ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000148551 SCV000073997 likely benign Long QT syndrome 2020-10-25 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington 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 2018-12-19 criteria provided, single submitter clinical testing The p.R452W variant (also known as c.1354C>T), located in coding exon 10 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1354. The arginine at codon 452 is replaced by tryptophan, an amino acid with dissimilar properties, and is located in the C-terminal region of the protein. This variant was detected in a long QT syndrome genetic testing cohort, and in a sudden death cohort; however, clinical details were limited (Tester DJ et al. Heart Rhythm. 2005; 2(5):507-17; Lahrouchi N et al. J Am Coll Cardiol. 2017;69(17):2134-2145). This alteration has also been seen in exome cohorts, but cardiovascular history was not provided (Refsgaard L et al. Eur J Hum Genet. 2012; 20(8):905-8; Dorschner MO et al. Am J Hum Genet. 2013;93(4):631-40; Amendola LM et al. Genome Res. 2015;25(3):305-15; Campuzano O et al. Sci Rep. 2015; 5:7953). Based on data from gnomAD, the T allele has an overall frequency of approximately 0.01% (25/275928) total alleles studied. The highest observed frequency was 0.1% (24/23880) of African alleles. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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
Color Health, Inc RCV001179579 SCV001344273 uncertain significance Arrhythmia 2019-09-10 criteria provided, single submitter clinical testing
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV001248784 SCV001422294 uncertain significance Long QT syndrome 1 2020-02-18 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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