ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.2403G>T (p.Met801Ile) (rs1554425149)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000703830 SCV000832751 pathogenic Long QT syndrome 2018-08-29 criteria provided, single submitter clinical testing This sequence change falls in intron 9 of the KCNH2 gene. It does not directly change the encoded amino acid sequence of the KCNH2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with long QT syndrome (PMID: 19841300). 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. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000703830 SCV001478567 likely pathogenic Long QT syndrome 2021-01-07 criteria provided, single submitter clinical testing Variant summary: KCNH2 c.2398+5G>T alters a 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: Four predict that the variant weakens or abolishes a canonical 5-prime donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250960 control chromosomes. c.2398+5G>T has been reported in the literature in individuals affected with Long QT Syndrome (e.g. Tester_2005, Kapplinger_2009) and in individual with sudden unexpected death (Tester_2012) . These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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