ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.563A>G (p.Tyr188Cys) (rs74462309)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182138 SCV000234441 pathogenic not provided 2018-11-29 criteria provided, single submitter clinical testing The Y315C pathogenic variant has been reported multiple times in association with LQTS (Splawski et al., 1998; Priori et al., 1999; Chen et al., 2003; Nemec et al., 2003; Zareba et al., 2003; Choi et al., 2004; Tester et al., 2005; Yasuda et al., 2008; Jons et al., 2009; Kapplinger et al., 2009; Couderc et al., 2012; Stattin et al., 2012; Fukuyama et al., 2013; Hedley et al., 2013; Christiansen et al., 2014). This variant has also been observed in multiple other unrelated individuals referred for arrhythmia genetic testing at GeneDx, and segregates with disease in many affected individuals from several families.The Y315C variant is not observed in large population cohorts (Lek et al., 2016). The Y315C 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. The Y315 residue is located in the canonical GYGD motif of the selectivity filter in the pore region of the potassium ion channel. Functional studies by Bianchi et al. (2000) demonstrated that Y315C results in reduced potassium channel current in vitro. Furthermore, other pathogenic missense variants in the same residue (Y315H, Y315S) and in nearby residues (V310I, T312I, G314S, D317N, P320S) have been classified as pathogenic/likely pathogenic at GeneDx and reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this residue and this region of the protein.
Ambry Genetics RCV000619103 SCV000737748 pathogenic Cardiovascular phenotype 2019-03-12 criteria provided, single submitter clinical testing The p.Y315C pathogenic mutation (also known as c.944A>G), located in coding exon 7 of the KCNQ1 gene, results from an A to G substitution at nucleotide position 944. The tyrosine at codon 315 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration impacts the highly conserved ion selectivity filter (TIGYGD) located between transmembrane helices S5 and S6. This alteration has been seen in multiple unrelated individuals reported to have confirmed or suspected long QT syndrome, with variable expressivity in some cases (LQTS) (Splawski I et al. Genomics. 1998;51(1):86-97; Chen S et al. Clin Genet. 2003;63(4):273-82; Moss AJ et al. Circulation. 2007; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; 115(19):2481-9; Itoh H et al. Heart Rhythm. 2010;7(10):1411-8; Bartos DC et al. Heart Rhythm. 2014;11(3):459-68). One study reported this alteration to result in a dominant negative effect on wild-type IKs current when expressed with wild-type channel in vitro (Bianchi L et al. Am J Physiol Heart Circ Physiol. 2000;279(6):H3003-11). Internal structural analysis indicates that this variant disrupts the ion channel pore and is expected to eliminate the K+ selectivity of the K+ channel (Tao X et al. Science. 2009;326(5960):1668-74; Whorton MR and MacKinnon R. Cell. 2011;147(1):199-208; Ambry internal data). In addition, another alteration affecting this codon (p.Y315S, c.944A>C) has also been associated with LQTS (Jongbloed RJ et al. Hum Mutat. 1999;13(4):301-10). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000709732 SCV000839970 likely pathogenic Long QT syndrome 1 2017-11-03 criteria provided, single submitter clinical testing The c.944A>G (p.Tyr315Cys) variant in the KCNQ1 gene has been observed in multiple individuals with long QT syndrome (PMID: 9693036, 10868744, 12702160, 15840476, 14760488, 15466642). In addition, experimental studies have shown that this missense change leads to altered KCNQ1 protein function (PMID: 11087258). The c.944A>G (p.Tyr315Cys) variant in the KCNQ1 gene is classified as likely pathogenic.
