Submissions for variant NM_000238.4(KCNH2):c.1750G>A (p.Gly584Ser) (rs199473428)

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181816	SCV000234119	pathogenic	not provided	2018-10-24	criteria provided, single submitter	clinical testing	The G584S pathogenic variant in the KCNH2 gene has been reported multiple times in association with LQTS (Swan et al., 1999; Laitinen et al., 2000; Splawski et al., 2000; Tester et al., 2005; Kapplinger et al., 2009; Zhao et al. 2009; Stattin et al., 2012; Christiansen et al., 2014; Itoh et al., 2016). This variant has been shown to segregate with a prolonged QT interval and syncopal episodes in multiple relatives from one family (Zhao et al., 2009). G584S has also been observed in several unrelated individuals referred for LQTS genetic testing at GeneDx.The G584S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). G584S is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, G584S is located within the S5-S6 extracellular linker domain of the KCNH2 channel (Bohnen et al., 2017). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, functional studies performed using patch clamp assays in transfected Chinese hamster ovary (CHO) cells and Xenopus oocytes suggest that the G584S mutant channel causes a loss of the rapid delayed rectifier current due trafficking and gating defects (Zhao et al., 2009; Perry et al., 2016).In summary, G584S in the KCNH2 gene is interpreted as a pathogenic variant.
Invitae	RCV000470290	SCV000543426	pathogenic	Long QT syndrome	2020-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with serine at codon 584 of the KCNH2 protein (p.Gly584Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs199473428, ExAC 0.003%). This variant has been reported to segregate with long QT syndrome (LQTS) in a large multigenerational family and has been found in many individuals affected with LQTS (PMID: 10862094, 10973849, 19490267, 22949429, 24606995). ClinVar contains an entry for this variant (Variation ID: 67261). Experimental studies have shown that this missense change enhances the inactivation of the channel (PMID: 19490267). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000057974	SCV000731739	likely pathogenic	Congenital long QT syndrome	2019-01-29	criteria provided, single submitter	clinical testing	The p.Gly584Ser variant in KCNH2 has been reported in 4 individuals with long QT syndrome, segregated with disease in at least 11 affected relatives from 2 families (Swan 1999, Laitinen 2000, Zhao 2009, Giudicessi 2012, and Li 2015), and has also been reported by other clinical laboratories in ClinVar (Variation ID: 67261). In vitro functional studies provide some evidence that the p.Gly584Ser variant may impact protein function (Zhao 2009). This variant was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Gly584Ser variant is likely pathogenic.
Ambry Genetics	RCV000618627	SCV000738197	likely pathogenic	Cardiovascular phenotype	2019-12-02	criteria provided, single submitter	clinical testing	The p.G584S variant (also known as c.1750G>A), located in coding exon 7 of the KCNH2 gene, results from a G to A substitution at nucleotide position 1750. The glycine at codon 584 is replaced by serine, an amino acid with similar properties, and is located in the S5/pore transmembrane spanning region. This alteration has been detected in long QT syndrome (LQTS) cohorts, a sudden cardiac arrest/death cohort, and cohorts referred for LQTS genetic testing with varying levels of clinical detail (Splawski I et al. Circulation. 2000;102:1178-85; Kapa S et al. Circulation. 2009;120:1752-60; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Stattin EL et al. BMC Cardiovasc Disord. 2012;12:95; Christiansen M et al. BMC Med Genet. 2014;15:31; Li MH et al. Hum Genomics. 2015;9:15; Nakajima T et al. Circ J. 2015;79(6):1185-92). This alteration has been reported to segregate with disease in a family with symptomatic individuals and members with moderate QTc prolongation where, overall, carriers had longer QT intervals than non-carriers; however, some individuals with QT prolongation were not indicated as carriers of this alteration, suggesting that this alteration is associated with reduced phenotypic penetrance (Kerr SM et al. Sci Rep, 2019 Jul;9:10964; Swan H et al. J Am. Coll Cardiol. 1999;34:823-9; Laitinen P et al. Hum Mutat. 2000;15:580-1). In vitro functional studies have suggested this alteration may have some impact on channel function or protein trafficking (Zhao JT et al. J Cardiovasc Electrophysiol. 2009;20:923-30; Perry MD et al. J Physiol Lond. 2016;594:4031-49). Internal analysis indicates this alteration may be structurally disruptive (Wang W et al. Cell. 2017;169(3):422-430.e10). Furthermore, other alterations affecting this amino acid (p.G584V, p.G584C and p.G584R) have been detected in LQTS cohorts or cohorts referred for LQTS genetic testing (Berge KE et al. Scand J Clin Lab Invest. 2008;68(5):362-8; Nagaoka I et al. Circ J. 2008;72(5):694-9; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc	RCV001184214	SCV001350154	likely pathogenic	Arrhythmia	2019-07-14	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000181816	SCV001715980	pathogenic	not provided	2019-08-17	criteria provided, single submitter	clinical testing	PS3_Supporting, PS-Moderate, PP2, PP3, PP1_Moderate, PM1
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000181816	SCV001746020	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Genomics England Pilot Project,Genomics England	RCV000157264	SCV001760195	likely pathogenic	Long QT syndrome 2		criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust	RCV000057974	SCV000089494	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10483966;PMID:10862094;PMID:10973849;PMID:15840476;PMID:19490267;PMID:19716085;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Blueprint Genetics	RCV000157264	SCV000206994	pathogenic	Long QT syndrome 2	2014-09-29	no assertion criteria provided	clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia	RCV000477917	SCV000536779	pathogenic	Short QT syndrome 1; Long QT syndrome 2	2016-02-10	no assertion criteria provided	research