ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.394C>T (p.Arg132Cys) (rs199472719)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046123 SCV000074136 pathogenic Long QT syndrome 2020-08-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 259 of the KCNQ1 protein (p.Arg259Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in numerous individuals of several ethnicities affected with long QT syndrome (LQTs) (PMID: 11021476, 22949429, 23158531, 21350584, 15234419, 12402336) including LQTS patients with early symptom onset (PMID: 23124029) and it has been reported as de novo in an LQTs patient that had no family history of disease (PMID: 21350584). ClinVar contains an entry for this variant (Variation ID: 53100). Experimental studies have shown that this missense change causes some disruption in function of the KCNQ1 sodium channel protein (PMID: 11021476). This variant identified in the KCNQ1 gene is located in the transmembrane spanning S4/S5 region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit It is unclear how this variant impacts the function of this protein. This missense change is located in a region of the KCNQ1 protein where a significant number of previously reported KCNQ1 missense mutations are found several mutations affecting residues 258 and 259 have been reported in individuals affected with LQTs (PMID: 23392653, 22708720, 16414944). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000223916 SCV000234415 pathogenic not provided 2020-12-23 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate a damaging effect as mammalian cells transfected with R259C resulted in functional channels with a significantly smaller current compared to wild-type channels (Kubota et al., 2000); This variant is associated with the following publications: (PMID: 22949429, 28992529, 27868350, 29439887, 31518351, 25525159, 11021476, 25559286, 12402336, 16922724, 23124029, 17470695, 19716085, 21350584, 28749187, 19841300, 23995044, 24190995, 12566525, 15840476, 15234419, 23158531, 22581653, 30591322, 31737537)
Ambry Genetics RCV000619999 SCV000737903 pathogenic Cardiovascular phenotype 2017-02-23 criteria provided, single submitter clinical testing The p.R259C pathogenic mutation (also known as c.775C>T), located in coding exon 5 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 775. The arginine at codon 259 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the S4-S5 linking region. This alteration has been previously reported in multiple long QT syndrome (LQTS) cohorts with varying levels of clinical detail, and, in one case, was reported as occurring de novo (Jongbloed R et al. Hum Mutat. 2002;20:382-91; Tester DJ et al. Heart Rhythm. 2005 May;2:507-17; Millat G et al. Clin Genet. 2006;70:214-27; Moss AJ et al. Circulation, 2007 May;115:2481-9; Hofman N et al. Neth Heart J. 2011;19:10-16; Crotti L et al. J Am Coll Cardiol. 2012;60:2515-24). In addition, this alteration was detected in a clinically "definite" LQTS case, and has also been reported in association with hypokalemia-induced LQTS and fetal arrhythmia (Kubota T et al. J Cardiovasc Electrophysiol. 2000;11:1048-54; Kapa S et al. Circulation. 2009;120:1752-60; Cuneo BF et al. Circ Arrhythm Electrophysiol. 2013;6:946-51). Furthermore, other alterations affecting this amino acid (p.R259H, c.776G>A and R259L, c.776G>T) have also been reported in association with LQTS (Millat G et al. Clin Genet. 2006;70:214-27​; Kapa S et al. Circulation. 2009;120(18):1752-60). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000678929 SCV000805138 pathogenic Long QT syndrome 1 2018-01-31 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057755 SCV000089274 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:11021476;PMID:12402336;PMID:12566525;PMID:15840476;PMID:16922724;PMID:19716085;PMID:19841300;PMID:15234419;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223916 SCV000280163 likely pathogenic not provided 2014-12-02 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Arg259Cys Based on the strong case data and the absence in general population samples, we consider this variant likely disease causing. This variant has been reported in at least 9 unrelated cases. There is no segregation data available. Kubota T et al (2000) first reported the variant in a 47 year old female with hypokalemia-induced long QT. She presented with Torsades de Pointes, QTc of 620msec and recurrent syncopal episodes. Three of her relatives were genotyped and all were negative for the variant (their QTC was 430ms, 380ms and 440ms). This is likely the same case later