ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182127 SCV000234430 uncertain significance not provided 2021-07-26 criteria provided, single submitter clinical testing Reported in association with LQTS (Choi et al., 2004; Tester et al., 2005; Bdier et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22581653, 28438721, 29197658, 31737537, 28944242, 27884173, 25637381, 25985138, 26077850, 19716085, 15840476, 15466642)
Ambry Genetics RCV000621242 SCV000735774 uncertain significance Cardiovascular phenotype 2018-07-13 criteria provided, single submitter clinical testing The p.R293C variant (also known as c.877C>T), located in coding exon 6 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 877. The arginine at codon 293 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was detected in conjunction with a mutation in KCNQ1 (p.G269D) in a child who had experienced a swimming-triggered cardiac event (Choi G et al. Circulation. 2004;110:2119-24). In a study of long QT syndrome clinical genetic testing, this alteration was reported in four patients; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). This alteration has also been observed in cis with KCNQ1 p.V172M in the homozygous state in several Saudi individuals with LQTS but not the autosomal recessive Jervell and Lange-Nielson Syndrome (Al-Hassnan ZN et al. Heart Rhythm. 2017;14:1191-1199; Bdier AY et al. Mol Genet Genomic Med. 2017;5:592-601). In another Saudi family, this variant was detected in conjunction with both the KCNQ1 mutation c.1032G>A and the aforementioned KCNQ1 alteration p.V172M in several family members with LQTS; however, other family members with LQTS were heterozygous for only c.1032G>A (Al-Hassnan ZN et al. Heart Rhythm. 2017;14:1191-1199). This variant has also been seen in exome and genome cohorts, but cardiovascular history was not provided (Amendola LM et al. Genome Res. 2015;25:305-15; Taylor JC et al. Nat Genet. 2015;47:717-26; Yavarna T et al. Hum Genet. 2015;134:967-80). Based on data from the Saudi Human Genome project, the T variant has a frequency of approximately 0.5% (41/4145, frequency calculation adjusted for consanguinity) of Saudi alleles and was detected in one homozygote without a disease phenotype (Abouelhoda M et al. Genome Biol. 2016;17:235). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear.
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 2019-02-13 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.
Color Health, Inc RCV001177679 SCV001341932 uncertain significance Arrhythmia 2020-12-02 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 293 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sudden death (PMID: 15466642). This variant has also been reported in multiple individuals affected with long QT syndrome in Saudi Arabia and Iran, all of whom carried p.Val172Met in cis (PMID: 28438721, 28944242, 29033053, 30919684). In Clinvar, internal data from a clinical laboratory indicate that p.Val172Met (most likely in cis with p.Arg273Cys) is present in the Arab population at a frequency greater than expected for long QT syndrome, suggesting that this allele may be a benign variant in that population (RCV000414067.1). This variant has also been identified in 10/276558 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity this variant conclusively.
Baylor Genetics RCV001331076 SCV001523000 uncertain significance Atrial fibrillation, familial, 3 2019-09-06 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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 RCV000148555 SCV000190268 uncertain significance Long QT syndrome 2014-06-01 no assertion criteria provided research
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000678913 SCV001469209 uncertain significance Long QT syndrome 1 2020-09-10 no assertion criteria provided clinical testing

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