Submissions for variant NM_000238.4(KCNH2):c.2453C>T (p.Ser818Leu)

dbSNP: rs121912510

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631649	SCV000752732	pathogenic	Long QT syndrome	2024-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 818 of the KCNH2 protein (p.Ser818Leu). This variant is present in population databases (rs121912510, gnomAD 0.003%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 10086971, 17088455, 18441445, 23158531, 26669661). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 14432). 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: 10996323, 16432067, 23303164). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000631649	SCV000987593	likely pathogenic	Long QT syndrome		criteria provided, single submitter	clinical testing
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000015513	SCV001244881	pathogenic	Long QT syndrome 2	2019-09-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426506	SCV002731577	pathogenic	Cardiovascular phenotype	2020-07-27	criteria provided, single submitter	clinical testing	The p.S818L pathogenic mutation (also known as c.2453C>T), located in coding exon 10 of the KCNH2 gene, results from a C to T substitution at nucleotide position 2453. The serine at codon 818 is replaced by leucine, an amino acid with dissimilar properties. This variant was described in a confirmed de novo case with torsades de pointes and syncope, as well as in her asymptomatic young daughter with prolonged QTc (Berthet M et al. Circulation, 1999 Mar;99:1464-70). This variant has also been reported in additional long QT syndrome cohorts (Nagaoka I et al. Circ. J., 2008 May;72:694-9; Crotti L et al. J. Am. Coll. Cardiol., 2012 Dec;60:2515-24; Stattin EL et al. BMC Cardiovasc Disord, 2012 Oct;12:95). Functional studies have demonstrated trafficking deficiency with significant reduction in potassium channel function (Anderson CL et al. Circulation, 2006 Jan;113:365-73; Perry MD et al. J. Physiol. (Lond.), 2016 07;594:4031-49). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV003591634	SCV004358315	pathogenic	Cardiac arrhythmia	2023-10-10	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 818 in the KCNH2 protein. This variant is found within the highly conserved cyclic nucleotide binding domain (aa 742-842). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes trafficking defects resulting in reduced membrane expression and impaired channel function (PMID: 10996323, 16432067, 23303164, 26958806, 31557540). This variant has been reported in over twenty individuals affected with long QT syndrome (PMID: 10086971, 18441445, 21440677, 23158531, 26669661, 27920829, 32893267, 35253369, 36102233) and has been observed to be a de novo occurrence in at least one of the probands (PMID: 10086971). This variant has also been reported in an individual affected with sudden cardiac death and idiopathic left ventricular hypertrophy (PMID: 32011662). Two relatives of this proband also carried this variant, who were both affected with long QT syndrome. This variant has been identified in 1/251432 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV004696637	SCV005196710	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000631649	SCV005426215	pathogenic	Long QT syndrome	2024-09-18	criteria provided, single submitter	clinical testing	The c.2453C>T (p.Ser818Leu) variant in KCNH2 gene, that encodes for potassium voltage-gated channel subfamily H member 2, has been identified in numerous (>30) individuals affected with long QT syndrome (LQTS) (PMID: 21440677, 18441445, 23158531, 27920829, 32893267, 26669661), including one individual with de novo occurrence (PMID: 10086971). Functional studies using Xenopus oocytes, HEK293 cells and rescue experiments on morpholino kcnh2-knockdown zebra fish revealed that KCNH2-S818L mutant can cause significantly reduced current amplitude, trafficking deficiency, reduced membrane expression and channel dysfunction (PMID: 10996323, 16432067, 26958806, 23303164). This variant is located in the C-terminal cyclic nucleotide binding domain and this domain is characterized by high enrichment of case variants and >95% probability of pathogenicity (PMID: 32893267). In-silico computational prediction tools suggest that the p.Ser818Leu variant may have deleterious effect on the protein function (REVEL score: 0.97). This variant is rare (4/1614168 chromosomes; 0.0002478%) in the general population database, gnomAD (v4.1.0), and classified as pathogenic by multiple submitters in ClinVar (ID: 14432). Therefore, the c.2453C>T (p.Ser818Leu) variant in the KCNH2 gene is classified as pathogenic.
OMIM	RCV000015513	SCV000035778	pathogenic	Long QT syndrome 2	2000-09-15	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058123	SCV000089643	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:10086971;PMID:10996323;PMID:11222472;PMID:16432067;PMID:16831322;PMID:18441445). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.