ClinVar Genomic variation as it relates to human health

Published functional studies in HEK293 cells demonstrate a significant decrease or loss of enzyme activity compared to controls (Nino et al., 2013); Not observed in large population cohorts (Lek et al., 2016); 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: 31086307, 32064362, 21637107, 29122469, 23430493, 31342611, 30564623)

Variant summary: GAA c.2236T>C (p.Trp746Arg) 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. This alters a highly conserved residue (HGMD) in which other missense variants have been found in association with disease and some have been classified as pathogenic by ClinVar submitters (e.g. p.Trp746Cys). The variant was absent in 250780 control chromosomes (gnomAD). c.2236T>C has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease; Nino_2013, Mori_2017, Nallamilli_2018, Kishnani_2019), and some were reported as compound heterozygous with a pathogenic variant. 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 (Nino_2013), finding that the variant results in <10% of normal GAA activity. The following publications have been ascertained in the context of this evaluation (PMID: 29122469, 23430493, 30564623, 31086307, 31254424, 33202836). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=5) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

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 GAA protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp746 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9535769, 21232767, 21757382, 25093132, 27099502). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GAA function (PMID: 23430493). ClinVar contains an entry for this variant (Variation ID: 499293). This missense change has been observed in individuals with GAA-related conditions (PMID: 23430493, 29122469). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 746 of the GAA protein (p.Trp746Arg).