Submissions for variant NM_000238.4(KCNH2):c.982C>T (p.Arg328Cys)

gnomAD frequency: 0.00063  dbSNP: rs199473505

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000157262	SCV000206992	likely benign	not specified	2015-11-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000058281	SCV000234077	uncertain significance	not provided	2024-01-19	criteria provided, single submitter	clinical testing	Reported in multiple unrelated individuals with LQTS (PMID: 19716085, 11334843, 15840476, 16922724, 22949429, 23347029); Reported in an individual who developed Torsades de Pointes in the context of postpartum respiratory distress, left ventricular dysfunction, and a prolonged QT interval while being treated with multiple medications; several relatives who were also found to harbor this variant, including the patient's identical twin, had no clinical evidence of LQTS, leading authors to conclude this patient's arrhythmia likely resulted from multiple factors (PMID: 16720674); Functional studies are inconsistent regarding the effect of this variant on channel function (PMID: 16253915, 11334843, 16432067); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23303164, 16432067, 17275752, 22949429, 23347029, 11334843, 14760488, 15840476, 16922724, 19841300, 28988457, 31737537, 37614113, 37199999, 19716085, 16720674, 16253915)
CSER _CC_NCGL, University of Washington	RCV000210884	SCV000264604	likely benign	Long QT syndrome	2015-12-01	criteria provided, single submitter	research
Invitae	RCV000210884	SCV000283991	benign	Long QT syndrome	2024-01-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620416	SCV000737614	likely benign	Cardiovascular phenotype	2020-05-06	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.
Illumina Laboratory Services, Illumina	RCV001162645	SCV001324606	uncertain significance	Long QT syndrome 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV001841763	SCV001343653	likely benign	Cardiac arrhythmia	2018-11-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000058281	SCV004010741	likely benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	KCNH2: PP2, BS1
PreventionGenetics, part of Exact Sciences	RCV004549488	SCV004720833	likely benign	KCNH2-related disorder	2019-06-19	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058281	SCV000089801	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:11334843;PMID:14760488;PMID:15840476;PMID:16253915;PMID:16432067;PMID:16720674;PMID:16922724;PMID:17275752;PMID:19716085;PMID:19841300).
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000058281	SCV000280132	likely benign	not provided	2016-11-15	no assertion criteria provided	provider interpretation	Given the weak case data and presence in population controls, we consider this variant likely benign. One possibility is that this variant contributes to an arrhythmic phenotype, perhaps behaving as a modifier, but not be the primary driver. This is based on the fact that several of the reported cases involved either a more convincing pathogenic variant or QT-prolonging medication, several other reported cases are from cohorts that include individuals who do not have long QT, and the variant is present in individuals not selected for a long QT phenotype, with ~1% of one such cohort having the variant. This is a previously reported variant in the N-terminal region. To date, the reported cases include - drug-induced long QT, complete AV block and Torsades: 2 - patients referred for long QT genetic testing, 25-50% likely don't have long QT: 6 - patients with long QT, all major genes analyzed with no other variants: 4 - patients with long QT and another, high confidence variant: 1 - patient with prolonged QT in the setting of evidence of arrhythmogenic right ventricular cardiomyopathy and a PKP2 frameshift variant: 1 Comparing frequencies: - 4/2500 in Kapplinger series (0.16%) - 64/60,618 in ExAC (0.11%) - 38/3189 Finnish in ExAC (1.2%) -162/141,162 in gnomAD (0.11%); -115/13031 Finnish in gnomAD (0.88%) Chevalier et al (2001) reported the variant in association with what the authors described as acquired long QT syndrome. They found the variant in 1 of 16 cases. The individual with the variant was a 45yo male with no prior medical history of family history of sudden death. He was hospitalized for recent syncopal episodes. An ECG at admission showed QT prolongation and complete AV block, he was diagnosed with "Torsades de pointes" complicating an AV bock and a pacemaker was placed and the QT interval returned to normal once he was paced. Tester et al (2005) observed the variant in 2 of 541 cases. This publication is a compendium of variants identified in cases referred to Dr. Ackerman's research lab for long QT genetic testing. No individual clinical or segregation data was provided. Of note when considering this paper, it is likely that ~25% of patients in this cohort did not actually have long QT syndrome (based on the reported yield). Millat et al (2006) reported the variant in 3 of 44 unrelated individuals from their French cohort with long QT syndrome with QTc intervals ranging from 483 to 540 ms. No segregation data was provided. They analyzed 5 long QT genes. Hinterseer et al (2006) reported the variant in a 25yo woman who suffered Torsades de Pointes in the setting of transiently impaired LV function, acute respiratory distress syndrome, transient hypokalaemia and QT-prolonging drugs, with a QTc of 485-510 ms. Once her status had normalized and QT-prolonging drugs had been discontinued her QTc was 430 ms and a Dl-sotalol challenge evoked a QTc of 515 ms, which the authors felt was suggestive of a latent susceptibility to QT-prolonging drugs. Four other family members were found to have the variant, "all without clinical manifestations of LQTS". The variant was reported in 4 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Those cases likely overlap with the data in Kapa et al (2009) and Giudicessi et al (2012) since these are all from Ackerman's group and use data from his cohort and from the Familion cohort. Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). Stattin et al (2012) analyzed 5 long QT genes in 200 unrelated long QT patients from their Swedish cohort and identified this variant in one individual. Hedley et al (2013) reported on sequencing of five long QT genes in 44 South African patients with long QT syndrome. One patient carried was a double heterozygote for a founder variant, KCNQ1:p.A341V, and this variant, KCNH2:p.R328C. They did not provide any details about the patient's phenotype or segregation in the family. Tisma-Dupanovic et al (2013) reported a 14yo male who had a QTc of 497 ms as well as two major and two minor criteria for arrhythmogenic right ventricular cardiomyopathy (nonsustained ventricular tachycardia of LBBB morphology with a superior axis, MRI findings of regional right ventricular dyskinesia and ejection fraction less than 35%, inverted T waves in lead V1 and V2 and filtered QRS >114 ms on signal-averaged ECG). Genetic testing identified p.Arg328Cys in KCNH2. a frameshift in PKP2, and a missense in DSC2. Functional studies on the variant have reported conflicting results. Chevalier et al (2001) studied the functional impact of the variant on whole-cell current using patch-clamp measurements in transfected COS-7 cells and observed a reduced voltage-activated K current. Grunnet et al (2005) studied a family with this variant and a KCNQ1 variant (p.Arg591His). The KCNH2 variant showed no functional phenotype when studied in xenopus oocytes using two-electrode voltage clamp and by confocal imaging. Review of the pedigree reveals that one individual had both variants and had a QTc of 500 ms, two individuals had just the KCNQ1 variant had QTc of 499 ms and 460 ms, and one individual had just the KCNH2 variant with a QTc of 440 ms and t-wave-related abnormalities of repolarization on exercise and T-wave inversion in leads in V1-V3 on ECG. Ackerman’s group subsequently published functional characterization of several KCNH2 variants, including p.Arg328Cys (Anderson et al 2006). They too found no evidence of functional impact and suggested that this may be a rare benign variant. The Arginine at 328 is not uniformly conserved across species. The variant was reported online in 161 of 141,162 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The highest frequency was 115 of 13,031 Finnish individuals (0.88%). The variant was not observed in the following published control samples :200 individuals studied by Grunnet et al (2005), 1300 individuals reported by Kapplinger et al (2009, redundant with Tester et al 2005), 50 individuals reported by Chevalier et al (2001), 100 individuals reported by Millat et al (2006).