical for protein function. One ClinVar submitter (evaluation after 2014) cites 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 glutamine, which is neutral and polar, at codon 186 of the ASL protein (p.Arg186Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 17326097). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 933174). 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: 19703900). This variant disrupts the p.Arg186 amino acid residue in ASL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29326055). 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.

ASL: PM3:Very Strong, PM1, PM2, PM5, PS3:Supporting