The NM_000203.5:c.876del (p.Asp292GlufsTer25) variant in IDUA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant has been reported in two individuals with clinical features consistent with MPS I, one of whom also had documented laboratory values showing deficiency leukocyte IDUA activity and elevated urine GAGs prior to initiation of treatment with enzyme replacement therapy (PMID: 35848209) (PP4). One of these individuals is compound heterozygous for the variant (labeled as 964del in the publication, using older numbering) and a variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908); the phase was not confirmed (PMID: 7951228, 0.5 points). Another patient is compound heterozygous for the variant and c.1499A>G (p.Gln500Arg) (PMID: 35848209). The allelic data from this patient will be used in the classification of p.Gln500Arg and is not included here to avoid circular logic. Total 0.5 points (PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001280 (15/1172250 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). There is a ClinVar entry for this variant (Variation ID: 456720). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type I. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0.): PVS1, PP4, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024)