Invitae RCV000678812 SCV001588720 pathogenic Long QT syndrome 2020-08-14 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 315 of the KCNQ1 protein (p.Tyr315Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with long QT syndrome (PMID: 24217263, 12702160, 18774102, 21451124, 9693036, 24606995). ClinVar contains an entry for this variant (Variation ID: 53140). This variant has been reported to affect KCNQ1 protein function (PMID: 11087258, 21451124). For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057816 SCV000089336 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:9693036;PMID:10868744;PMID:12702160;PMID:12877697;PMID:14678125;PMID:14760488;PMID:15466642;PMID:15840476;PMID:19716085;PMID:9927399;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 RCV000182138 SCV000280167 pathogenic not provided 2016-03-02 no assertion criteria provided provider interpretation p.Tyr315Cys (c.944A>G, p.Y315C) in the KCNQ1 gene The variant was re-reviewed March 2nd, 2016. There was both new case data and new allele frequency data, both of which further support pathogenicity and shift our classification from likely pathogenic to pathogenic. The variant has been seen in at least 13 unrelated cases of long QT syndrome (not including this patient). We seen this variant in one other family with long QT in our center. Splawski et al (1998) reported this variant in a patient with long QT syndrome, presumably from their American cohort (ancestry not noted). Priori et al (1999) reported the variant in a patient from their Italian cohort with long QT syndrome. Chen et al (2003) observed the variant in two siblings with long QT syndrome (cohort studied at Cleveland clinic, recruited from clinics in North America, South America, Europe; ancestry not provided). Choi et al (2004) reported the variant in an "LQT1 index case" (no other phenotypic data provided) who had a cousin with exertional syncope and a near-drowning event (cohort studied in Dr. Ackerman's lab at Mayo; ancestry not provided). This case likely overlaps with Nemec et al (2003) and Tester et al (2005), also from Dr. Ackerman's group. The variant was observed in 4 patients included in the Familion compendium publication with no phenotype or ancestry data (Kapplinger et al 2009). This publication reports on variants observed in patients referred for long QT syndrome genetic testing using the Familion test at PGxHealth (now Transgenomics). Napolitano et al (2000) reported the variant in a woman with QT-prolongation and arrest in the setting of a QT-prolonging medication (cisapride) (ancestry not noted but patient likely from Italy). Patients with this variant are included in two papers on genotype-phenotype correlations (Zareba et al 2003, Moss et al 2007). The subjects were drawn from the various long QT registries and many of the authors overlap with the other publications reviewed here, so at least some of the cases are likely redundant with those summarized above. Stattin et al (2012) studied 200 unrelated index cases of LQTS referred for care in Sweden between 3/2006 and 10/2009. KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A were analyzed. The variant of interest was found in a single proband; no segregation data is reported. Hedley et al (2013) studied 44 South African congenital LQTS patients, screening them for variants in the coding regions of KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A. The variant of interest was found in one patient (no segregation data reported). Christiansen et al (2014) assessed 70 unrelated Danish LQTS probands by variant screening of KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A. The variant of interest was found in a single proband; no segregation data is reported. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Grantham score is 5.29. The tyrosine at codon 315 is completely conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Tyr315Ser, p.Tyr315Phe) and nearby codons (p.Ile313Met, p.Gly314Asp, p.Gly314Ala, p.Gly314Ser, p.Gly314Cys, p.Gly314Arg, p.Gly314Val, p.GLy316Glu, p.GLy316Arg). Functional studies have shown a decrease in potassium current (Bianchi et al 2000). The variant is in the pore region of the channel. Variants in this region are much more likely to be pathogenic than benign. There is also some evidence that they confer a higher risk of events (Moss et al 2007), though other studies have not found such a difference (Zareba et al 2003). Barsheshet et al (2012) found that carriers of missense variants in the cytoplasmic loops had the highest risk of events as well as the greatest response to beta-blockade. The patient's variant is not in the cytoplasmic loop. Moss et al (2007) reported a higher risk with dominant negative variants and classify this variant as dominant negative. In total the variant has not been seen in ~65,000 published controls and individuals from publicly available population datasets. The variant was not observed in the following laboratory and published control samples: Splawski et al (1998) did not observe the variant in 200 controls (ancestry not reported), Kapplinger et al (2009) did not observe the variant in 1300 control individuals of varying ancestries. The variant is not listed in the Exome Aggregation Consortium dataset (, which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 3/1/16). However, another variation at codon 315 is listed (p.Tyr315Tyr; 11:2604688T/C), having been observed in 1 (east Asian) out of 121060 total alleles.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678812 SCV000804998 likely pathogenic Long QT syndrome 2017-01-18 no assertion criteria provided clinical testing

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