ClinVar Genomic variation as it relates to human health

Variant summary: IDUA c.386-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.3e-05 in 245660 control chromosomes (gnomAD). The variant, c.386-2A>G, has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 (Ghosh 2017, Beesley 2001), and most of the cases presented with a severe disease phenotype (Hurler syndrome). These data indicate that the variant is very likely to be associated with disease. Two publications reported no enzyme activity associated with this variant (Ghosh 2017, Bunge 1998). ClinVar has one entry for this variant after 2014 with a classification of "pathogenic". Based on the evidence outlined above, the variant was classified as pathogenic.

The c.386-2A>G variant in IDUA (also known as c.474-2A>G due to a difference in cDNA numbering) has been reported in at least 6 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568, 24368159, 11735025, 8019563) and has been identified in 0.008% (9/112774) of European (non-Finnish) chromosomes. 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: 222994) as pathogenic by Invitae, Counsyl, and GeneReviews. Functional studies demonstrating that the variant causes exon skipping provide some evidence that the c.386-2A>G variant may slightly impact protein function (PMID: 8019563). However, these types of assays may not accurately represent biological function. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal 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 4 reported pathogenic variants in individuals with MPS increases the likelihood that the c.386-2A>G variant is pathogenic (PMID: 24368159, 11735025, 8019563). The phenotype of an individual heterozygous for this variant is highly specific for MPS based on undetectable iduronidase activity, consistent with disease (PMID: 28752568). In summary, this variant meets criteria to be classified as pathogenic for IDUA in an autosomal recessive manner based on the prediction that it causes loss of function of the IDUA gene, the presence of the variant in combination with other pathogenic variants in affected individuals, and functional studies. ACMG/AMP Criteria applied: PM3_strong, PM2, PVS1_moderate, PS3_supporting, PP4 (Richards 2015).

Not observed at a significant frequency in large population cohorts (gnomAD); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 9748610, 11735025, 21480867, 25525159, 8019563, 23837464, 28752568, 15300847, 24368159, 31194252, 31589614)

This sequence change affects an acceptor splice site in intron 3 of the IDUA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs777295041, gnomAD 0.007%). Disruption of this splice site has been observed in individuals with mucopolysaccharidosis type I (PMID: 8019563, 11735025, 23837464, 24368159). This variant is also known as c.474-2 a>g and Int3-2a>g. ClinVar contains an entry for this variant (Variation ID: 222994). Studies have shown that disruption of this splice site results in exon skipping and introduces a premature termination codon (PMID: 8019563). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.