ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.524C>T (p.Ala175Val) (rs193922365)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618395 SCV000738185 likely pathogenic Cardiovascular phenotype 2020-09-25 criteria provided, single submitter clinical testing The p.A302V variant (also known as c.905C>T), located in coding exon 6 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 905. The alanine at codon 302 is replaced by valine, an amino acid with similar properties. This alteration has been identified in trans with a KCNQ1​ pathogenic alteration in an individual with Jervell and Lange-Nielsen syndrome, as well as in her asymptomatic father (Wang C et al. Acta Otolaryngol., 2017 May;137:522-528). This variant has also been detected in an individual with a history of arrhythmia events while swimming, who also harbored an additional KCNQ1 alteration, but information about phase was not provided (Choi G et al. Circulation, 2004 Oct;110:2119-24). In addition, this alteration has been reported in individuals with lone atrial fibrillation and long QT syndrome (LQTS), as well as in LQTS clinical genetic testing cohorts; however, clinical details were limited (Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Chung SK et al. Heart Rhythm, 2007 Oct;4:1306-14; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Olesen MS et al. Heart Rhythm, 2014 Feb;11:246-51). Functional studies have demonstrated reduced I<sub>Ks</sub> current and abnormal trafficking (Yang T et al. Circ Arrhythm Electrophysiol, 2009 Aug;2:417-26; Steffensen AB et al. J. Cardiovasc. Electrophysiol., 2015 Jul;26:715-23). 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000709734 SCV000839972 likely pathogenic Long QT syndrome 1 2018-05-01 criteria provided, single submitter clinical testing A heterozygous c.905C>T (p.Ala302Val) likely pathogenic variant in the KCNQ1 gene was detected in this individual. This variant has been previously described in multiple individuals with long QT syndrome and atrial fibrillation (PMID 15840476, 19716085, 17905336, 24144883, 25786344). In addition, experimental studies have shown that this variant result in altered biophysical properties of the KCNQ1 protein (PMID 19808498, 25786344). Therefore, we consider this variant to be likely pathogenic.
Invitae RCV000030111 SCV001224616 likely pathogenic Long QT syndrome 2020-10-05 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 302 of the KCNQ1 protein (p.Ala302Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals affected with long QT syndrome (PMID: 17905336, 22456477, 24606995), atrial fibrillation (PMID: 25786344), Jervell and Lange-Nielsen syndrome (PMID: 27917693), or other KCNQ1-related disease (PMID: 15466642, 22677073). ClinVar contains an entry for this variant (Variation ID: 36439). This variant has been reported to affect KCNQ1 protein function (PMID: 19808498, 25786344). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001532623 SCV001748268 pathogenic not provided 2021-04-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030111 SCV000052766 pathogenic Long QT syndrome 2015-04-03 no assertion criteria provided clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057792 SCV000089311 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:15466642;PMID:15840476;PMID:17905336;PMID:19716085;PMID:19808498). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Clinical Genetics,Academic Medical Center RCV001532623 SCV001917112 likely pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV001532623 SCV001954798 likely pathogenic not provided no assertion criteria provided clinical testing

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