The NM_000203.5(IDUA):c.895G>T (p.Glu299Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant exon 7 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 2 patients with this variant had documented IDUA deficiency within the affected range in leukocytes and clinical features specific to MPS I including dysostosis multiplex, hepatosplenomegaly, arthropathy, and corneal involvement (PMIDs: 16438163, 27146977) (PP4). Of those individuals, one was compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, c.223G>A (p.Ala75Thr) (ClinVar Variation ID: 222993); the phase was not confirmed (0.5 points; PMID: 27146977). One individual was homozygous for the variant (ClinVar SCV002562742.2) (0.5 points). Total 1 point (PM3). Another patient was compound heterozygous for the variant and c.164dup (PMID: 16438163). The allelic data for this patient will be used to support the classification of c.164dup and is not included here in order to avoid circular logic. The highest population minor allele frequency in gnomAD v4.1.0. is 0.000023 (2/86636 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 987878). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PVS1, PP4, PM3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 16, 2025)