ClinVar Genomic variation as it relates to human health

Experimental studies have shown that this missense change affects IDS function (PMID: 9573369, 12572848). 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. ClinVar contains an entry for this variant (Variation ID: 996919). This missense change has been observed in individual(s) with clinical features of mucopolysaccharidosis type II (PMID: 8111411, 30639582; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 86 of the IDS protein (p.Pro86Arg). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro86 amino acid residue in IDS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9573369, 17063374, 24515576, 28077157). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.

Variant summary: IDS c.257C>G (p.Pro86Arg) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) 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 113502 control chromosomes. c.257C>G has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type II (Hunter Syndrome) with reported severe phenotype (e.g. Hopwood_1995, Goldenfum_1996, Zhang_2019, Agrawal_2022, Zhong_2023) or intermediate phenotype (e.g. Popowska_1995). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal IDS activity (e.g. Millat_1998). The following publications have been ascertained in the context of this evaluation (PMID: 35144014, 8664909, 8111411, 9573369, 7728156, 30639582, 36945845). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

In vitro or in vivo functional studies supportive of a damaging effect (PS3_Strong), Prevalence of the variant significantly increased in affected individuals compared with controls (PS4_Moderate), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Missense variant in a gene with a low rate of benign missense variation (PP2_Supporting), Multiple lines of computational evidence support a deleterious effect (PP3_Supporting), Patient’s phenotype or family history highly specific for the disease (PP4_Moderate)