ClinVar Genomic variation as it relates to human health

Variant summary: IDUA c.1614delG (p.His539ThrfsX21) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.5e-05 in 137732 control chromosomes. c.1614delG has been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1 (Scott_1993, Vazna_2009). These data indicate that the variant may be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.His539Thrfs*21) in the IDUA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IDUA are known to be pathogenic (PMID: 11735025, 21480867). This variant is present in population databases (rs727503967, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with mucopolysaccharidosis type I (PMID: 8213840, 19396826). This variant is also known as delG1702. ClinVar contains an entry for this variant (Variation ID: 167191). For these reasons, this variant has been classified as Pathogenic.

The p.His539ThrfsTer21 variant in IDUA has been reported in at least 2 individuals with mucopolysaccharidosis (MPS) (PMID: 19396826, 8213840) and has been identified in 0.012% (1/8140) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP 167191). 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: 167191) as pathogenic by EGL Genetic Diagnostics and Counsyl. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 539 and leads to a premature termination codon 21 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the IDUA gene is an established disease mechanism in autosomal recessive MPS. The presence of this variant in combination with a reported pathogenic variant in an individual with MPS slightly increases the likelihood that the p.His539ThrfsTer21 variant is pathogenic (VariationID: 11909; VariationID: 8213840). The phenotype of an individual compound heterozygous for this variant is highly specific for MPS based on null alpha-L-iduronidase protein activity, consistent with disease (PMID: 8213840). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the prediction that it will cause loss of function of the IDUA gene, the presence of the variant in combination with pathogenic variants, and the phenotype of an individual with the variant being highly specific for MPS. ACMG/AMP Criteria applied: PVS1, PM3_supporting, PM2_supporting, PP4 (Richards 2015).