ClinVar Miner

Submissions for variant NM_000218.2(KCNQ1):c.1669A>G (p.Lys557Glu) (rs199472801)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000249066 SCV000320599 likely pathogenic Cardiovascular phenotype 2015-11-12 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057615 SCV000089134 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:12402336;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV000489493 SCV000576598 pathogenic not provided 2017-04-26 criteria provided, single submitter clinical testing The K557E variant in the KCNQ1 gene has been reported in a large kindred of Dutch ancestry with LQTS-associated features (Spätjens et al., 2014). Moreover, the variant was de novo in the proband from this kindred, and non-paternity was excluded. In relatives, the variant segregated with moderate QTc prolongation (i.e. average 476+/-13ms) at rest, which was significantly augmented during exercise (i.e. >550ms). K557E has also been reported in additional individuals with LQTS and/or referred for LQTS testing (Jongbloed et al., 2002; Kapplinger et al., 2009; Barsheshet et al., 2012). The K557E variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The K557E 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. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, in vitro functional analysis of the KCNQ1-associated potassium channel showed that, in the presence of K557E, there was a decrease in current density, a voltage-right shift of channel activation, a faster current decline, and a weaker interaction with the KCNE1-associated protein, as compared to wild-type (Heijman et al., 2012, Spätjens et al., 2014, Dvir et al., 2014).

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