included in a genotype-phenotype study by the same group (Shimizu et al 2004). Jongbloed et al (2002) reported the variant in 1 out of 32 patients with long QT syndrome from Belgium and Holland. The same group reported this variant in another paper the following year on genotype-phenotype correlations (Van Langen et al 2003). Given the described recruitment these are likely the same patient. Tester et al (2005) also reported the variant in 1 out of 541 unrelated cases referred for long QT genetic testing at a research lab lead by Dr. Mike Ackerman. Individual phenotype was not reported, however the average QTc of the study population was 482 ms and 29% of the total cohort had a Schwarts score > 4. Millat et al (2006) observed p.Arg259Cys in a 9 year old female of either Spanish or French ancestry who presented with syncope triggered by exercise, her QTc was not measured. The variant was reported in 5 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). Kapa et al (2009) report p.Arg259Cys in 1 out of 388 unrelated “definite” (Schwarts score >4 and/or QTc >480ms) cases., however that case may overlap with Kapplinger et al (2009) and Tester et al (2005) as the sample came from the Mayo, Familion, and Dutch cohorts. Cueno et al (2013) reported two patients with this variant in a cohort of long QT cases presenting with fetal arrhythmia. Dr. Ackerman is a co-author on that paper, however the cases were recruited from centers in Chicago, Japan, and Salt Lake City so they likely do not overlap with Ackerman’s cohort (recruitment described in Mitchell et al 2012). However, the genetic analysis was done either at GeneDx or Familion, so these two cases may overlap with those published by Kapplinger et al (2009). Moss et al (2007) include one individual with this variant and long QT in a genotype-phenotype correlation study. That sample was drawn from the international registry, the Dutch registry, and the Japanese registry, so that case may overlap with Kutoba et al, Shimizu et al, Jongbloed et aland Van Langen e al. The variant was also included in a paper by Ackerman’s group on variant classification, which likely overlaps prior reports (Guidicessi et al 2012). This is a non-conservative amino acid change with a polar, hydrophilic Arginine replaced with a nonpolar hydrophobic Cysteine. The variant is located in the cytoplasmic loop (S4-S5) of the transmembrane KCNQ1 channel. PolyPhen predicts the amino acid change to be probably damaging. Additional missense variants at the same (p.Arg259Cys, p,Arg259Lys) and nearby codons (p.Val254Leu, p.Val254Met, p.His258Asn, p. His258Arg, p.His258Pro, p.Glu261Asp, p.Glu261Lys, p.Glu261Gln, p.Leu262Val, p.Thr265Ile) have been reported in association with Long QT Syndrome. This variant is listed in dbSNP (rs199472719) from a long QT locus specific database submission. There is no variation at codon 259 in the NHLBI ESP, which currently includes variant calls from ~6500 individuals (as of November 1st 2012). In total the variant has not been seen in 1500 published control samples. Kubota et al (2000) did not identify the variant in 50 presumably healthy controls of unspecified race. Jongbled et al (2002) and Van Langen et al (2003) each report the absence of the variant in 50 presumably healthy controls of unspecified race, since the two authors are from the same research group it is highly likely that the two control populations are the same. Millat et al (2006) did not find the variant in 100 presumably healthy controls. Kapplinger et al (2009) reported that the variant was not observed in 1,300 presumed healthy individuals (47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, and 6% unknown/other). Tester et al (2005) and Kapa et al (2009) did not observe the variant in 744 presumed healthy individuals. However, it seems likely that these controls are redundant with the ones reported by Kapplinger et al (2009) since both papers point to Ackerman et al (2003) for details on the reference samples. Ackerman et al (2003) notes that samples came from volunteer blood donors or the Human Genetic Cell Repository sponsored by the National Institute of General Medicine and the Coriell institute.
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000678929 SCV000863905 pathogenic Long QT syndrome 1 2018-06-18 no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000223916 SCV001919883 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000223916 SCV001955772 pathogenic not provided no assertion criteria provided clinical testing

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