The NM_000203.5:c.457A>T (p.Lys153Ter) in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 4 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Furthermore, SpliceAI predicts that the variant may impact splicing (score for loss of intron 3 acceptor = 0.55; score for loss of intron 4 donor = 0.42). Three individuals reported in the MPS I registry are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, two with a reported severe phenotype with c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908), and one with an attenuated phenotype with c.1598C>G (p.Pro533Arg) (ClinVar Variation ID: 11910). The phase is unknown is all three cases (PM3, based on 3 x 0.5 points). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00003332 (2/60024 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type I. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications Version 1.0.0.): PVS1, PM3, PM2_Supporting (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 21, 2025).