ClinVar

Description

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.