ClinVar Genomic variation as it relates to human health

Variant summary: ASL c.331C>T (p.Arg111Trp) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the Fumarate lyase, N-terminal (IPR022761) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250184 control chromosomes (gnomAD). c.331C>T has been reported in the literature in individuals affected with Argininosuccinic Aciduria (Barbosa_1991, Wang_2019, Lui_2021), and one was reported as compound heterozygous with a likely pathogenic variant. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 1705937, 31737040, 33611823). One submitter has provided a clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

ClinVar contains an entry for this variant (Variation ID: 1489478). For these reasons, this variant has been classified as Pathogenic. 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. This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 1705937, 24927999, 33611823). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 111 of the ASL protein (p.Arg111Trp).