ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1946-2A>C (rs794728488)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182039 SCV000234342 pathogenic not provided 2018-09-11 criteria provided, single submitter clinical testing The IVS7-2 A>C mutation in KCNH2 has not been reported previously in association with LQTS to our knowledge, this mutation alters the canonical splice acceptor site in intron 7 and is expected to cause abnormal gene splicing. In silico analysis using different splice algorithms predicts that this mutation destroys the splice acceptor site. This may lead to loss of protein function due to protein truncation or absence of protein from this allele due to mRNA decay. Other splice site site mutations in the KCNH2 gene have been reported in association with LQTS. The variant is found in LQT panel(s).
Invitae RCV001035147 SCV001198462 likely pathogenic Long QT syndrome 2019-06-17 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 7 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 individuals referred for long QT syndrome genetic testing or affected with clinical features of this disease (PMID: 23631430, Invitae). ClinVar contains an entry for this variant (Variation ID: 200757). 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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