ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1379C>T (p.Thr460Met) (rs120074189)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046026 SCV000074039 pathogenic Long QT syndrome 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 587 of the KCNQ1 protein (p.Thr587Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (rs120074189, ExAC no frequency). This variant has been reported in many individuals affected with long QT syndrome and has been shown to segregate with the disease (PMID: 9799083, 11162126, 15234419, 20487114, 24217263). In addition, it has been seen in several individuals with Jervell-Lange Nielsen syndrome (PMID: 10024302, 18752142). ClinVar contains an entry for this variant (Variation ID: 3138). 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. Experimental studies have shown that this missense change causes the KCNQ1 protein to be unable to properly traffic to the cell membrane (PMID: 11162126, 19959132, 20348026). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000182221 SCV000234524 pathogenic not provided 2017-12-08 criteria provided, single submitter clinical testing The T587M variant has been published in many individuals of various ethnic backgrounds with LQTS, and the variant has segregated with disease in family studies (Itoh et al., 1998; Yamashita et al., 2001; Chen et al., 2003l; Shimizu et al., 2004; Giudicessi et al., 2009; Hedley et al., 2013). Furthermore, there have been at least two reports of compound heterozygous individuals, harboring the T587M variant and an additional KCNQ1 variant, with Jervell and Lange-Nielsen Syndrome. In testing parents, Neyroud et al. (1999) was able to conclude that the T587M variant was de novo on the paternal allele in an affected child, while the second KCNQ1 variant was maternally inherited. The T587M variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T587M 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. This substitution occurs at a position where only amino acids with similar properties to threonine are tolerated across species, which does not include methionine. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, in vivo functional analyses showed that, in the presence of the T587M variant, protein trafficking was adversely affected (Yamashita et al., 2001; Biliczki et al., 2009; Hayashi et al., 2010). More specifically, the KCNQ1-encoded potassium channel is unable to properly localize to the cell membrane and delayed rectifier current, both KCNQ1- and KCNH2-associated, are reduced, which the authors postulate may explain the more severe LQTS phenotypes reported in some individuals with this variant. Lastly, T587M is located in the coiled coil domain that mediates tetramerization, where other pathogenic or likely pathogenic missense variants in nearby residues (G589D, A590T, R591C, R591H) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014).
Ambry Genetics RCV000619349 SCV000737556 pathogenic Cardiovascular phenotype 2019-03-07 criteria provided, single submitter clinical testing Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes);Confirmed de novo alteration in trans with 2nd mutation in individual with classic disease.-added back on 9/8/14;Deficient protein function by in vitro/ex vivo assay;Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000046026 SCV000987672 pathogenic Long QT syndrome criteria provided, single submitter clinical testing
OMIM RCV000003286 SCV000023444 pathogenic Jervell and Lange-Nielsen syndrome 1 1999-02-19 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057632 SCV000089151 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:9799083;PMID:10024302;PMID:11162126;PMID:12702160;PMID:15840476;PMID:17329209;PMID:18752142;PMID:19716085;PMID:19841300;PMID:19959132;PMID:15234419;PMID:17329207;PMID:9386136;PMID:20348026). 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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