ClinVar Genomic variation as it relates to human health

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 231 of the IDS protein (p.Pro231Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis II (PMID: 9762601, 12572848, 27146977, 30639582). ClinVar contains an entry for this variant (Variation ID: 1065825). 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%. For these reasons, this variant has been classified as Pathogenic.

Prevalence of the variant significantly increased in affected individuals compared with controls (PS4_Supporting), 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)

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is absent from gnomAD (v2, v3 and v4); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic in ClinVar and has been reported in multiple individuals in the literature with variable severity of mucopolysaccharidosis II ranging from attenuated to severe (PMIDs: 30639582, 27146977, 24125893, 9762601, 36945845, 35144014, 19167723); This variant has moderate functional evidence supporting abnormal protein function. IDS enzyme activity was decreased in an individual who was shown to be hemizygous for this variant (PMID: 27146977); Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. An alternative change, p.(Pro231Arg), has been classified as likely pathogenic or pathogenic by clinical laboratories in ClinVar; Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from Pro to Leu; This variant is hemizygous; This gene is associated with X-linked disease. Heterozygous females can be asymptomatic or affected similarly to hemizygous males, usually due to skewed X inactivation (PMID: 23232253); Alternative amino acid change(s) at the same position are present in gnomAD (Highest allele count: v4: 1 heterozygote(s), 0 homozygote(s), 0 hemizygote(s)); No published evidence of segregation with disease has been identified for this variant; Variant is located in the annotated sulfatase domain (DECIPHER); Loss of function is a known mechanism of disease in this gene and is associated with mucopolysaccharidosis II (MIM#309900); This variant has been shown to be maternally inherited by trio analysis.

The change c.692C>T, (p.P231L) was found to be a missense variant, where the cyclic nonpolar neutral amino acid Proline at 231 position was substituted by aliphatic nonpolar neutral amino acid Leucine. It was detected in the hemizygous condition in one case with attenuated phenotype from Delhi, India.