Submissions for variant NM_000218.3(KCNQ1):c.1354C>T (p.Arg452Trp)

gnomAD frequency: 0.00016  dbSNP: rs140452381

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000148551	SCV000073997	likely benign	Long QT syndrome	2023-12-11	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	2024-04-02	criteria provided, single submitter	clinical testing	Reported in association with LQTS and death during sleep (PMID: 28449774, 15840476); 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: 24055113, 22378279, 25637381, 25608792, 15840476, 29197658, 22581653, 28449774)
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	benign	Cardiovascular phenotype	2023-05-22	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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 type 2	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001841631	SCV001344273	uncertain significance	Cardiac arrhythmia	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 452 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected to be affected with long QT syndrome (PMID: 15840476) and in an individual affected with sudden unexplained death (PMID: 28449774). It has also been reported in two healthy control individuals (PMID: 22378279). This variant has been identified in 25/281126 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224680	SCV004565164	uncertain significance	not provided	2022-12-21	criteria provided, single submitter	clinical testing	The KCNQ1 c.1354C>T; p.Arg452Trp variant (rs140452381) is reported in the literature in an individual affected with long QT syndrome (Tester 2005) and an individual with sudden arrhythmic death syndrome (Lahrouchi 2017), but without clear association with disease. This variant is also reported in ClinVar (Variation ID: 52980), and is found in the African/African-American population with an allele frequency of 0.0097% (24/24776 alleles) in the Genome Aggregation Database. The arginine at codon 452 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.626). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Lahrouchi N et al. Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome. J Am Coll Cardiol. 2017 May 2;69(17):2134-2145. PMID: 28449774. Tester DJ et al. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005 May;2(5):507-17. PMID: 15840476.
All of Us Research Program, National Institutes of Health	RCV000148551	SCV004836426	uncertain significance	Long QT syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 452 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected to be affected with long QT syndrome (PMID: 15840476) and in an individual affected with sudden unexplained death (PMID: 28449774). It has also been reported in two healthy control individuals (PMID: 22378279). This variant has been identified in 25/281126 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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.