ClinVar Genomic variation as it relates to human health

The p.G657S variant (also known as c.1969G>A), located in coding exon 8 of the KCNH2 gene, results from a G to A substitution at nucleotide position 1969. The glycine at codon 657 is replaced by serine, an amino acid with similar properties. This alteration has been reported in long QT syndrome cohorts; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Berge KE et al. Scand J Clin Lab Invest, 2008;68:362-8; Kim JA et al. Heart Rhythm, 2010 Dec;7:1797-805; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). Additionally, an in vitro study showed this alteration impacts protein function (Perry MD et al. J Physiol, 2016 Jul;594:4031-49). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Identified in a patient with suspected long QT syndrome (Marschall et al., 2019); Published functional studies demonstrate a damaging effect, including defective protein expression, reduced charge during repolarization, reduced IKv11.1 amplitude in response to premature depolarization, and slower deactivation kinetics (Perry et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 17823114, 20393304, 25348405, 19716085, 20850565, 26958806, 31737537)

The p.Gly657Ser variant in KCNH2 has been previously reported in 1 individual referred for long QT syndrome (LQTS) genetic testing, and it has also been observed in 3 individuals with a reported diagnosis of LQTS by a clinical testing laboratory (Kapplinger 2009, personal communication ClinVar SCV000261846.3). It was absent from large population studies. In vitro functional studies have demonstrated an impact to normal KCNH2 potassium channel function, including when the variant is co-expressed with wild-type (Perry 2016, Hardman 2007). This variant is located in the transmembrane spanning S5/pore region of the KCNH2 protein, which has been deemed important for proper channel function (Kapa 2009 PMID: 19841300).Computational prediction tools and conservation analyses suggest an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant LQTS. ACMG/AMP criteria applied: PM2_Supporting, PP3, PM1, PS3_Supporting, PS4_Supporting.

This missense change has been observed in individuals with KCNH2-related conditions (PMID: 19716085; Invitae). ClinVar contains an entry for this variant (Variation ID: 67348). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 17823114, 19841300, 25348405, 26958806). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Gly657Cys amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18752142, 18955593, 19862833, 26675252). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 657 of the KCNH2 protein (p.Gly657Ser).

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.