ClinVar Genomic variation as it relates to human health

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.

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.

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.

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.

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.