Submissions for variant NM_172057.2(KCNH2):c.1982G>A (p.Trp661Ter) (rs794728401)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181904	SCV000234207	pathogenic	not provided	2018-08-20	criteria provided, single submitter	clinical testing	The W1001X variant in the KCNH2 gene has been reported in multiple individuals with LQTS (Kapplinger et al., 2009; Neubauer et al., 2016). Functional studies show that W1001X results in a significant decrease in mRNA levels due to nonsense-mediated mRNA decay (Gong et al., 2007). Other nonsense variants in the KCNH2 gene have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014). Furthermore, the W1001X variant is not observed in large population cohorts (Lek et al., 2016).
Invitae	RCV000228852	SCV000283980	pathogenic	Long QT syndrome	2018-07-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp1001*) in the KCNH2 gene. It is expected to result 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 with Long QT syndrome (PMID: 19716085, 17576861). ClinVar contains an entry for this variant (Variation ID: 200513). Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 19862833). For these reasons, this variant has been classified as Pathogenic.