Submissions for variant NM_000238.4(KCNH2):c.2371C>T (p.Arg791Trp)

gnomAD frequency: 0.00026  dbSNP: rs138498207

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000148535	SCV000055275	likely benign	Long QT syndrome	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000586962	SCV000234155	likely benign	not provided	2019-07-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32048431, 19716085, 23861362, 26332594, 25637381, 22581653, 29247119, 25417810, 29752375)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228167	SCV000696024	likely benign	not specified	2024-02-05	criteria provided, single submitter	clinical testing	Variant summary: KCNH2 c.2371C>T (p.Arg791Trp) results in a non-conservative amino acid change located in the Cyclic nucleotide-binding domain (IPR000595) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.9e-05 in 281704 control chromosomes, predominantly at a frequency of 0.00093 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNH2 causing Long QT Syndrome phenotype (0.00012), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2371C>T has been reported in the literature in individuals affected with Long QT Syndrome and sudden infant death syndrome (Kapplinger_2009, Smith_2018), however without strong evidence for causality (e.g., lack of co-segregation data). These reports therefore do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. One functional study showed this variant with competent trafficking and moderate alteration on gating (Anderson_2014) with nearly normal values for the repolarizing outward potassium current density or Ikv11.1. Another functional study demonstrated this variant expressed and generated peak Kv11.1 current levels similar to cells expressing wild-type-Kv11.1 channels but altered gating (Smith_2018). The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 25417810, 32048431, 19716085, 29247119, 26332594, 29752375). ClinVar contains an entry for this variant (Variation ID: 67391). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV000618893	SCV000738111	likely benign	Cardiovascular phenotype	2024-02-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000148535	SCV000752905	likely benign	Long QT syndrome	2024-01-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001162548	SCV001324505	uncertain significance	Long QT syndrome 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health	RCV001841708	SCV001351080	uncertain significance	Cardiac arrhythmia	2023-03-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 791 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant altered Kv11.1 channel activation and deactivation (PMID: 25417810, 29752375). This variant has been reported in one case of sudden infant death syndrome (PMID: 29752375) and one individual with long QT syndrome (PMID: 31521807 ). This variant has been identified in 25/281704 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively.
All of Us Research Program, National Institutes of Health	RCV000148535	SCV004843910	uncertain significance	Long QT syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 791 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant altered Kv11.1 channel activation and deactivation (PMID: 25417810, 29752375). This variant has been reported in one case of sudden infant death syndrome (PMID: 29752375) and one individual with long QT syndrome (PMID: 31521807 ). This variant has been identified in 25/281704 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058113	SCV000089633	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:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington	RCV000148535	SCV000190248	uncertain significance	Long QT syndrome	2014-06-01	no assertion criteria provided	research
Research Institute, Imperial College London Diabetes Centre	RCV001162548	SCV002014573	pathogenic	Long QT syndrome 2	2021-01-24	no assertion criteria provided	clinical testing	The KCNH2 p.R791W variant which was detected in the proband, in addition to her father and brother who both have a prolonged QT interval, has been reported previously in one individual with LQTS (PMID: 19716085), and was absent from more than 2,600 control alleles. It is reported in the population databases dbSNP (rs138498207) and Genome Aggregation Database (gnomAD) with a minor allele frequency (MAF) of 0.008875%. This missense mutation is also classified as a variant of uncertain clinical significance in the ClinVar database (Variation ID: 67391). It is located in a highly conserved residue and in silico and bioinformatic analysis (KvSNP, Polyphen2, Single Nucleotide Polymorphisms & Go, and SIFT) predicted this variant to be pathogenic and probably damaging to the protein structure and function. Functional studies by Anderson et al. showed that expression of the KCNH2 p.R791W variant in the absence of a wildtype allele results in normal protein trafficking to the cell membrane, but altered channel gating resulting in dysfunctional channels but with nearly normal values for the repolarizing outward potassium current (IKv11.1) density. On the basis of the genotypes - phenotypes associations in our study, segregation analysis and previous studies mentioned, we classify the p.R791W variant as the putative disease-causative variant that contributes to the LQTS phenotype observed.
Research Institute, Imperial College London Diabetes Centre	RCV001778698	SCV002014677	likely pathogenic	Brugada syndrome 1		no assertion criteria provided	clinical testing	The KCNH2 p.R791W variant which was detected in the proband, has been reported previously in one individual with LQTS (PMID: 19716085), and was absent from more than 2,600 control alleles. It is reported in the population databases dbSNP (rs138498207) and Genome Aggregation Database (gnomAD) with a minor allele frequency (MAF) of 0.008875%. This missense mutation is also classified as a variant of uncertain clinical significance in the ClinVar database (Variation ID: 67391). It is located in a highly conserved residue and in silico and bioinformatic analysis (KvSNP, Polyphen2, Single Nucleotide Polymorphisms & Go, and SIFT) predicted this variant to be pathogenic and probably damaging to the protein structure and function. Functional studies by Anderson et al. showed that expression of the KCNH2 p.R791W variant in the absence of a wildtype allele results in normal protein trafficking to the cell membrane, but altered channel gating resulting in dysfunctional channels but with nearly normal values for the repolarizing outward potassium current (IKv11.1) density. As suggested by Bezzina et al., BrS may not be a monogenic disorder but rather oligogenic and due to multiple susceptibility variants acting in concert via one or more mechanistic pathways that are associated with developing a Brugada syndrome phenotype. This result was interpreted in the clinical context of this patient and on the basis of the genotypes - phenotypes associations in our study, we may speculate that although rare; the LQT2- associated p.R791W variant may not have a direct disease-causative role in BrS but may act as a strong modifier variant that configures the BrS ECG pattern observed in the proband.