ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.973C>T (p.Arg325Trp) (rs140452381)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000148551 SCV000073997 uncertain significance Long QT syndrome 2017-03-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 452 of the KCNQ1 protein (p.Arg452Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs140452381, ExAC 0.1%). This variant has been reported in the literature in one individual referred for long QT syndrome testing (PMID: 15840476). ClinVar contains an entry for this variant (Variation ID: 52980). This variant identified in the KCNQ1 gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 19841300, 25348405), but it is unclear how this variant impacts the function of this protein. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
CSER_CC_NCGL; University of Washington Medical Center RCV000148551 SCV000190264 uncertain significance Long QT syndrome 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx RCV000224680 SCV000234491 uncertain significance not provided 2018-07-03 criteria provided, single submitter clinical testing Although the R452W variant has previously been reported in one individual referred for LQTS testing (Tester et al., 2005), several publications which incorporated ESP data from 2013 and ACMG classification guidelines from 2008 have reported R452W as a variant of uncertain significance (Amendola et al., 2015; Campuzano et al., 2015; Dorschner et al., 2013). Furthermore, R452W is classified as a variant of uncertain significance by a research laboratory in ClinVar (ClinVar SCV000190264.2; Landrum et al., 2016). The R452W variant was observed at a low frequency (0.1-0.2%) in individuals of African background in the NHLBI Exome Sequencing Project, 1000 Genomes Project and the Exome Aggregation Consortium. Nevertheless, the R452W variant results in 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, and occurs at a position where only amino acids with similar properties to Arginine are tolerated across species. Consequently, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224680 SCV000281483 uncertain significance not provided 2016-04-08 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
Ambry Genetics RCV000621439 SCV000738164 uncertain significance Cardiovascular phenotype 2017-09-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000764974 SCV000896151 uncertain significance 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
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057582 SCV000089101 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:15840476;PMID:22378279). 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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