ClinVar Genomic variation as it relates to human health

The KCNH2 c.1714G>A (p.Gly572Ser) variant is a missense variant. Across a selection of the available literature, this variant has been identified in a heterozygous state in at least seven unrelated individuals with long QT syndrome (Fodstad et al. 2004; Tester et al. 2005; Kapplinger et al. 2009; Zhao et al. 2009; Chae et al. 2017). Control data are unavailable for the p.Gly572Ser variant, which is not found in the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Co-expression of the p.Gly572Ser variant and wild type KCNH2 cDNA in continuous cell lines demonstrated that the p.Gly572Ser variant channel did not undergo glycosylation within the Golgi and has a dominant negative effect on the trafficking of KCNH2 to the cellular membrane, causing its retention in the ER and Golgi, and thereby reduction of channel activity with a reduction in current density of 90% compared to wild type (Anderson et al. 2006; Zhao et al. 2009; Liu et al. 2016). Based on the collective evidence and the application of the ACMG criteria, the p.Gly572Ser variant is classified as pathogenic for long QT syndrome.

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 572 of the KCNH2 protein (p.Gly572Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 15176425, 19490267, 22949429, 27803431). ClinVar contains an entry for this variant (Variation ID: 67248). 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: 16432067, 19490267, 23303164, 27803431, 28082916). For these reasons, this variant has been classified as Pathogenic.

The p.G572S pathogenic mutation (also known as c.1714G>A), located in coding exon 7 of the KCNH2 gene, results from a G to A substitution at nucleotide position 1714. The glycine at codon 572 is replaced by serine, an amino acid with similar properties. This alteration has been reported in multiple unrelated individuals with long QT syndrome (Fodstad H et al. Ann Med. 2004; 36 Suppl 1:53-63; Tester DJ et al. Heart Rhythm. 2005; 2(5):507-17; Chung SK et al. Heart Rhythm. 2007; 4(10):1306-14; Berge KE et al. Scand J Clin Lab Invest. 2008; 68(5):362-8; Horigome H et al. Circ Arrhythm Electrophysiol. 2010; 3(1):10-7; Hedley PL et al. Cardiovasc J Afr. 2013; 24(6):231-7). This alteration has also been reported to co-segregate with prolonged QTc interval or long QT syndrome phenotype in families (Horie M et al. Circ J 2007;71 Suppl A:A50-3; Ohno S et al. Hum Mutat. 2009; 30(4):557-63; Aziz PF et al, Heart Rhythm. 2010; 7(6):781-5). In vitro functional studies have reported this alteration to result in abnormal channel trafficking and dominant negative effect leading to loss of normal KCNH2 ion channel function (Anderson CL et al. Circulation. 2006; 113(3):365-73; Zhao JT et al. J Cardiovasc Electrophysiol. 2009; 20(8):923-30; Jou CJ et al. Circ Res. 2013; 112(5):826-30; Liu L et al. Front Physiol, 2016 Dec;7:650). In addition, multiple alterations affecting the same amino acid (p.G572C (c.1714G>T), p.G572R (c.1714G>C), p.G572D (c.1715G>A) and p.G572V (c.1715G>T)) have also been reported in association with long QT syndrome (Splawski I et al. Genomics. 1998; 51(1):86-97; Larsen LA et al. Clin Genet. 2000; 57(2):125-30; Napolitano C et al. JAMA. 2005; 294(23):2975-80; Kapplinger JD et al. Heart Rhythm. 2009; 6(9):1297-303). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, p.G572S is interpreted as a disease-causing mutation.

Reported multiple times in individuals with LQTS in the published literature and referred for genetic testing at GeneDx (Fodstad et al., 2004; Giudicessi et al., 2012; Ebrahim et al., 2017); Published functional studies demonstrate a dominant-negative effect that leads to a loss of normal potassium ion channel function (Anderson et al., 2006; Zhao et al., 2009; Jou et al., 2013; Mahati 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; This variant is associated with the following publications: (PMID: 28082916, 19490267, 23303164, 27803431, 22949429, 28532774, 30850667, 31737537, 32383558, 34570182, 15176425, 16432067)

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNH2 p.Gly572Ser This variant has been reported in multiple cases of long QT syndrome. Takashi et al (2004) reported the variant in at least one case of long QT syndrome (only the abstract was available with minimal data included). Tester et al (2005) reported this variant in their compendium of variants identified in patients referred to the Mayo Clinic's Sudden Death Genomics Laboratory for long QT genetic testing. They observed the variant in two presumably unrelated patients (unclear); no phenotypic data was provided. Horigome et al (2009) reported the variant in female child who presented with Torsades, AV block, and a QTc of 520 ms an was diagnosed with long QT syndrome with as a neonate (this case my overlap with the one reported by Takashi, thought Takashi is not in the author list of this publication). Kotta et al (2010) reported the variant in on individual their Greek cohort of patients with long QT syndrome. No segregation or functional data was provided in any of these reports. Two other variants have been reported at the same codon in association with long QT syndrome. Splawski et al (2000) report p.Gly572Cys in association with long QT syndrome. Larsen et al (2000) reported three family members with long QT syndrome and p.Gly572Arg in KCNH2. Lian et al (2010) studied the biophysical phenotype of p.Gly572Arg and concluded it generates a trafficking-deficient phenotype with a dominant negative effect. In silico analysis with Polyphen 2 predicts the p.Gly572Ser to be probably damaging. Codon 572 is highly conserved across species and isoforms. The variant is in the S5 segment, in the extracellular space, very close to the pore. Tester et al (2005) did not observe p.Gly572Ser in 744 control individuals from four different ethnic groups and Kotta et al (2010) did not see it in 100 control individuals of Greek origin. Control data was not published by the other groups. Based on these data it is very likely that this variant causes long QT syndrome.

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15176425;PMID:15840476;PMID:16432067;PMID:16831322;PMID:17905336;PMID:18752142;PMID:19490267;PMID:19716085;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.