ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1319T>C (p.Ile440Thr) (rs199472805)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046016 SCV000074029 pathogenic Long QT syndrome 2018-05-04 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 567 of the KCNQ1 protein (p.Ile567Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with long QT syndrome (LQTs) and referred for LQTs testing  (PMID: 16414944, 23130128, 22429796, 19716085). Furthermore, this variant has been reported in the homozygous state in individuals affected with Jervell and Lange-Nielsen syndrome (JLNS) (PMID: 24372464).  ClinVar contains an entry for this variant (Variation ID: 53007). This variant identified in the KCNQ1 gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNQ1-topology. Two different missense substitution at this codon (p.Ile567Phe and Ile567Ser) are reported to be deleterious (PMID: 17470695, 22456477). This indicates that the isoleucine residue is important for KCNQ1 protein function. In summary, this variant is a rare missense change that has been reported in individuals affected with LQTs and in homozygous individuals affected with JLNS, and it affects an amino acid residue important for adequate protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000182217 SCV000234520 pathogenic not provided 2016-08-15 criteria provided, single submitter clinical testing The I567T pathogenic variant in the KCNQ1 gene has been reported multiple times in individuals with Long QT syndrome (LQTS) (Napolitano et al., 2005; Kapplinger et al., 2009; Obeyesekere et al., 2012; Couderc et al., 2012). Additionally, Al-Ama et al. (2015) reported two unrelated Saudi Arabian probands with Jervell and Lange-Nielsen syndrome (JLNS) who were homozygous for the I567T variant. The I567T variant has been classified as a pathogenic variant by another clinical laboratory in ClinVar (SCV000074029.3; Landrum et al., 2016). Furthermore, missense variants in this same residue (I567S, I567F) and in nearby residues (S566F, S566P, S566Y, G568A, G568R, K569E) have been reported in HGMD in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this region of the protein.The I567T 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. The I567T 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. Finally, this substitution occurs at a position where only amino acids with similar properties to Isoleucine are tolerated across species.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000046016 SCV000987403 likely pathogenic Long QT syndrome criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057620 SCV000089139 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:16414944;PMID:19716085;PMID:22429796). 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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