ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.40G>A (p.Val14Met) (rs199472687)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000468931 SCV000543288 pathogenic Long QT syndrome 2018-03-07 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 141 of the KCNQ1 protein (p.Val141Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency) . This variant has been reported in individuals with very early onset atrial fibrillation (AF) and short QT syndrome (SQTS) (PMID: 16109388, 24818999, 23375927). ClinVar contains an entry for this variant (Variation ID: 67072). This variant identified in the KCNQ1 gene is located in the transmembrane S1 region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit Experimental studies using an animal cell models have shown that this variant results in large instantaneous activation of the K channel and shortening of the duration of ventricular and atrial action potentials (PMID: 16109388, 18599533, 24006450). In summary, this is a rare variant which has been reported in individuals affected with AF and SQTS and has been shown to affect protein function. For these reasons, it has been classified as Pathogenic.
GeneDx RCV000494365 SCV000582623 likely pathogenic not provided 2016-03-29 criteria provided, single submitter clinical testing The V141M variant that is likely pathogenic in the KCNQ1 gene was initially reported as a de novo variant in an infant with SQTS who did not have a family history of SQTS (Hong et al., 2005). This variant has also been reported in other individuals with SQTS and atrial fibrillation (Villafane et al., 2013; Villafane et al., 2014; Hasegawa et al., 2014; Harrell et al., 2015). The V141M variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. Functional studies demonstrate that V141M results in a slowed deactivation of the potassium channel which is consistent with the disease mechanism for SQTS (Hong et al., 2005; Restier et al., 2008; Chan et al., 2012). Nevertheless, the V141M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.Therefore, this variant is likely pathogenic
Ambry Genetics RCV000621525 SCV000737832 pathogenic Cardiovascular phenotype 2016-12-02 criteria provided, single submitter clinical testing The p.V141M pathogenic mutation (also known as c.421G>A), located in coding exon 2 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 421. The valine at codon 141 is replaced by methionine, an amino acid with highly similar properties. This mutation was reported in individuals with very early age onset atrial fibrillation (AF) and short QT syndrome (SQTS), including several reported de novo cases (Hong K et al. Cardiovasc. Res., 2005 Dec;68:433-40; Villafañe J et al. J. Am. Coll. Cardiol., 2013 Mar;61:1183-91; Harrell DT et al. Int. J. Cardiol., 2015 Apr;190:393-402; Sarquella-Brugada G et al. Heart Rhyth. Case Rpt, 2015 Jul;1:193-197). Functional studies demonstrated that this is a gain-of-function mutation resulting in slowed deactivation of the potassium channel (Hong K et al. Cardiovasc. Res., 2005 Dec;68:433-40; Restier L et al. J. Physiol. (Lond.), 2008 Sep;586:4179-91; Chan PJ et al. J. Gen. Physiol., 2012 Feb;139:135-44). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057674 SCV000089193 not provided Atrial fibrillation no assertion provided literature only This variant has been reported as associated with Atrial fibrillation in the following publications (PMID:16109388;PMID:18599533;PMID:22250012;PMID:17999538). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
OMIM RCV000417071 SCV000494620 pathogenic Short QT syndrome 2 2005-12-01 no assertion criteria provided literature only

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