Variant summary: IDS c.1477C>T (p.Arg493Cys) 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 7.4e-06 in 1209710 control chromosomes, including 3 hemizygotes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1477C>T has been reported in the literature in an individual without reported sex or genotype affected with iduronate-2-sulfatase enzyme pseudodeficiency without Mucopolysaccharidosis Type II phenotype by age 3 years (e.g. Burton_2023) and in a hemizygous male affected with intellectual disability and/or global developmental delay (e.g. Spataro_2023). These reports 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, 36980980). ClinVar contains an entry for this variant (Variation ID: 1404345). Based on the evidence outlined above, the variant was classified as uncertain significance.

The missense c.1477C>T (p.Arg493Cys) variant in IDS gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. Another missense variant in the same residue (c.1478G>A|p.R493H; c.1478G>C|p.R493P) was identified in patient affected with Mucopolysaccharidosis (Lin HY et al. 2019; Chuang CK et al. 2018). The p.Arg493Cys variant is present with allele frequency of 0.0005% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic / Uncertain Significance. Multiple lines of computational evidence (Polyphen - Probably damaging, SIFT – Damaging and Mutation Taster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position on IDS gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 493 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies are required to prove the pathogenicity for the variant, for these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).

PM1;PM2_supporting;PM5;PP3

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: 36907694, 38909121, 36980980)