ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1234C>T (p.Arg412Trp) (rs199472795)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046006 SCV000074019 pathogenic Long QT syndrome 2020-03-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 539 of the KCNQ1 protein (p.Arg539Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. While this variant is not present in population databases (ExAC), the frequency information is unreliable due to low sequence quality at this site. This variant has been reported to segregate with long QT syndrome in a single family (PMID: 10728423), and has been reported in multiple unrelated individuals with long QT syndrome (PMID: 14678125, 15840476, 23098067, 23631430). ClinVar contains an entry for this variant (Variation ID: 52998). Experimental studies have shown that this missense change has a deleterious effect on protein channel activity and function (PMID: 10728423, 15746441, 16556866, 21576493, 23251633, 24681627, 25559286). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000762836 SCV000893195 pathogenic Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome 2 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000046006 SCV000919559 pathogenic Long QT syndrome 2017-11-13 criteria provided, single submitter clinical testing Variant summary: The KCNQ1 c.1615C>T (p.Arg539Trp) variant located in the C-terminal domain involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. Multiple functional studies, Chouabe_2000 and Yamashita_2001, indicate the variant has a dominant-negative effect. This variant was found in 1/30938 control chromosomes (gnomAD) at a frequency of 0.0000323, which does not exceed the estimated maximal expected allele frequency of a pathogenic KCNQ1 variant (0.0000833). Multiple publications have cited the variant in individuals diagnosed with LQTS including one family, which the variant segregate with diseases including two affected family members dying suddenly at 16 and 18 years old (Chouabe_200). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000046006 SCV000987564 pathogenic Long QT syndrome criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000223851 SCV001248103 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV001248800 SCV001422312 pathogenic Long QT syndrome 1 2019-11-08 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057604 SCV000089123 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:9312006;PMID:14678125;PMID:15466642;PMID:15840476;PMID:18174212;PMID:19716085;PMID:19841300;PMID:10728423;PMID:15746441). 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 RCV000223851 SCV000280148 pathogenic not provided 2014-09-23 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.Arg539Trp Based on the information reviewed below, we classify it as very likely disease causing. This variant has previously been reported in at least 8 unrelated individuals with LQTS (Chouabe et al 2000, Zareba et al 2003, Choi et al 2004, Tester et al 2005, Kapplinger et al 2009, Kapa et al 2009). There is strong published segregation data in one family. There is in vitro functional data showing loss of potassium channel function. Chouabe and colleagues (2000) report the variant in a family with LQTS in which a 16 year old girl had died suddenly while riding her bicycle. Her father had a prolonged QTc of 489 msec. She had a sister who syncopized once under physical stress. This sister had one child who died suddenly at 16 years old while swimming and two sons who syncopized when they were 10. All of these family members were genotype positive (segregation in at least 5 family members-the girl who died bicycling was not herself genotyped). Zareba and colleagues (2003) report the variant in 2 individuals from the International LQTS Registry. That registry contained 294 subjects from 55 LQT1 families with pathogenic variants in KCNQ1. It is not clear if these two individuals are from the same family. No segregation data is presented. To be in the registry, subjects had to have a clinical diagnosis of LQTS. Additional phenotypic information is not presented. It’s unclear if these individuals are represented in other published studies. Kapa and colleagues (2009) of the Mayo Clinic reported the variant in 6 individuals in their cohort of 388 unrelated patients with LQTS genotyped by the Sudden Death Genomics Laboratory. No segregation data is presented. LQTS is defined by QTc > 480 msec or a Schwartz score greater than or equal to 4. Participants were assessed for variants in KCNQ1, KCNH2, and SCN5A. Mayo Clinic had published their data in other reports prior to this including Choi et al 2004, Tester et al 2005, Kapplinger et al 2009, and the individuals reported in Kapa et al likely include all previously reported individuals from this group. The LQTS patient reported in Choi et al (2004) had a first-degree family member with a swimming-triggered cardiac event. This residue is not conserved across paralogs (http://cardiodb.org/Paralogue_Annotation/gene.php?name=KCNQ1). However, residue 539 is in the cytoplasmic domain of the protein, in which missense variants are 22x more frequent in LQTS cases than in controls (Kapa et al. 2009). This is a nonconservative amino acid change, resulting in the replacement of a positively-charged Arginine with a nonpolar Tryptophan. Arginine at this location is highly conserved across mammalian species. The adjacent residues are also highly conserved. Another variant at this same codon, p.Arg539Gln, has also been reported in association with LQTS. Variation at nearby residues has been associated with LQTS, which may support the functional importance of this region of the protein: Arg533Trp, Val541Ile, Glu543Lys, Ser546Leu, Gln547Arg, Gly548Asp (HGMD professional version as of January 17, 2014). In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Probably Damaging” with a score of 1.0. SIFT predicts the variant is damaging with a score of 0.001. Mutation Taster predicts the variant is disease causing with a probability >0.9999. Functional studies show that this variant causes a positive voltage shift of channel activation (Chouabe et al 2000) and weaker stabilization of the open state of the potassium channel, decreasing the maximal current (Peroz et al 2008). The mutant channels reportedly have reduced affinity for phosphatidylinositol-4,5-biphosphate (PIP2), a molecule on the cytoplasmic side of the cell membrane that regulates channel activity by stabilizing the open state (Park et al 2005, Peroz et al 2008). In total the variant has not been seen in > 60,000 published controls and individuals from publicly available population datasets. The variant was not observed by Kapa et al in over 1300 presumably healthy controls, whom they list as 372 Black, 559 White, 172 Asian, 155 Hispanic, and 86 Unknown/Other. Chouabe et al 2000 did not report controls. There is no variation at this residue listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/) as of 7/16/2015, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is also no variation at this residue listed in 1000 Genomes (http://browser.1000genomes.org/index.htm). Variation at this codon has not been seen in the ExAC dataset, which currently includes variant calls on ~60,000 individuals of multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian). These individuals took part in a range of disease-specific and population genetic studies, and the curators made an effort to exclude individuals with severe pediatric diseases.

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