ClinVar Genomic variation as it relates to human health

Mucopolysaccharidosis type 2 or Hunter disease is a recessive X-linked disorder due to mutations in IDS gene. This gene codifies for iduronate-2-sulfatase, and enzyme crucial in the degradation of heparan and dermatan sulfate. We found the c.1454T>C (p.Ile485Thr) in the IDS gene in hemizygosity in a 2-year-old healthy boy. This variant could be classified as likely pathogenic if we apply the following criteria based on the ACMG guidelines: PP2, PP3, PM1, PM2, PM5. It is the rs782430567 in dbSNP. In ClinVar it is reported with the accession RCV001568383.1. It is not reported in HGMD although there is a variant reported as pathogenic in the same base: c.1454T>A (p.Ile485Lys). We then performed the iduronate-2-sulfatase enzymatic activity in leukocytes of the patient, and it was of 27 nmol/4h/mg prot (control range 18-69 nmol/4h/mg prot), so it was completely normal. His mother and his maternal grandmother were also carriers of the variant. We then analysed the patient's maternal uncle. He was a 37 years-old healthy man, and he was also found to be a carrier of the mutation in hemizygosity. We tested the iduronate-2-sulfatase enzymatic activity in leukocytes of this uncle and it was of 26.3 nmol/4h/mg prot (control range 18-69 nmol/4h/mg prot). The activity was also tested in Dried Blood Spots (DBS) and it was of 5.4 micromol/L.h (control range 3.2-8.5 micromol/L.h). Taking into account that the uncle was a carrier, that at 37 years old he was healthy and that the iduronate-2-sulfatase enzymatic activity tested in leukocytes and in DBS was absolutely normal in both males, we consider this variant as BENIGN

Prevalence of the variant significantly increased in affected individuals compared with controls (PS4_Strong), 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_Strong)