Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001000688 | SCV001157725 | likely pathogenic | not specified | 2018-07-24 | criteria provided, single submitter | clinical testing | The KCNH2 c.1418C>T; p.Thr473Ile variant, to our knowledge, is not reported in the medical literature or gene specific databases. Other variants at this codon (p.Thr473Pro, p.Thr473Asn), as well as an adjacent p.Thr474Ile variant, have been reported in individuals with Long QT syndrome and are considered pathogenic (Itoh 2010, Kapplinger 2009, Liu 2013, Tanaka 1997). Electrophysiological characterization of the p.Thr473Pro and p.Thr474Ile variants reveal dominant negative effects on channel activity and altered gating properties, respectively (Liu 2013, Zhou 1998), suggesting that the S2-S3 cytoplasmic loop containing Thr473 is functionally important. The c.1418C>T; p.Thr473Ile variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The threonine at codon 473 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Itoh H et al. Long QT syndrome with compound mutations is associated with a more severe phenotype: a Japanese multicenter study. Heart Rhythm. 2010 Oct;7(10):1411-8. Kapplinger JD et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009 Sep;6(9):1297-303. Liu L et al. A novel mutation in the transmembrane nonpore region of the KCNH2 gene causes severe clinical manifestations of long QT syndrome. Heart Rhythm. 2013 Jan;10(1):61-7. Tanaka T et al. Four novel KVLQT1 and four novel HERG mutations in familial long-QT syndrome. Circulation. 1997 Feb 4;95(3):565-7. Zhou Z et al. HERG channel dysfunction in human long QT syndrome. Intracellular transport and functional defects. J Biol Chem. 1998 Aug 14;273(33):21061-6. |