Submissions for variant NM_000238.4(KCNH2):c.2350C>T (p.Arg784Trp)

gnomAD frequency: 0.00001  dbSNP: rs12720441

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208497	SCV000263982	likely pathogenic	Brugada syndrome	2014-12-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001841245	SCV001348997	uncertain significance	Cardiac arrhythmia	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 784 of the KCNH2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In vitro experimental functional studies have shown that this variant may result in deficient protein trafficking (PMID: 25417810), reduced channel current (PMID: 11997281) and faster channel deactivation compared to wild type (PMID: 19172259). This variant has been reported in two individuals affected with long QT syndrome (PMID: 19841300, 22949429) and in an individual suspected to be affected with long QT syndrome (PMID: 15840476). This variant has also been reported in two individuals affected with drug-induced torsades de pointes, a form of ventricular tachycardia (PMID: 11997281, 24223155). This variant has been identified in 3/282186 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262685	SCV001440639	uncertain significance	Long QT syndrome 2	2019-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851875	SCV002205738	uncertain significance	Long QT syndrome	2024-09-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 784 of the KCNH2 protein (p.Arg784Trp). This variant is present in population databases (rs12720441, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 11997281, 15840476, 19841300, 22949429). ClinVar contains an entry for this variant (Variation ID: 14433). 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: 11997281, 19172259, 25417810). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
AiLife Diagnostics, AiLife Diagnostics	RCV002223758	SCV002502839	likely pathogenic	not provided	2022-02-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162252	SCV003900731	uncertain significance	Cardiovascular phenotype	2020-05-07	criteria provided, single submitter	clinical testing	The c.2350C>T (p.R784W) alteration is located in exon 9 (coding exon 9) of the KCNH2 gene. This alteration results from a C to T substitution at nucleotide position 2350, causing the arginine (R) at amino acid position 784 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001851875	SCV004843913	uncertain significance	Long QT syndrome	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 784 of the KCNH2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In vitro experimental functional studies have shown that this variant may result in deficient protein trafficking (PMID: 25417810), reduced channel current (PMID: 11997281) and faster channel deactivation compared to wild type (PMID: 19172259). This variant has been reported in two individuals affected with long QT syndrome (PMID: 19841300, 22949429) and in an individual suspected to be affected with long QT syndrome (PMID: 15840476). This variant has also been reported in two individuals affected with drug-induced torsades de pointes, a form of ventricular tachycardia (PMID: 11997281, 24223155). This variant has been identified in 3/282186 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
OMIM	RCV004720231	SCV000035779	uncertain significance	Reclassified - variant of unknown significance	2002-04-23	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058108	SCV000089628	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:11997281;PMID:14760488;PMID:15840476;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
PreventionGenetics, part of Exact Sciences	RCV004549372	SCV004774790	uncertain significance	KCNH2-related disorder	2023-12-06	no assertion criteria provided	clinical testing	The KCNH2 c.2350C>T variant is predicted to result in the amino acid substitution p.Arg784Trp. This variant was reported in individuals with long QT syndrome (KCNH2 gene described as HERG, Yang et al. 2002. PubMed ID: 11997281; Tester et al. 2005. PubMed ID: 15840476; Table S2, Giudicessi et al. 2012. PubMed ID: 22949429). Functional analyses suggest that this variant may result in destabilization of the resultant protein and a reduction in channel activity, and authors of one study speculated that this could be a mild variant (Yang et al. 2002. PubMed ID: 11997281; Anderson et al. 2014. PubMed ID: 25417810). However, this variant has also been documented in the general population and in a cohort of asymptomatic individuals with no prior history of cardiovascular events (Table S1, Chen et al. 2018. PubMed ID: 30662450; Lacaze et al. 2021. PubMed ID: 34135346). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.