ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs199473428
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Total submissions: 15
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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

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