The NM_000203.5:c.1A>G (p.Met1?) variant in IDUA is predicted to cause an N-terminal truncated or absent protein by altering the start codon of the coding sequence. The next in-frame ATG is at position 133. If that ATG is used as a start signal, the lysosomal signal sequence (amino acids 1-27) would be lost (https://www.uniprot.org/uniprotkb/P35475/entry) (PVS1). Two patients with severe MPS1 (Hurler syndrome) are reported to be homozygous for the variant (PMID: 27146977, 28752568) (PM3). One patient, from India, had clinical features consistent with a severe presentation of MPS 1 including dysostosis multiplex, coarse facial features, cardiomegaly, and intellectual disability, as well as documented deficient activity of IDUA in leukocytes (PMID: 27146977), while a second patient, from Spain, was reported to have a confirmed diagnosis based on IDUA deficiency (PMID: 21394825) (PP4). The highest population minor allele frequency in gnomAD v4.1.0. is 8.893e-7 (1/1124490) 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). Of note, other variants that abolish the start ATG have been identified in individuals with mucopolysaccharidosis type 1 (c.1A>C, ClinVar Variation ID: 550458; c.2T>C, ClinVar Variation ID: 639529). There is a ClinVar entry for c.1A>G (Variation ID:1323098). In summary, this variant, c.1A>G (p.Met1?) meets the criteria to be classified as pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1, PM3, PP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024)