ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.641C>A (p.Ala214Glu) (rs12720459)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045932 SCV000073945 pathogenic Long QT syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with glutamic acid at codon 341 of the KCNQ1 protein (p.Ala341Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with long QT syndrome in several large families (PMID: 8528244, 10086971, 16627448) and in other unrelated affected patients (PMID: 19716085, 22949429). ClinVar contains an entry for this variant (Variation ID: 3120). Experimental studies have shown that this missense change has a dominant negative effect in vitro (PMID: 10376919, 22095730). In addition, transgenic mice expressing a murine equivalent missense change develop long QT symptoms (PMID: 20368164). The p.Ala341 amino acid residue in KCNQ1 has been determined to be clinically significant (PMID: 15028050, 17984373). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000182154 SCV000234457 pathogenic not provided 2018-01-17 criteria provided, single submitter clinical testing The A341E pathogenic variant in the KCNQ1 gene has been reported previously in multiple individuals in association with LQTS (Wang et al., 1996; Berthet et al., 1999; Splawksi et al., 2000; Chen et al., 2003; Kapplinger et al., 2009; Tester et al., 2012; Hedley et al., 2013; Laksman et al., 2014). Additionally, A341E has been reported to segregate with LQTS in at least nine relatives from three separate families (Wang et al., 1996; Laksman et al., 2014). It has been observed in multiple unrelated individuals referred for LQTS genetic testing at GeneDx. Moreover, A341E is not observed in large population cohorts (Lek et al., 2016).The A341E pathogenic 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. Additionally, A341E is located within the S6 transmembrane segment of the KCNQ1 channel, at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, voltage clamp studies in Xenopus oocytes co-expressing both wild-type and mutant KCNQ1 channels have shown that A341E causes a dominant negative suppression of the delayed rectifier potassium current (Wang et al., 1999). Finally, pathogenic/likely pathogenic missense variants in the same residue (A341V, A341G) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this residue.
Ambry Genetics RCV000621485 SCV000738058 pathogenic Cardiovascular phenotype 2017-06-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Well-characterized mutation at same position
OMIM RCV000003267 SCV000023425 pathogenic Long QT syndrome 1 1999-03-23 no assertion criteria provided literature only
OMIM RCV000003268 SCV000023426 pathogenic Long QT syndrome 1/2, digenic 1999-03-23 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057526 SCV000089045 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:8528244;PMID:10086971;PMID:10973849;PMID:12702160;PMID:14678125;PMID:17984373;PMID:19716085;PMID:19841300;PMID:20368164;PMID:10376919;PMID:17470695). 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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