ClinVar Genomic variation as it relates to human health

Variant summary: The ASL c.637C>T (p.Arg213X) variant results in a premature termination codon, predicted to cause a truncated or absent ASL protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 1/118802 control chromosomes at a frequency of 0.0000084, which does not exceed the estimated maximal expected allele frequency of a pathogenic ASL variant (0.0042258). Multiple publications have cited the variant in affected compound heterozygotes and homozygote individuals. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

The R213X variant has been reported previously in association with argininosuccinic aciduria (Trevisson et al. 2007). The R213X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R213X variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret this variant as pathogenic.

The ASL c.637C>T (p.Arg213Ter) variant is a stop-gained variant that is predicted to result in a premature termination or absence of the protein. The p.Arg213Ter variant is reported in at least eight individuals with argininosuccinate lyase deficiency, including in a homozygous state in one individual and in a compound heterozygous state, most often with a missense variant, in at least seven individuals (Trevisson et al. 2007; Balmer et al. 2014; Bijarnia-Mahay et al. 2018; Zhao et al. 2019; Zhang et al. 2021; Kido et al. 2021). Commonly reported phenotypic features in these individuals included hyperammonemia, elevated argininosuccinic acid, intellectual disability, epilepsy, and hepatic disease. The p.Arg213Ter variant is reported at a frequency of 0.000163 in the South Asian population of the Genome Aggregation Database (version 2.1.1). Transfection of the ASL p.Arg213Ter variant into HEK293T cells resulted in a significantly reduced enzyme activity as compared to cells transfected with the wild type protein (Zhao et al. 2019). Based on the available evidence, the p.Arg213Ter variant is classified as pathogenic for argininosuccinate lyase deficiency.

This sequence change creates a premature translational stop signal (p.Arg213*) in the ASL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASL are known to be pathogenic (PMID: 2263616, 24166829). This variant is present in population databases (rs761651320, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 17326097, 30285816, 31183366). ClinVar contains an entry for this variant (Variation ID: 426366). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.