ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1385G>A (p.Gly462Asp) (rs120074190)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182223 SCV000234526 pathogenic not provided 2016-11-22 criteria provided, single submitter clinical testing The G589D pathogenic variant in the KCNQ1 gene has been reported multiple times in association with both LQTS and JLNS (Swan et al., 1999; Piippo et al., 2001; Saucerman et al., 2004; Marjamma et al., 2009; Kapplinger et al., 2009; Hintsa et al., 2010; Stattin et al., 2012). Several studies have reported G589D is a founder mutation in the Finnish population, with one study identifying the pathogenic G589D variant in 34 out of 114 Finnish individuals with autosomal dominant LQTS (Piippo et al., 2001; Marjamma et al., 2009). Furthermore, the G89D variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and was not observed with any significant frequency in the Exome Aggregation Consortium (ExAC). G589D is a non-conservative amino acid substitution that is conserved across species. Multiple functional studies have demonstrated that G589D disrupts normal KCNQ1 channel function (Piippo et al., 2001; Saucerman et al., 2004; Heijman et al., 2012; Aromolaran et al., 2014). In addition, Kiviaho et al. (2015) reported that cardiomyocytes harboring G489D exhibited abnormal mechanical beating behavior with a prolonged phase of contracted state before relaxation. Finally, multiple pathogenic missense variants in nearby residues (T587M, A590T, R591H, R594P, R594Q) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), supporting the functional importance of this region of the protein.In summary, G589D in the KCNQ1 gene is interpreted as a pathogenic variant.
Ambry Genetics RCV000622145 SCV000737529 pathogenic Cardiovascular phenotype 2017-07-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Strong segregation with disease (lod >3 = >10 meioses)
Invitae RCV000699476 SCV000828189 pathogenic Long QT syndrome 2018-02-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 589 of the KCNQ1 protein (p.Gly589Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs120074190, ExAC 0.02%). This variant has been reported in heterozygosis in several individuals affected with long QT syndrome and in homozygosis in individuals with Jervell and Lange-Nielsen syndrome. It is also a well known  founder variant in Finland and Sweden although it has also been found in affected individuals from other populations (PMID: 10483966, 19160088, 20659946, 22629021, 28619993, 23098067, 11216980). ClinVar contains an entry for this variant (Variation ID: 3140). Experimental studies have shown that this missense change has a dominant-negative effect causing loss of cAMP-dependent upregulation of the KCNQ1 channel in vitro (PMID: 25344363, 22095730). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003288 SCV000023446 pathogenic Long QT syndrome 1 2001-02-01 no assertion criteria provided literature only
OMIM RCV000003289 SCV000023447 pathogenic Jervell and Lange-Nielsen syndrome 1 2001-02-01 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057633 SCV000089152 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:10483966;PMID:11216980;PMID:12477631;PMID:12690509;PMID:17329209;PMID:19160088;PMID:19716085;PMID:20659946;PMID:12402336;PMID:17467628;PMID:17329207;PMID:11799244;PMID:22095730). 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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