ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1714G>A (p.Gly572Ser) (rs9333649)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181811 SCV000234114 pathogenic not provided 2016-12-16 criteria provided, single submitter clinical testing The G572S pathogenic variant in the KCNH2 gene has been reported multiple times in association with LQTS (Fodstad et al., 2004; Khositseth et al., 2004; Chung et al., 2007; Berge et al., 2008; Kapplinger et al., 2009; Mahati et al., 2016). G572S is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G572S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at a position that is conserved across species. Located in the linker between the S5 and pore segments in KCNH2, functional studies have reported G572S results in 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). Multiple variants at the same residue (G572R, G572D, G572C, G572V) as well as variants in nearby residues (I567T, W568R, W568C, Y569H, Y569C, I571L, I571V, I571M, M574V, E575K, E575G) have been reported in HMGD association with LQTS (Stenson et al., 2014), further supporting the functional importance of this residue and region of the protein.
Ambry Genetics RCV000619615 SCV000737642 pathogenic Cardiovascular phenotype 2016-10-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000631548 SCV000752630 pathogenic Long QT syndrome 2018-10-04 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 572 of the KCNH2 protein (p.Gly572Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with long QT syndrome (PMID: 15176425, 22949429, 27803431, 19490267). ClinVar contains an entry for this variant (Variation ID: 67248). Experimental studies have shown that this missense change causes a trafficking defect in the KCNH2 protein causing suppression of the KCNH2 channel current density and prolonged action potential duration and affects channel repolarization (PMID:  16432067, 23303164, 27803431, 28082916, 19490267). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000678923 SCV000805130 pathogenic Long QT syndrome 2 2017-12-15 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057959 SCV000089479 not provided Congenital long QT syndrome no assertion provided literature only 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000181811 SCV000280119 pathogenic not provided 2015-05-04 no assertion criteria provided clinical testing 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.

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