ClinVar Genomic variation as it relates to human health

Variant summary: IDUA c.1861C>T (p.Arg621X) 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. The variant allele was found at a frequency of 2.5e-05 in 243934 control chromosomes (gnomAD and publications). The variant, c.1861C>T, has been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1 (Uttarilli_2016, Bunge_1994, Oussorena_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Uttarilli_2016). The most pronounced variant effect results in <10% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.Arg621Ter variant in IDUA has been reported in at least 4 individuals with mucopolysaccharidosis (MPS) (PMID: 11735025, 7951228, 27146977, 7550242) and has been identified in 0.014% (5/34554) of Latino chromosomes, 0.003% (1/30604) of South Asian chromosomes and 0.001% (1/112398) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965025). 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: 11917) as pathogenic by Counsyl, Integrated Genetics, and OMIM. This nonsense variant leads to a premature termination codon at position 621. This alteration occurs within 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 presence of this variant in 1 affected homozygote and in combination with reported pathogenic variants in 2 individuals with MPS increases the likelihood that the p.Arg621Ter variant is pathogenic (VariationID: 11908, 550799; PMID: 11735025, 7951228, 27146977). The phenotype of an individual compound heterozygous for this variant is highly specific for MPS based on alpha-L-iduronidase activity being <1% of normal consistent with disease (PMID: 23786846). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the prediction that the variant will cause loss of function, the presence of the variant in affected homozygotes and compound heterozygotes, and the phenotype of an individual with this variant being highly specific for MPS. ACMG/AMP Criteria applied: PVS1_strong, PM3_strong, PM2_supporting, PP4 (Richards 2015).

This sequence change creates a premature translational stop signal (p.Arg621*) in the IDUA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 33 amino acid(s) of the IDUA protein. This variant is present in population databases (rs121965025, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with mucopolysaccharidosis type 1 (PMID: 7550242, 7951228, 21394825, 23786846, 27146977, 28752568). ClinVar contains an entry for this variant (Variation ID: 11917). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the IDUA protein in which other variant(s) (p.Trp626*) have been determined to be pathogenic (PMID: 19396826, 21462124, 28752568). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

This nonsense variant is found in exon 14 of 14 and is predicted to result in the disruption of the final 33 amino acids of the protein. This variant has been previously reported as compound heterozygous or homozygous change in patients with Mucopolysaccharidosis type I (PMID: 7951228, 27146977, 23786846, 21394825). Functional characterization of the variant indicates that it reduces enzyme activity to less than 10% residual activity (PMID: 23786846). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (7/248290) and thus is presumed to be rare. Based on the available evidence, the c.1861C>T (p.Arg621Ter) variant is classified as Pathogenic.