ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.308-2A>G (rs1057520598)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000427208 SCV000516544 likely pathogenic not provided 2018-07-06 criteria provided, single submitter clinical testing The c.308-2 A>G variant has been reported previously in association with LQTS (Berge K et al., 2008). This substitution destroys the canonical splice acceptor site in intron 2 and is predicted to cause abnormal gene splicing. Other splice site variants in theKCNH2 gene have been reported in the Human Gene Mutation Database in association with LQTS (Stenson P et al., 2014). Furthermore, the c.308-2 A>G variant 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.Based on currently available evidence, c.308-2 A>G is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded.
Invitae RCV000460573 SCV000543453 likely pathogenic Long QT syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 2 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 not been reported in the literature in individuals with KCNH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 379451). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 10973849, 19862833). 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.

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