ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.2399G>T (p.Gly800Val) (rs794728391)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413790 SCV000490552 pathogenic not provided 2017-04-28 criteria provided, single submitter clinical testing The c.2398+1 G>T pathogenic variant in the KCNH2 gene has been reported in association with LQTS (Kapplinger J et al., 2009). Kapplinger et al. (2009) identified c.2398+1 G>T in one individual with LQTS and was absent from more than 2600 alleles from control individuals. This variant destroys the canonical splice donor site in intron 9 and is predicted to cause abnormal gene splicing. The variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Another splice site variant at the same nucleotide position in the KCNH2 gene (c.2398+1 G>C) has also been reported in association with LQTS (Curran M et al., 1995). Furthermore, c.2398+1 G>T was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.2398+1 G>T in the KCNH2 gene is interpreted as a pathogenic variant.
Invitae RCV000473168 SCV000543475 likely pathogenic Long QT syndrome 2016-10-01 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 9 of the KCNH2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in 3 individuals referred for long QT syndrome testing (PMID: 19716085). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547), and loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 19862833). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic.

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