ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1256C>T (p.Ser419Leu) (rs199473480)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046008 SCV000074021 pathogenic Long QT syndrome 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 546 of the KCNQ1 protein (p.Ser546Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (rs199473480, ExAC no frequency). This variant has been observed to segregate with long QT syndrome in a family and has been reported in several unrelated individuals affected with this condition (Invitae, PMID: 17905336, 22456477, 22949429, 26675252, 27026747). It has also been observed in several individuals with suspected long QT syndrome (PMID: 15466642, 15840476, 19716085). ClinVar contains an entry for this variant (Variation ID: 53000). Experimental studies have shown that this missense change leads to slower KCNQ1 activation kinetics and faster deactivation (PMID: 19808498, 25037568). For these reasons, this allele has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000182209 SCV000225759 pathogenic not provided 2014-11-10 criteria provided, single submitter clinical testing
GeneDx RCV000182209 SCV000234512 pathogenic not provided 2018-08-13 criteria provided, single submitter clinical testing The S546L pathogenic variant in the KCNQ1 gene has been reported many times in association with LQTS (Choi etal., 2004; Chung et al., 2007; Kapplinger et al., 2009; Guidicessi et al., 2012; Yoshinaga et al., 2016). Additionally,S546L has been identified independently in multiple unrelated individuals with LQTS referred for genetic testing atGeneDx, and was found to segregate with disease phenotype in at least three families. Moreover, S546L is not observed in large populationcohorts (Lek et al., 2016). The S546L variant is a non-conservative amino acid substitution, which is likely toimpact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silicoanalyses, including protein predictors and evolutionary conservation, support a deleterious effect. Finally, functionalstudies performed by Yang et al. (2009) suggested that S546L results in reduced IKs currents in heterologous cells.
Ambry Genetics RCV000619557 SCV000737393 pathogenic Cardiovascular phenotype 2020-06-18 criteria provided, single submitter clinical testing The p.S546L pathogenic mutation (also known as c.1637C>T), located in coding exon 13 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1637. The serine at codon 546 is replaced by leucine, an amino acid with dissimilar properties, and is located in the C-terminal region of the protein. This alteration has been reported in multiple individuals with long QT syndrome (LQTS) (Choi G et al. Circulation 2004 Oct; 110(15):2119-24; Chung SK et al. Heart Rhythm 2007 Oct; 4(10):1306-14; Albertella L et al. Arch. Dis. Child. 2011 Aug; 96(8):704-7). Furthermore, the p.S546L variant disrupts KCNQ1 function in in vitro electrophysiological assays (Yang T et al. Circ Arrhythm Electrophysiol 2009 Aug; 2(4):417-26; Dvir M, J. Cell. Sci. 2014 Sep; 127(Pt 18):3943-55). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Health, Inc RCV001190404 SCV001357884 likely pathogenic Arrhythmia 2019-06-06 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057608 SCV000089127 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:15176425;PMID:15466642;PMID:15840476;PMID:17905336;PMID:19716085;PMID:19808498;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.