ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1898A>G (p.Asn633Ser) (rs199472961)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181825 SCV000234128 pathogenic not provided 2020-01-24 criteria provided, single submitter clinical testing Identified several unrelated individuals from different ethnic backgrounds with LQTS in published literature (Satler et al., 1998; Lupoglazoff et al., 2001; Nemec et al., 2003; Khositseth et al., 2004; Tester et al., 2005; Tan et al., 2006; Nagaoka et al., 2008; Berge et al., 2008; Kapa et al., 2009; Itoh et al., 2010; Giudicessie et al., 2012; Christiansen et al., 2014; Itoh et al., 2016; Izumi et al., 2016) and referred for genetic testing at GeneDx; Not observed in large population cohorts (Lek et al., 2016); Functional studies suggest that this variant impairs proper KCNH2 channel trafficking and channel function (She et al., 2006; Anderson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID# 67323; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 18752142, 17088455, 18441445, 16842670, 25417810, 22949429, 9544837, 11222472, 15840476, 26669661, 27041096, 24606995, 23158531, 20541041, 19841300, 15851119, 12877697, 31557540, 31737537, 32940533)
Ambry Genetics RCV000617489 SCV000736310 likely pathogenic Cardiovascular phenotype 2016-08-18 criteria provided, single submitter clinical testing The p.N633S variant (also known as c.1898A>G), located in coding exon 7 of the KCNH2 gene, results from an A to G substitution at nucleotide position 1898. The asparagine at codon 633 is replaced by serine, an amino acid with highly similar properties. This alteration has been previously reported in a number of individuals with long QT syndrome (LQTS) (Satler CA et al. Hum Genet. 1998;102:265-72; Tan HL et al. Circulation. 2006;114:2096-103; Nagaoka I et al. Circ J. 2008;72:694-9; Berge KE et al. Scand J Clin Lab Invest. 2008;68:362-8; Kapa S et al. Circulation. 2009;120:1752-60; Christiansen M et al. BMC Med. Genet. 2014;15:31). In functional in vitro analyses, this variant has been suggested to affect the potassium channel current (She HR et al. Zhonghua Xin Xue Guan Bing Za Zhi. 2006;34:523-7) and to cause protein trafficking deficiency (Anderson CL et al. Nat Commun. 2014;5:5535). Other alterations involving the same amino acid, p.N633D (c.1897A>G), p.N633I (c.1898A>T), and p.N633K (c.1899C>A), have been reported in LQTS cohorts (Lai LP et al. J Hum Genet. 2005;50:490-6; Itoh H et al. Heart Rhythm. 2010;7:1411-8; Yoshinaga M et al. Circ Arrhythm Electrophysiol. 2014;7:107-12). This p.N633S variant was previously reported in the SNPDatabase as rs199472961, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000678919 SCV000805125 pathogenic Long QT syndrome 2 2017-11-27 criteria provided, single submitter clinical testing
Invitae RCV000799027 SCV000938674 pathogenic Long QT syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 633 of the KCNH2 protein (p.Asn633Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with long QT syndrome (LQTS) (PMID: 9544837, 22949429, 17088455, 19996378). ClinVar contains an entry for this variant (Variation ID: 67323). This variant has been reported to affect KCNH2 protein function (PMID:25417810). 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.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058042 SCV000089562 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:9544837;PMID:11222472;PMID:12877697;PMID:15840476;PMID:16842670;PMID:18441445;PMID:18752142;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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