The NM_000203.5:c.1402+2T>G variant alters the canonical donor splice site dinucleotide of intron 9 of IDUA. This variant is predicted to result in skipping of biologically-relevant-exon 9 (IDUA has 14 exons), resulting in an in-frame deletion of amino acids 397-467 which represents >10% of the protein (PVS1_Strong). Two patients with this variant had documented IDUA deficiency within the affected range in leukocytes (0.2-3.4 versus normal range 27.2–52 nmol/h/mg protein), and clinical features specific to MPS I including macrocephaly, arthropathy, hepatomegaly, and airway disease. These patients also had documented increased urinary excretion of HS and DS. Thus three areas are met, giving the evidence to meet PP4 at the moderate level (PP4_Moderate). One patient is compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP, c.1037T>G (p.Leu346Arg) (ClinVar Variation ID: 11927). The variants were confirmed to be in trans by parental testing (PMID: 21480867) (1 point). Another patient is compound heterozygous for the variant and c.98A>C (p.His33Pro). This variant has not yet been classified by the ClinGen LD VCEP. The allelic data from the second patient will be used in the classification of p.His33Pro and is not included here to avoid circular logic. Total points for PM3 = 1 point (PM3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000002819 (3/1064228 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Two additional variants at this canonical splice donor site c.1402+1G>A and c.1402+1G>T) have been classified as likely pathogenic by the ClinGen LD VCEP. However PS1 does not apply (Table 2, PMID: 37352859). There is a ClinVar entry for this variant (ClinVar Variation ID: 553131). In summary, this variant meets the criteria to be classified as likely pathogenic for mucopolysaccharidosis type I. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications Version 1.0.0.): PVS1_Strong, PM3, PM2_Supporting (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 21, 2025)