ClinVar Genomic variation as it relates to human health

Variant summary: HEXA c.1525_1526+27del29 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 a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251012 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1525_1526+27del29 in individuals affected with Tay-Sachs Disease and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Other variants affecting this 5' splicing donor site or the 3' acceptor site between exons 13 and 14 of the HEXA gene have been cited in ClinVar [c.1526+1G>T: likely pathogenic (n=1) and VUS (n=1); c.1526+2T>C: likely pathogenic (n=1)] and reported in HGMD [c.1527-2A>T (DM)]. Truncations within the last exon (exon 14) of the HEXA gene have been reported as pathogenic/likely pathogenic by our laboratory (p.Arg510X, p.Leu517ProfsX7). Based on the evidence outlined above, the variant was classified as likely pathogenic.

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the HEXA protein. Other variant(s) that disrupt this region (p.Arg510*) have been determined to be pathogenic (PMID: 22789865, 27896118, 21567908). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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 HEXA-related conditions. This variant is not present in population databases (ExAC no frequency). This variant results in the deletion of part of exon 13 (c.1525_1526+27del) of the HEXA gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.