ClinVar Miner

Submissions for variant NM_000218.3(KCNQ1):c.1664G>A (p.Arg555His)

gnomAD frequency: 0.00001  dbSNP: rs199472800
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046012 SCV000074025 pathogenic Long QT syndrome 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 555 of the KCNQ1 protein (p.Arg555His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with long QT syndrome (PMID: 14998624, 22949429, 23098067, 23130128). ClinVar contains an entry for this variant (Variation ID: 53003). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 25037568, 25344363). This variant disrupts the p.Arg555 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9386136, 19934648). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000182212 SCV000234515 pathogenic not provided 2022-10-21 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect as this variant results in abnormal potassium channel function (Dvir et al., 2014; Aromolaran et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); 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: 19716085, 23098067, 23130128, 26745405, 25705178, 22581653, 34505893, 34697415, 25037568, 19841300, 15840476, 14998624, 22949429, 27761162, 26412604, 9386136, 30609406, 32048431, 32383558, 31006312, 33087929, 25344363)
Ambry Genetics RCV000619418 SCV000736460 likely pathogenic Cardiovascular phenotype 2023-12-21 criteria provided, single submitter clinical testing The p.R555H variant (also known as c.1664G>A), located in coding exon 13 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1664. The arginine at codon 555 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in individuals reported to have long QT syndrome (LQTS), and in several LQTS testing cohorts, although clinical details were limited (Lupoglazoff JM et al. J. Am. Coll. Cardiol., 2004 Mar;43:826-30; Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Giudicessi JR et al. Circ Cardiovasc Genet, 2012 Oct;5:519-28; Stattin EL et al. BMC Cardiovasc Disord, 2012 Oct;12:95). Functional studies by different investigators have demonstrated reduced current, slower activation, and faster deactivation with this alteration, while conclusions about possible trafficking defects were conflicting (Dvir M et al. J. Cell. Sci., 2014 Sep;127:3943-55; Aromolaran AS et al. Cardiovasc. Res., 2014 Dec;104:501-11). Based on internal structural analysis, this variant is predicted to be structurally disruptive (Long SB et al. Nature. 2007 Nov;450(7168):376-82; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center RCV000182212 SCV001755310 pathogenic not provided 2021-07-10 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002483049 SCV002783361 pathogenic Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2 2021-10-16 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000182212 SCV003916687 pathogenic not provided 2023-01-01 criteria provided, single submitter clinical testing KCNQ1: PM1, PM2, PM5, PS4:Moderate, PP3, PP4, PS3:Supporting
Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes RCV003319308 SCV004024163 pathogenic Long QT syndrome 1 2023-08-01 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV003591637 SCV004358434 likely pathogenic Cardiac arrhythmia 2023-10-30 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 555 of the KCNQ1 protein. This variant is found within a highly conserved region of the C-terminal cytoplasmic domain of the KCNQ1 protein (a.a. 509-575). Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Functional studies have shown that this variant impairs potassium channel function without disrupting protein trafficking to the cell surface (PMID: 25037568, 25344363). This variant has been reported in over ten individuals affected with long QT syndrome (PMID: 14998624, 19841300, 22949429, 23130128, 32383558, 34505893, 36102233, 37457655, ClinVar SCV000234515.13) and in another few individuals suspected of having long QT syndrome (PMID: 15840476, 19716085, 23098067, 26412604). This variant has been identified in 4/176120 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg555Cys, is known to be pathogenic (ClinVar variation ID 3126), indicating that arginine at this position is important for KCNQ1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000046012 SCV004803441 pathogenic Long QT syndrome 2024-01-16 criteria provided, single submitter clinical testing Variant summary: KCNQ1 c.1664G>A (p.Arg555His) results in a non-conservative amino acid change located in the Potassium channel, voltage dependent, KCNQ, C-terminal domain (IPR013821) of the encoded protein sequence. This alters a highly conserved residue (HGMD) in which another missense variant (p.Arg555Cys) is classified as pathogenic. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 176120 control chromosomes (gnomAD). c.1664G>A has been reported in the literature in multiple individuals affected with Long QT Syndrome (e.g. Lupoglazoff_2004, Giudicessi_2012, Yee_2022). These data indicate that the variant is very likely to be associated with disease. Publications report experimental evidence evaluating an impact on protein function, finding that the variant disrupts channel current (Ademuyiwa_2014, Dvir_2014). The following publications have been ascertained in the context of this evaluation (PMID: 14998624, 22949429, 25344363, 25037568, 36102233). ClinVar contains an entry for this variant (Variation ID: 53003). Based on the evidence outlined above, the variant was classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000046012 SCV005045720 likely pathogenic Long QT syndrome 2024-01-15 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust RCV000057614 SCV000089133 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:14998624;PMID:15840476;PMID:19716085;PMID:19841300;PMID:15214551). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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