ClinVar Genomic variation as it relates to human health

The p.Glu293fs variant in ASPA has been reported in 3 individuals with Canavan d isease, including at least one compound heterozygote (Kaul 1996). This variant h as been identified in 1/66340 of European chromosomes by the Exome Aggregation C onsortium (ExAC, http://exac.broadinstitute.org). In vitro assays suggest that t his variant abolished ASPA protein activity (Kaul 1996); however, these types of assays may not accurately represent biological function. This variant is predic ted to cause a frameshift, which alters the protein?s amino acid sequence beginn ing at position 293 and leads to a premature termination codon 8 amino acids dow nstream. This termination codon occurs within the last exon and is more likely t o escape nonsense mediated decay (NMD) and result in a truncated protein. In sum mary, although additional studies are required to fully establish its clinical s ignificance, the p.Glu293fs variant is likely pathogenic.

Variant summary: ASPA c.876_879delAGAA (p.Glu293LeufsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8e-06 in 251438 control chromosomes. c.876_879delAGAA has been reported in the literature in individuals affected with Canavan Disease (example, Kaul_1996, Zeng_2002). These data indicate that the variant is 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 undetectable ASPA enzyme activity in-vitro (example, Kaul_1996). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Glu293Leufs*8) in the ASPA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 21 amino acid(s) of the ASPA protein. This variant is present in population databases (rs766720790, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Canavan disease (PMID: 8659549). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 876 delAGAA. ClinVar contains an entry for this variant (Variation ID: 371665). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects ASPA function (PMID: 8659549). This variant disrupts the p.Ala305 amino acid residue in ASPA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8023850, 10909858, 16217711, 22850825). 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.