ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1391G>A (p.Arg464His) (rs199472814)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000505785 SCV000234528 pathogenic not provided 2018-09-12 criteria provided, single submitter clinical testing The R591H pathogenic variant in the KCNQ1 gene has been reported multiple times in association with LQTS (Neyroud et al., 1999; Inoue et al., 2003; Shimizu et al., 2004; Grunnet et al., 2005; Tester et al., 2005; Moss et al,. 2007; Yasuda et al., 2008; Kapa et al., 2009; Kapplinger et al., 2009; Andrsova et al., 2012; Medlock et al., 2012; Stattin et al., 2012; Robinson et al., 2015). R591H was first reported by Neyroud et al. (1999) in a mother and daughter with prolonged QT intervals. Segregation of this variant with disease has also been reported in subsequent publications (Grunnet et al., 2005; Yasuda et al., 2008) as well as in one family with LQTS tested at GeneDx. Most recently, Robinson et al. (2015) identified the R591H variant in a patient who was diagnosed with LQTS at birth who also harbored a second variant (S28L) in the KCNE1 gene. This patient had a prolonged QTc interval and experienced multiple episodes of loss of consciousness due to breath holding spells, once with prolonged asystole (Robinson et al., 2015). The R591H pathogenic variant was absent from over 5,400 control alleles, collectively (Inoue et al., 2003; Tester et al., 2005; Kapa et al., 2009; Medlock et al., 2012) and 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. Although R591H results in a conservative amino acid substitution, this substitution occurs at an evolutionarily conserved position in the C-terminal domain which is involved in channel assembly and processing (Grunnet et al., 2005). In addition, functional studies by Grunnet et al. (2005) demonstrated that R591H causes a reduction in potassium ion current due to a reduction in the number of functional voltage gated potassium channels in the cell membrane. Similarly, Kanki et al. (2004) observed markedly reduced cell surface channel expression as a result of the R591H variant, along with no or markedly reduced potassium current, and Xu et al. (2009) demonstrated that R591H affects channel trafficking to the cell membrane. Finally, different missense variants affecting the same residue (R591C, R591L) and multiple missense variants in nearby residues (T587M, T587R, G589D, A590T, N593K, R594P, R594Q) have been reported in HGMD in association with LQTS and sudden unexplained death (Stenson et al., 2014).
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000678914 SCV000805118 pathogenic Long QT syndrome 1 2017-11-14 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057636 SCV000089155 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:10024302;PMID:15840476;PMID:16253915;PMID:16818214;PMID:17329209;PMID:19716085;PMID:19841300;PMID:15234419;PMID:17470695;PMID:17329207;PMID:9386136). 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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