Description
The p.Arg619Ter variant in IDUA has been reported in at least 12 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568, 11735025, 27146977) and has been identified in 0.001% (1/112290) of European (non-Finnish) chromosomes by the the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965031). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 280976) as pathogenic by EGL Genetic Diagnostics and Counsyl. This nonsense variant leads to a premature termination codon at position 619. This alteration occurs in the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the IDUA gene is an established disease mechanism in autosomal recessive MPS. The phenotype of individuals homozygous for this variant is highly specific for MPS based on very low alpha-L-iduronidase activity consistent with disease (PMID: 27146977). The presence of this variant in 6 affected homozygotes and in combination with reported pathogenic variants in at least 5 individuals with MPS increases the likelihood that the p.Arg619Ter variant is pathogenic (VariationID: 11908, 11909, 11910, 496834; PMID: 28752568, 11735025, 27146977). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the prediction that it results in a truncated protein, the presence of the variant in affected homozygotes and compound heterozygotes, and the phenotype of individuals with the variant being highly specific for MPS. ACMG/AMP Criteria applied: PVS1_strong, PM3_strong, PM2, PP4 (Richards 2015).
# | Sample | Method | Observation |
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Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
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1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |