ClinVar Genomic variation as it relates to human health

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).

This variant causes a G>A nucleotide substitution at the canonical +1 position of intron 2 of the KCNQ1 gene. Functional RNA studies have shown that this variant causes out-of-frame skipping of exon 2, resulting in a premature truncation (PMID: 16987820). This variant has been reported in multiple individuals affected with long QT syndrome (Polyak et al., 2016; Marschall et al., 2019) and in one individual referred for long QT syndrome genetic test (PMID: 19716085). This variant has also been reported in at least four individuals affected with Jervell and Lange-Nielsen syndrome, either in homozygous (PMID: 16987820) or compound heterozygous state (PMID: 22539601, 24552659, 29037160). A few heterozygous family members of these probands have been reported to be asymptomatic for cardiac phenotype (PMID: 16987820, 29037160). This variant has been identified in 2/251080 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNQ1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.

The c.477+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the KCNQ1 gene. In a study of long QT syndrome (LQTS) clinical genetic testing, this alteration was reported in one patient (Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). This alteration has also been reported in the homozygous state in siblings with Jervell and Lange-Nielsen syndrome; however, heterozygous family members reportedly did not have LQTS phenotype. The same study reported this alteration to result in altered splicing and premature protein truncation as well as abnormal ion channel function in vitro (Zehelein J et al. J Biol Chem. 2006; 281(46):35397-403). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.

KCNQ1: PVS1, PM2

Observed in association with LQTS in the published literature (Splawski et al., 2000; Van Langen et al., 2003; Choi et al., 2004; Kapplinger et al., 2009) and in several unrelated individuals referred for genetic testing of LQTS at GeneDx; Not observed at a significant frequency in large population cohorts (gnomAD); Canonical splice donor site variant a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate this variant results in aberrant splicing (Zehelein et al., 2006); This variant is associated with the following publications: (PMID: 9386136, 28264985, 33552729, 19027783, 25525159, 19716085, 10973849, 12566525, 29037160, 22629021, 24552659, 30645170, 31737537, 22539601, 15466642, 26582918, 16987820)

Criteria: PVS1_Strong, PS3_Moderate, PM2, PP1

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 1 and introduces a premature termination codon (PMID: 16987820). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 200874). Disruption of this splice site has been observed in individual(s) with Jervell and Lange-Nielsen syndrome (PMID: 16987820, 19716085, 22629021, 24552659). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs762814879, gnomAD 0.002%). This sequence change affects a donor splice site in intron 2 of the KCNQ1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.

This variant causes a G>A nucleotide substitution at the canonical +1 position of intron 2 of the KCNQ1 gene. Functional RNA studies have shown that this variant causes out-of-frame skipping of exon 2, resulting in a premature truncation (PMID: 16987820). This variant has been reported in multiple individuals affected with long QT syndrome (Polyak et al., 2016; Marschall et al., 2019) and in one individual referred for long QT syndrome genetic test (PMID: 19716085). This variant has also been reported in at least four individuals affected with Jervell and Lange-Nielsen syndrome, either in homozygous (PMID: 16987820) or compound heterozygous state (PMID: 22539601, 24552659, 29037160). A few heterozygous family members of these probands have been reported to be asymptomatic for cardiac phenotype (PMID: 16987820, 29037160). This variant has been identified in 2/251080 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNQ1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.