Submissions for variant NM_172056.2(KCNH2):c.453del (p.Thr152fs) (rs761863251)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181956	SCV000234259	pathogenic	not provided	2018-08-15	criteria provided, single submitter	clinical testing	The c.453delC pathogenic variant in the KCNH2 gene has been reported in association with LQTS (Swan et al., 1999; Stattin et al., 2012; Park et al., 2013; Christiansen et al., 2014). This variant causes a shift in reading frame starting at codon threonine 152, changing it to a proline, and creating a premature stop codon at position 14 of the new reading frame, denoted p.Thr152ProfsX14. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the KCNH2 gene have been reported in Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.453delC variant has not been observed in large population cohorts (Lek et al., 2016). In summary, c.453delC in the KCNH2 gene is interpreted as a pathogenic variant.
Blueprint Genetics	RCV000208221	SCV000263972	pathogenic	Long QT syndrome 2	2015-11-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619865	SCV000737442	pathogenic	Cardiovascular phenotype	2017-12-07	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)