ClinVar

Description

Variant summary: IDUA c.757G>T (p.Gly253Cys) 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 0.0006 in 218446 control chromosomes, predominantly at a frequency of 0.0046 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 phenotype (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.757G>T has been reported in the literature in at least an individual (in homozygous state) affected with Mucopolysaccharidosis Type 1 - subtype Hurler-Scheie (Uttarilli_2016). No enzymatic activity was found from patient derived leucocytes who was homozygous for this variant of interest (Uttarilli_2016). Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.