ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.496C>T (p.Arg166Cys) (rs199472737)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182127 SCV000234430 uncertain significance not provided 2018-09-24 criteria provided, single submitter clinical testing The R293C variant of uncertain significance in the KCNQ1 gene has been previously published in association with LQTS (Choi et al., 2004; Tester et al., 2005; Kapplinger et al., 2009; Bdier et al., 2017); however, clinical and segregation data for the majority of these probands were not provided. One proband had an episode at age four while swimming, and also harbored another missense variant (G269D) in the KCNQ1 gene (Choi et al., 2004). Another proband reported to have autosomal recessive LQTS was homozygous for R293C and another KCNQ1 variant (V172M) (Bdier et al., 2017); parents heterozygous for both variants (in cis) were reported to be unaffected (Bdier et al., 2017). The R293C variant has been identified in multiple individuals referred for LQTS genetic testing at GeneDx, several with a second variant in the KCNQ1 gene (both in cis and in trans). Segregation data for the probands tested at GeneDx have been uninformative thus far. The R293C variant is also observed in 0.02% (5/30,772) of alleles from individuals of South Asian background in large population cohorts (Lek et al., 2016). The R293C 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. In-silico analyses, including protein predictors and evolutionary conservation, also support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000621242 SCV000735774 uncertain significance Cardiovascular phenotype 2017-02-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000678913 SCV000805117 likely pathogenic Long QT syndrome 1 2017-11-14 criteria provided, single submitter clinical testing
Invitae RCV000148555 SCV000817918 uncertain significance Long QT syndrome 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 293 of the KCNQ1 protein (p.Arg293Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs199472737, ExAC 0.01%). This variant has been reported in an individual with suspected long QT syndrome (PMID: 15466642). ClinVar contains an entry for this variant (Variation ID: 67117). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057785 SCV000089304 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:15466642;PMID:15840476;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER_CC_NCGL; University of Washington Medical Center RCV000148555 SCV000190268 uncertain significance Long QT syndrome 2014-06-01 no assertion criteria provided research

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