ClinVar

Description

The c.477+1G>A variant in KCNQ1 has been reported in the heterozygous state in at least in at least 3 individuals with long QT syndrome (LQTS; one of whom also carried another missense variant of uncertain significance in the same gene), and in 1 individual referred for LQTS clinical genetic testing; however, their detailed clinical information was not available (Splawski 2000 PMID: 10973849, Van Langen 2003 PMID: 12566525, Kapplinger 2009 PMID: 19716085). Additionally, it has been reported in 1 individual with swimming triggered arrhythmia (Choi 2004 PMID: 15466642). It has also been reported in the homozygous state or in the compound heterozygous state with another well-established pathogenic variant in at least 3 individuals with with Jervell-Lange-Nielsen syndrome (JLNS) and segregated with disease in 1 affected relative (Zehelein 2006 PMID: 16987820, Winbo 2014 PMID: 24552659, Uysal 2017 PMID: 29037160). Relatives of these individuals, who were heterozygous carriers of this variant, were clinically asymptomatic for LQTS suggesting reduced penetrance and variable expressivity. This variant has been reported by other clinical laboratories in ClinVar (Variation ID: 200874) and has been identified in 0.002% (2/113746) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Furthermore, functional studies using RNA from patients' lymphocytes suggests that this variant causes the skipping of exon 1 skipping and leads to a premature termination codon in exon 4, causing a frameshift which is predicted to lead to a truncated or absent protein. Additionally, this study suggests that this variant impacts protein function, by impairing channel formation and reducing ion current (Zehelein 2006 PMID: 16987820). Loss-of-function variants in KCNQ1 are associated with autosomal dominant LQTS (also known as Romano-Ward syndrome) and autosomal recessive JLNS. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant LQTS (ACMG/AMP criteria applied: PVS1, PS4_supporting, PM2_supporting) and autosomal recessive JLNS (ACMG/AMP criteria applied: PVS1, PM2_Supporting, PM3_Strong).