ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.188G>T (p.Arg63Leu) (rs120074178)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182299 SCV000234602 pathogenic not provided 2017-11-07 criteria provided, single submitter clinical testing The R190L pathogenic variant in the KCNQ1 gene has been reported multiple times in association with LQTS (Kapplinger et al., 2009; Kanovsky et al., 2010; Andrsova et al., 2012; Crehalet et al., 2012; Wang et al., 2015). Kanovsky et al. (2010) identified the R190L variant on both KCNQ1 alleles in two siblings with severe LQTS, one of whom had sub-clinical, bilateral hearing impairment that the authors termed incomplete" Jervell Lange-Nielsen syndrome. In the same study, the heterozygous parents of these two siblings had normal QT intervals at rest, but each parent had QT prolongation during stress testing (Kanovsky et al., 2010). R190L has been reported in combination with a KCNQ1 splice variant in a young male patient with LQTS (Crehalet et al., 2012). Additionally, Wang et al. (2015) identified R190L in conjunction with variants in the MYH7, MYLK2, and TMEM70 genes among four individuals in a Chinese family with overlapping phenotypes of LQTS and hypertrophic cardiomyopathy. R190L 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) data set.The R190L 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. Moreover, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies conducted by Eckey et al. (2014) demonstrated that R190L impairs phosphatidylinositol 4,5-bisphosphate (PIP2) regulation of ion channels, presumptively leading to ion channel dysfunction and LQTS phenotype. Finally, missense pathogenic variants in nearby residues, as well as in the same residue (G186S, R190W, R190Q) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this region of the protein."
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000678947 SCV000805161 pathogenic Long QT syndrome 1 2018-04-04 criteria provided, single submitter clinical testing
Invitae RCV000698459 SCV000827124 likely pathogenic Long QT syndrome 2019-09-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 190 of the KCNQ1 protein (p.Arg190Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs120074178, ExAC 0.002%). This variant has been reported to segregate with Jervell and Lange-Nielsen syndrome in a family (PMID: 20138589). Additionally, this variant has been reported in individuals referred for long QT genetic testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67084). Experimental studies have shown that this missense change impairs PIP2 regulation of the KCNQ1 channel (PMID: 24947509). A different missense substitution at this codon (p.Arg190Gln) has been determined to be pathogenic (PMID: 8528244, 10728423, 20660394, 17470695, 10376919, 10728423). This suggests that the arginine residue is critical for KCNQ1 protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color RCV001185985 SCV001352305 likely pathogenic Arrhythmia 2019-07-02 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057707 SCV000089226 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:19716085;PMID:20138589). 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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