ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1894C>T (p.Pro632Ser) (rs199473527)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181824 SCV000234127 pathogenic not provided 2014-07-23 criteria provided, single submitter clinical testing p.Pro632Ser (CCC>TCC): c.1894 C>T in exon 7 of the KCNH2 gene (NM_000238.2). The P632S mutation in the KCNH2 gene has been reported in one individual with LQTS and it was absent from more than 400 control chromosomes (Splawski I et al., 2000). Furthermore, the P632S mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, P632S results in 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, at a position that is conserved across mammalian species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, a mutation in this residue (P632A) and mutations in nearby residues (S631A, N633D, N633I, N633S, N633K) have been reported in association with LQTS, further supporting the functional importance of this residue andregion of the protein. In summary, P632S in the KCNH2 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s).
Ambry Genetics RCV000621397 SCV000737460 likely pathogenic Cardiovascular phenotype 2019-09-17 criteria provided, single submitter clinical testing The p.P632S variant (also known as c.1894C>T), located in coding exon 7 of the KCNH2 gene, results from a C to T substitution at nucleotide position 1894. The proline at codon 632 is replaced by serine, an amino acid with similar properties. This variant was reported in two studies of individuals and families reported to have long QT syndrome (LQTS)(SplawskiI et al.Circulation. 2000;102(10):1178-85;AndrsovaIet al.JElectrocardiol.2012;45(6):746-51). Onestudy with in vitro analysessuggestedthis alteration to result in abnormal protein trafficking (Anderson CL et al.NatCommun.2014;5:5535). In addition, another alteration affecting the same amino acid (p.P632A (c.1894C>G)) has alsobeen reported in association with LQTS (MullallyJ et al.Heart Rhythm. 2013;10(3):378-82).This variant was previously reported in the SNPDatabase as rs199473527. This variant was not reported in population-based cohorts in the following databases: NHLBIExome Sequencing Project (ESP), and 1000 Genomes Project.This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058040 SCV000089560 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:10973849). 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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