ClinVar Genomic variation as it relates to human health

Variant summary: ASL c.571C>T (p.Arg191Trp) results in a non-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 7.7e-05 in 207286 control chromosomes, predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ASL causing Argininosuccinic Aciduria (7.7e-05 vs 0.0042), allowing no conclusion about variant significance. c.571C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Argininosuccinic Aciduria (Grioni_2011, Balmer_2014, Zielonka_2020). These data indicate that the variant is very 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 ~60% of normal activity (Zielonka_2020). Four ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=2), likely pathogenic (n=1) and pathogenic (n=1). 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 191 of the ASL protein (p.Arg191Trp). This variant is present in population databases (rs143508372, gnomAD 0.01%). This missense change has been observed in individuals with a positive newborn screening result for ASL-related disease and argininosuccinic aciduria (PMID: 21744316, 24166829, 31943503). ClinVar contains an entry for this variant (Variation ID: 445881). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ASL protein function. Experimental studies have shown that this missense change affects ASL function (PMID: 31943503). This variant disrupts the p.Arg191 amino acid residue in ASL. Other variant(s) that disrupt this residue have been observed in individuals with ASL-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Functional studies found this variant is associated with only a slight reduction of mRNA expression and retains significant enzyme activity, approximately 60%, compared to wild-type (Zielonka M et al., 2020); Observed with a second variant in the ASL gene in asymptomatic individuals identified by newborn screening (Balmer C et al., 2014; Zielonka M et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 31943503, 24166829, 21744316)