ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.472+1G>A (rs794728477)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483249 SCV000567701 pathogenic not provided 2015-08-17 criteria provided, single submitter clinical testing Although the c.472+1 G>A variant has not been reported as a pathogenic variant or as a benign polymorphism to our knowledge, it has been reported in one other individual tested at GeneDx. This substitution destroys the canonical splice donor site in intron 3 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. Other splice site variants in the KCNH2 gene have been reported in HGMD in association with LQTS (Stenson P et al., 2014). Furthermore, the c.472+1 G>A 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. In summary, c.472+1 G>A in the KCNH2 gene is interpreted as a pathogenic variant.
Invitae RCV001379769 SCV001577634 likely pathogenic Long QT syndrome 2020-04-15 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 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 observed in individual(s) with clinical features of long QT syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 419715). 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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