ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.311G>A (p.Arg104His) (rs199472709)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046107 SCV000074120 pathogenic Long QT syndrome 2020-08-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 231 of the KCNQ1 protein (p.Arg231His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been identified in several families and unrelated individuals with long QT syndrome (PMID: 16414944, 23350853, 24861447). ClinVar contains an entry for this variant (Variation ID: 53087). This variant identified in the KCNQ1 gene is located in the transmembrane S4 region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit Experimental studies have shown that this missense change increases KCNQ1 current to shorten the atrial action potential duration (PMID: 23350853). A different missense substitution at this codon (p.Arg231Cys) is reported to be deleterious (PMID: 15176425, 20850564, 22509038). This indicates that the arginine residue is important for KNCQ1 protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000182101 SCV000234404 pathogenic not provided 2017-04-10 criteria provided, single submitter clinical testing A R231H pathogenic variant was identified in the KCNQ1 gene. This variant has previously been reported in association with LQTS (Napolitano et al., 2005; Johnson et al., 2008; Kapplinger et al., 2009; Bartos et al. 2013; Laksman et al., 2014). In addition, different pathogenic variants affecting the same residue (R231C, R231S) have been reported in association with LQTS (Lupoglazoff et al., 2004; Itoh et al., 2009; Bartos et al., 2011; Zienciuk et al., 2009). The R231H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although the R231H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs within the S4 transmembrane voltage sensor of the potassium channel at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies by Bartos et al. (2013) have shown that R231H results in a gain of function by increasing the potassium current and shortening the atrial action potential duration. In addition, R231H demonstrated resistance to PKA stimulation and this loss of channel regulation by PKA may account for QTc prolongation (Bartos et al. 2013).
Fulgent Genetics,Fulgent Genetics RCV000762833 SCV000893192 pathogenic Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome 2 2018-10-31 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057734 SCV000089253 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:16414944;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
OMIM RCV000115007 SCV000148916 pathogenic Atrial fibrillation, familial, 3 2013-09-01 no assertion criteria provided literature only
OMIM RCV000115008 SCV000148917 pathogenic Long QT syndrome 1 2013-09-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000182101 SCV000924827 pathogenic not provided 2017-04-06 no assertion criteria provided provider interpretation

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