Submissions for variant NM_000218.3(KCNQ1):c.1597C>T (p.Arg533Trp)

gnomAD frequency: 0.00001  dbSNP: rs199472793

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000234802	SCV000240228	pathogenic	Long QT syndrome 1	2014-01-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456908	SCV000543304	uncertain significance	Long QT syndrome	2022-03-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 533 of the KCNQ1 protein (p.Arg533Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive Jervell and Lange-Nielsen syndrome (JLNS) (PMID: 10728423, 19716085, 20851114, 27041150). ClinVar contains an entry for this variant (Variation ID: 67041). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect KCNQ1 function (PMID: 10728423, 24190995). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001841671	SCV001352005	uncertain significance	Cardiac arrhythmia	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 533 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a positive shift in the voltage dependence of activation (PMID: 10728423) and a large reduction in channel peak current density (PMID: 34930020). This variant has been reported in three unrelated individuals referred for long QT syndrome genetic test (PMID: 19716085, 20851114), as well as in an individual with no indication for cardiac genetic screening (PMID: 34930020). This variant has also been reported in a few individuals affected with recessive long QT syndrome (PMID: 10728423, 27041150, 27485560). Heterozygous relatives in their families have been reported to be asymptomatic. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
AiLife Diagnostics, AiLife Diagnostics	RCV002223181	SCV002501192	uncertain significance	not provided	2022-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162437	SCV003900383	uncertain significance	Cardiovascular phenotype	2023-02-14	criteria provided, single submitter	clinical testing	The p.R533W variant (also known as c.1597C>T), located in coding exon 13 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1597. The arginine at codon 533 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported as homozygous in individuals with syncope, who had a normal QTc interval and hearing evaluation, and compound heterozygous with an additional alteration in KCNQ1 in an individual with a QTc interval of 491ms (Chouabe C et al. Cardiovasc Res, 2000 Mar;45:971-80; Vyas B et al. Indian Pacing Electrophysiol J, 2016 Mar;16:8-18). Additionally, this alteration was detected in long QT syndrome cohorts; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Millat G et al. Clin Chim Acta, 2011 Jan;412:203-7). Lastly, in vitro studies showed this alteration may not impact protein function (Chouabe C et al. Cardiovasc Res, 2000 Mar;45:971-80). This amino acid position is highly 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.
All of Us Research Program, National Institutes of Health	RCV000456908	SCV004836464	uncertain significance	Long QT syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 533 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant has a minor effect on the potassium channel activation (PMID: 10728423). This variant has been reported in three unrelated individuals referred for long QT syndrome genetic test (PMID: 19716085, 20851114). This variant has also been reported in a few individuals affected with recessive long QT syndrome (PMID: 10728423, 27041150, 27485560). Heterozygous family members of these patients have been reported to be asymptomatic. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although studies suggest that this variant may be associated with autosomal recessive phenotype, the available evidence is insufficient to determine the role of this variant in autosomal dominant long QT syndrome. Therefore, this variant is classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057603	SCV000089122	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:10728423;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.