ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.808C>T (p.Arg270Trp) (rs199472776)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182181 SCV000234484 uncertain significance not provided 2018-11-20 criteria provided, single submitter clinical testing The R397W variant of uncertain significance in the KCNQ1 gene has been reported multiple times in association with LQTS or sudden death and in individuals referred for LQTS genetic testing (Moss et al., 2007; Kapa et al., 2009; Kapplinger et al., 2009; Crotti et al., 2013; Bagnall et al., 2014); however, the majority of these publications did not provide specific clinical details, familial segregation data, or information concerning whether the tested individual(s) harbored other genetic variants. This variant has also been reported in asymptomatic individuals (Taylor et al., 2015; Ghouse et al., 2015). The R397W variant has been identified independently and/or in conjunction with additional cardiogenetic variants in several individuals referred for arrhythmia genetic testing at GeneDx. While segregation data is overall limited, the R397W variant was absent in an affected relative in at least one family. In addition, the R397W variant was observed in 39/126,676 (0.03%) alleles from individuals of European (Non-Finnish) ancestry, and in 8/10,152 (0.08%) alleles from individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek et al., 2016). The R397W 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. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, functional studies demonstrated R397W, located in a highly conserved residue in the C-terminus region of the voltage gated potassium channel (Kv7.1), resulted in a reduction in the potassium ionic current and reduced ATP sensitivity, suggesting this residue is part of the ATP binding site (Crotti et al., 2013; Li et al., 2013).
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000203070 SCV000257644 likely pathogenic Long QT syndrome 1 2015-03-25 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000148545 SCV000370280 likely pathogenic Long QT syndrome 2016-06-14 criteria provided, single submitter clinical testing The c.1189C>T (p.Arg397Trp) variant has been identified in a heterozygous state in at least seven patients with clinically-diagnosed long QT syndrome, in a heterozygous state in three individuals with an unclear clinical diagnosis, and in a heterozygous state in two unaffected individuals (Moss et al. 2007; Kapa et al. 2009; Kapplinger et al. 2009; Amin et al. 2012; Ghouse et al. 2015). The p.Arg397Trp variant was absent from 2300 controls but is reported at a frequency of 0.00058 in the European American population of the Exome Sequencing Project. Functional studies of electrophysiological properties in HEK293 cells and Xenopus oocytes demonstrated that the p.Arg397Trp variant reduced the hIK currents and ATP sensitivity of the channel (Crotti et al. 2013; Li et al. 2013). Based on the evidence, the p.Arg397Trp variant is classified as likely pathogenic for long QT syndrome.
Illumina Clinical Services Laboratory,Illumina RCV000265217 SCV000370281 uncertain significance Jervell and Lange-Nielsen syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000299301 SCV000370282 benign short QT syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000356516 SCV000370283 uncertain significance Familial atrial fibrillation 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000259588 SCV000370284 uncertain significance Romano-Ward syndrome 2016-06-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000619428 SCV000735521 uncertain significance Cardiovascular phenotype 2016-09-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000203070 SCV000883083 likely pathogenic Long QT syndrome 1 2018-11-21 criteria provided, single submitter clinical testing
Color RCV000777876 SCV000913883 uncertain significance Arrhythmia 2018-10-09 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the C-terminal cytoplasmic domain of the KCNQ1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental functional studies have shown that this variant may result in reduced potassium ionic current (PMID: 23571586) and reduced ATP sensitivity (PMID: 24190995), although clinical significance of these findings is not clear. This variant has been reported in individuals with a family history of LQTS (PMID:17470695), in individuals referred for LQTS genetic testing (PMID:19716085), and in individuals with sudden death (PMID:23571586, 24440382). This variant has also been identified in individuals showing normal QTc intervals (PMID: 26159999). This variant occurs at an appreciable frequency in the general population and has also been identified in 51/277162 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825350 SCV000966645 uncertain significance not specified 2019-01-29 criteria provided, single submitter clinical testing The p.Arg397Trp variant in KCNQ1 has been reported in 9 individuals with LQTS (M oss 2007, Kapplinger 2009, Giudicessi 2012, Amin 2012). However, it has also bee n detected in asymptomatic individuals (Ghouse 2015, Taylor 2015) and in 0.03% ( 39/129098) of European chromosomes and 0.09% (9/10364) of Ashkenazi Jewish chrom osomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been repor ted in ClinVar (Variation ID 52970). In vitro functional studies provide some ev idence that the p.Arg397Trp variant may impact protein function (Li 2013); howev er, these types of assays may not accurately represent biological function. Comp utational prediction tools and conservation analysis support an impact to the pr otein, though this information is not predictive enough to determine pathogenici ty. In summary, due to the presence of conflicting evidence, the clinical signif icance of the p.Arg397Trp variant is uncertain. ACMG/AMP Criteria applied: BS1_S upporting, PP3.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057571 SCV000089090 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:17470695;PMID:19716085;PMID:19841300). 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 RCV000148545 SCV000190258 likely benign Long QT syndrome 2014-06-01 no assertion criteria provided research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000656189 SCV000678383 likely pathogenic Wolff-Parkinson-White pattern 2017-07-14 no assertion criteria provided research This variant was identified in an individual with Wolff-Parkinson-White syndrome

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