ClinVar

Description

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 224 of the IDS protein (p.Gly224Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Hunter syndrome (PMID: 18500569). 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 IDS protein function. Experimental studies have shown that this missense change affects IDS function (PMID: 18500569). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Gly224 amino acid residue in IDS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27246110; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.