ClinVar Genomic variation as it relates to human health

Variant summary: ASL c.556C>T (p.Arg186Trp) 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 9e-06 in 221462 control chromosomes (gnomAD). c.556C>T has been reported in the literature in multiple individuals (both homozygous and compound heterozygous) affected with Argininosuccinic Aciduria (example: Imtiaz_2010, Balmer_2014). These data indicate that the variant is very likely to be associated with disease. Very low enzymatic activity (% of wild type control) was found in a patient derived sample who was compound heterozygous for the variant of interest and another splice site variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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 186 of the ASL protein (p.Arg186Trp). 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 argininosuccinic aciduria (PMID: 20298553, 29326055, 31709144). ClinVar contains an entry for this variant (Variation ID: 1050820). 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 variant disrupts the p.Arg186 amino acid residue in ASL. Other variant(s) that disrupt this residue have been determined to be pathogenic (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.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with argininosuccinic aciduria (MIM#207900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 4 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated lyase 1 domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Arg186Gln) variant has been reported as pathogenic (ClinVar) and fibroblasts of a compound heterozygote patient showed a reduction of less than 2% of activity compared to wild type (PMID: 17326097). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple homozygous and compound heterozygous individuals with argininosuccinic aciduria (ClinVar, PMIDs: 20298553, 31709144). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign