The p.R493H variant (also known as c.1478G>A), located in coding exon 9 of the IDS gene, results from a G to A substitution at nucleotide position 1478. The arginine at codon 493 is replaced by histidine, an amino acid with highly similar properties. Another alteration affecting the same amino acid, p.R493P (c.1478G>C), has been reported in a mucopolysaccharidosis cohort (Pollard LM et al. J. Inherit. Metab. Dis., 2013 Mar;36:179-87). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 493 of the IDS protein (p.Arg493His). This variant is present in population databases (rs782347729, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with abnormal newborn screening results (PMID: 29801497, 36907694). ClinVar contains an entry for this variant (Variation ID: 968479). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt IDS protein function with a positive predictive value of 80%. This variant disrupts the p.Arg493 amino acid residue in IDS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22976778, 24515576, 31877959). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Variant summary: IDS c.1478G>A (p.Arg493His) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 1.6e-05 in 183355 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1478G>A has been observed in individuals affected with Mucopolysaccharidosis Type II (Hunter Syndrome) (Chuang_2018, Lin_2019, Burton_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Mucopolysaccharidosis Type II (Hunter Syndrome). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36907694, 29801497, 38053932, 35887520). ClinVar contains an entry for this variant (Variation ID: 968479). Based on the evidence outlined above, the variant was classified as uncertain significance.