ClinVar Genomic variation as it relates to human health

Variant summary: GAA c.923A>C (p.His308Pro) results in a non-conservative amino acid change located in the glycoside hydrolase family 31, N-terminal domain (IPR025887) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 244682 control chromosomes (gnomAD). c.923A>C has been reported in the literature as a compound heterozygous genotype in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. Hermans_2004, Bali_2012, van Capelle_2016, Vanherpe_2020). These data indicate that the variant is likely to be associated with disease. Publications reporting experimental evidence evaluating an impact on protein function found that the variant effect results in <2% of normal activity (e.g. Hermans_2004, Flanagan_2009). One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

ClinVar contains an entry for this variant (Variation ID: 1493530). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GAA protein function. Experimental studies have shown that this missense change affects GAA function (PMID: 14695532, 19862843). This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 308 of the GAA protein (p.His308Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Pompe disease (PMID: 14695532, 28624228, 31086307). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His308 amino acid residue in GAA. 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.