ClinVar Genomic variation as it relates to human health

Variant summary: ASPA c.79G>A (p.Gly27Arg) results in a non-conservative amino acid change in 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 2.9e-05 in 277212 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ASPA causing Canavan Disease (2.9e-05 vs 0.0079), allowing no conclusion about variant significance. c.79G>A has been reported in the literature in multiple individuals affected with Canavan Disease as both a homozygous and compound heterozygous allele. It was also reported to co-segregate with family history in a recessive manner. These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating enzyme activity in cell culture, which shows <10% of normal ASPA enzyme activity (Kaul_1996). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant is interpreted as a Likely Pathogenic, for Canavan disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS3 => Well-established functional studies show a deleterious effect (PMID:8659549).

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 27 of the ASPA protein (p.Gly27Arg). This variant is present in population databases (rs766328537, gnomAD 0.02%). This missense change has been observed in individual(s) with Canavan disease (PMID: 8659549, 10909858, 12638939, 18978679, 22611636). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188888). 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 ASPA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ASPA function (PMID: 8659549). For these reasons, this variant has been classified as Pathogenic.

Expression studies found this variant is associated with 3% of residual enzyme activity compared to wild-type (Kaul et al., 1996); 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: 10407784, 23233226, 18978679, 22611636, 8659549, 12638939, 25668701, 10909858, 31589614)