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

gnomAD frequency: 0.00001  dbSNP: rs199473428

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181816	SCV000234119	pathogenic	not provided	2022-06-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies 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 to trafficking and gating defects (Zhao et al., 2009; Perry et al., 2016); Reported as a pathogenic/likely pathogenic variant in ClinVar (ClinVar Variant ID#67261; ClinVar); This variant is associated with the following publications: (PMID: 21440677, 27807201, 24606995, 22581653, 31447099, 15176425, 20659946, 20566482, 22949429, 25417810, 25649125, 26187847, 26669661, 19490267, 26958806, 19716085, 10862094, 23098067, 15840476, 10973849, 10483966, 19841300, 31358886, 28431243, 32048431, 34319147, 33087929)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470290	SCV000543426	pathogenic	Long QT syndrome	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 584 of the KCNH2 protein (p.Gly584Ser). This variant is present in population databases (rs199473428, gnomAD 0.002%). This missense change has been observed in individuals with long QT syndrome (LQTS) (PMID: 10862094, 10973849, 19490267, 22949429, 24606995). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67261). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 19490267). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham 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	2025-01-24	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). 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 Diagnostics, LLC DBA Color Health	RCV001841704	SCV001350154	likely pathogenic	Cardiac arrhythmia	2019-07-14	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 584 in the extracellular linker region between transmembrane domain S5 and pore-forming region of the KCNH2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental functional studies have shown that the mutant protein carrying this variant traffics to the cell membrane normally but has moderate impact on the channel function (PMID: 19490267, 26958806). This variant has been reported to segregate with long QT syndrome in a large multigenerational family (PMID: 19490267). This variant has also been reported in multiple unrelated individuals affected with long QT syndrome (PMID: 10862094, 10973849, 22949429, 23098067, 24606995, 25925977). This variant has been identified in 2/251412 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.
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 Center for Human Genetics 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
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000157264	SCV004045970	pathogenic	Long QT syndrome 2	2023-06-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004562234	SCV005049835	pathogenic	Short QT syndrome type 1	2024-03-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000157264	SCV005049912	pathogenic	Long QT syndrome 2	2024-03-11	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV005250010	SCV005900685	pathogenic	KCNH2-related disorder	2023-11-24	criteria provided, single submitter	clinical testing	The KCNH2 gene is constrained against missense variation (Z-score= 3.37), and missense variants are a common mechanism of disease (HGMD, ClinVar database; PMID: 20301308). The c.1750G>A (p.Gly584Ser) variant affects a highly conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. This variant has been reported in families and individuals with long QT syndrome and is one of the most common alterations in the KCNH2 gene (PMID: 10862094, 10973849, 22949429, 24606995, 32048431, 34319147, 26187847, 19490267, 31358886). Different amino acid changes at the same residue (p.Gly584Arg, p.Gly584Cys, p.Gly584Val) have been previously reported in individuals with long QT syndrome (PMID: 19716085, 18441445, 18752142). Functional studies indicate this variant causes potassium channel gating defects (PMID: 19490267). The c.1750G>A (p.Gly584Ser) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (2/251412) and thus is presumed to be rare. Based on the available evidence, c.1750G>A (p.Gly584Ser) is classified as Pathogenic.
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 type 1; Long QT syndrome 2	2016-02-10	no assertion criteria provided	research