ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.2230C>T (p.Arg744Ter) (rs189014161)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181843 SCV000234146 pathogenic not provided 2018-08-21 criteria provided, single submitter clinical testing The R744X pathogenic variant in the KCNH2 gene was initially reported in a Taiwanese proband with LQTS and was found to segregate with disease in six additional family members (Ko et al., 2001). The R744X variant has also been reported in a neonate with LQTS, two unrelated Caucasian probands with prolonged QT intervals, and an individual with sudden unexpected death in epilepsy (Schwartz et al., 2009; Crotti et al., 2012; Bagnall et al., 2016). R744X has been identified in several unrelated probands with LQTS referred for cardiogenetic testing at GeneDx, as was shown to segregate with disease in relatives from two different families. Furthermore, this variant is reported as a pathogenic variant by a different clinical laboratory in ClinVar (SCV000543429.1; Landrum et al., 2016). R744X is a nonsense variant that 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 nonsense variants in the KCNH2 gene have been reported in the Human Genome Mutation Database in association with LQTS, indicating that loss of function is a known disease mechanism (Stenson et al., 2014). Finally, the R744X variant is not observed in large population cohorts (Lek et al., 2016).
Invitae RCV000473013 SCV000543429 pathogenic Long QT syndrome 2016-08-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 744 (p.Arg744*) of the KCNH2 gene. It is expected to result in an absent or disrupted protein product. Truncating variants in KCNH2 are known to be pathogenic. This particular truncation has been reported in two families affected with long QT syndrome, segregating with the disease in one of them, and has been reported as de novo in a case of sudden death (PMID: 11802537, 19841298, 26704558). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000617781 SCV000737741 pathogenic Cardiovascular phenotype 2016-10-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Blueprint Genetics RCV000157266 SCV000206996 pathogenic Long QT syndrome 2 2014-08-29 no assertion criteria provided clinical testing

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