The NM_000203.5:c.1499A>G variant in IDUA is predicted to result in a missense substitution, p.Gln500Arg. This variant has been identified in at least 3 individuals, including an adult with clinical features consistent with MPS1, and documented laboratory values showing elevated urine GAGs, and deficient IDUA activity in leukocytes (PMID: 35848209) (PP4_Moderate). Each of these patients is compound heterozygous for the variant and a variant in IDUA that has been classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases VCEP, including c.876delC (ClinVar Variation ID: 456720), phase not confirmed (PMID: 35848209), c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909), phase not confirmed (clinical diagnostic laboratory); and c.536C>T (p.Thr179Met) (ClinVar Variation ID: 1455223), confirmed in trans (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002389 (1/41866 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). The computational predictor REVEL gives a score of 0.603 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on IDUA function. No impact on splicing was predicted by SpliceAI. There is a ClinVar entry for this variant (Variation ID: 1309246). In summary, this variant meets the criteria to be classified as likely pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Disease Variant Curation Expert Panel (Specifications Version 1.0.0): PM3_Strong, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024)