ClinVar Genomic variation as it relates to human health

Variant summary: IDS c.419-1G>A 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: Four predict the variant abolishes the canonical 3' acceptor site. Four predict the variant creates an adjacent alternative canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 181712 control chromosomes. To our knowledge, no occurrence of c.419-1G>A in individuals affected with Mucopolysaccharidosis Type II (Hunter Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic based on the identification of another splice variant, c.419-1G>C that has been reported in a patient with Mucopolysaccharidosis Type II (Hunter Syndrome). Based on the evidence outlined above, the variant was classified as likely pathogenic.

A different variant affecting this nucleotide (c.419-1G>C) has been determined to be pathogenic (PMID: 27351199). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IDS are known to be pathogenic (PMID: 8940265, 9875019). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with IDS-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 3 of the IDS gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.

Null variant (PVS1_VeryStrong), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Patient’s phenotype or family history highly specific for the disease (PP4_Strong)