ClinVar Genomic variation as it relates to human health

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this variant results in skipping of exon 2 and introduces a premature termination codon (PMID: 19027783). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 200872). This variant has been observed in individuals with long QT syndrome (PMID: 28944242). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 1 of the KCNQ1 gene. It does not directly change the encoded amino acid sequence of the KCNQ1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.

Variant summary: KCNQ1 c.387-5T>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 3' splice acceptor site. Two predict the variant weakens the canonical 3' splice acceptor site. Three predict the variant creates a new intronic 3' splice acceptor site at nucleotide c.387-5. At least one publication reports experimental evidence that this variant affects mRNA splicing with the majority of transcripts resulting in exon 2 skipping (example, Bhuiyan_2008). The variant was absent in 251336 control chromosomes. c.387-5T>A has been reported in the literature as a homozygous founder variant in at-least 5 consanguineous Saudi Arabian families with Long QT Syndrome and preserved normal hearing (example, Bhuiyan_2008, Bhuiyan_2009, Bdier_2017) and these studies continue to be cited by others in the field. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Bhuiyan_2008). The most pronounced variant effect results in non-functional mutant KCNQ1 + KCNE1 channels as determined by electrophysiological studies in a HEK-293 cell expression system. 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 uncertain significance. Based on the evidence outlined above, until families from additional ethnicities with this variant are identified, the variant was classified as likely pathogenic.

The c.387-5T>A variant of KCNQ1 has been reported in individuals with Long-QT syndrome (PMID: 28944242, PMID: 1918417). This variant is predicted to disrupt mRNA splicing (SpliceAI: 0.77). RNA studies have shown that this variant causes the skipping of exon 2 and introduces a premature termination codon, resulting in incomplete transcriptional aberration of the KCNQ1 gene (PMID: 19027783). This variant is not present in population databases (gnomAD no frequency). Based on this evidence, the c.387-5T>A variant of KCNQ1 is classified as likely pathogenic.