Submissions for variant NM_000238.4(KCNH2):c.3140G>T (p.Arg1047Leu)

dbSNP: rs36210421

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171814	SCV000050825	benign	Torsades de pointes	2013-06-24	criteria provided, single submitter	research
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000172896	SCV000223887	likely benign	Sudden unexplained death	2015-03-27	criteria provided, single submitter	research	The KCNH2 Arg1047Leu variant has previously been reported as a polymorphism and suggested to be associated with increased risk to Torsades de Pointes (Mank-Seymour AR et al., 2006; Sun Z et al., 2004; Kapa S et al., 2009). It is present in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) with an allele frequency of 0.008 (105/11944 alleles); and the frequency in the European (non-Finnish) sub-population is 0.02 (73/3656 alleles). We identified this variant in a 16 yo boy who had a sudden cardiac arrest with no pre-morbid diagnosis and Greek ethnicity. Post-mortem examination was unremarkable and there is no family history of any cardiac disease. Based on the frequency of the KCNH2 Arg1047Leu variant in 2% of the European (non-Finnish) population, we do not expect this variant to cause disease in isolation. We therefore classify this variant as "likely benign".
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000203011	SCV000257647	uncertain significance	Long QT syndrome 2	2015-07-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000243613	SCV000317415	benign	Cardiovascular phenotype	2015-06-11	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000203011	SCV000467508	benign	Long QT syndrome 2	2018-03-06	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000401763	SCV000555899	benign	Long QT syndrome	2025-02-04	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000517346	SCV000613854	benign	not specified	2017-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001841531	SCV000902611	benign	Cardiac arrhythmia	2018-03-15	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000058202	SCV000987332	benign	not provided		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000517346	SCV001364010	benign	not specified	2019-11-04	criteria provided, single submitter	clinical testing	Variant summary: KCNH2 c.3140G>T (p.Arg1047Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.027 in 171128 control chromosomes in the gnomAD database, including 44 homozygotes. The observed variant frequency is approximately 270- fold the estimated maximal expected allele frequency for a pathogenic variant in KCNH2 causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is benign. c.3140G>T has been reported in the literature in individuals affected with various cardiovascular phenotypes without strong evidence for causality (e.g. LQTS: Mazzadi_2003; SQTS: Hu_2017; Brugada Syndrome: Kauferstein_2017; drug-induced Torsades de Pointes : Sun_2014, VanDriest_2016; sudden infant death syndrome: Anson_2004, Arnestad_2007, Glengarry_2014, Smith_2018), in many cases being found in both patients and controls. These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. Co-occurrence with another pathogenic variant has been reported (KCNH2 c.215C>A, p.Pro72Gln; internal sample), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating the impact of the variant on hERG channel activity. Several reports indicate that the biochemical activity of hERG channels in cells expressing the variant are similar to wild-type (Anson_2004, Mannikko_2010), while others others indicate that the levels of channel activation or repolarization may be altered to varying degrees in cells expressing the variant (Sun_2004, Chevalier_2007, Jou_2013). Seven ClinVar submitters (evaluation after 2014) have cited the variant four times as benign, two times as likely benign, and one time as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000058202	SCV001472181	benign	not provided	2024-08-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000058202	SCV001942834	benign	not provided	2020-03-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 14975928, 17275752, 22949429, 20167303, 24596401, 23303164, 27153395, 15522280, 28472724, 26412604, 31043699)
Cohesion Phenomics	RCV000401763	SCV003803664	benign	Long QT syndrome	2022-09-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000401763	SCV004835852	benign	Long QT syndrome	2024-10-01	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058202	SCV000089722	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:11468227;PMID:14661677;PMID:15522280;PMID:16487223;PMID:17161064;PMID:17210839;PMID:17275752;PMID:19841300).
PreventionGenetics, part of Exact Sciences	RCV004549392	SCV004736236	benign	KCNH2-related disorder	2019-05-15	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).