ClinVar Miner

Submissions for variant NM_000238.3(KCNH2):c.3140G>T (p.Arg1047Leu) (rs36210421)

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Total submissions: 12
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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: 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 Clinical Services Laboratory,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.
Invitae RCV000401763 SCV000555899 benign Long QT syndrome 2020-12-08 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000517346 SCV000613854 benign not specified 2017-06-14 criteria provided, single submitter clinical testing
Color Health, Inc RCV000771077 SCV000902611 benign 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 RCV001285705 SCV001472181 benign none provided 2020-05-05 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).

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