ClinVar Genomic variation as it relates to human health

The R111Q variant has been published in a patient with argininosuccinic aciduria who was homozygous for R111Q and who was diagnosed following an abnormal newborn screening result (Al-Shamsi et al. 2014). The R111Q variant was not observed with any significant frequency in either the 1000 Genomes Project Consortium or in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R111Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

Variant summary: ASL c.332G>A (p.Arg111Gln) 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 6e-05 in 250184 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ASL causing Argininosuccinic Aciduria (6e-05 vs 0.0042), allowing no conclusion about variant significance. c.332G>A has been reported in the literature in multiple homozygous individuals affected with Argininosuccinic Aciduria (e.g., Al-Shamsi_2014, Al-Jasmi_2016, Saleh_2021). These data indicate that the variant is very 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: 26589311, 24516753, 34374989). Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (pathogenic, n = 1; likely pathogenic, n = 1; uncertain significance, n = 2). Additionally, a different missense variant disrupting the same codon, c.331C>T (p.Arg111Trp), has been reported in patients with Argininosuccinic Aciduria (PMIDs: 1705937, 31737040, 33611823) and classified as likely pathogenic by our lab. 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 111 of the ASL protein (p.Arg111Gln). This variant is present in population databases (rs561367199, gnomAD 0.04%). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 24516753; Invitae). ClinVar contains an entry for this variant (Variation ID: 288770). 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.Arg111 amino acid residue in ASL. Other variant(s) that disrupt this residue have been observed in individuals with ASL-related conditions (PMID: 1705937), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.