ClinVar Genomic variation as it relates to human health

Variant summary: KCNQ1 c.1552C>T (p.Arg518X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00011 in 246226 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in KCNQ1 causing autosomal recessive LQTS (0.00011 vs 0.013), allowing no conclusion about variant significance. The variant, c.1552C>T, has been reported in the literature as a founder mutation in the Swedish population, in several homozygous and compound heterozygous individuals, who were affected with autosomal recessive long QT syndrome (LQTS) with intact auditory phenotype or with deafness (later designated as Jervell and Lange-Nielsen syndrome) (Larsen 1999, Giudicessi 2013, Winbo 2012). In these reports, family members, who were heterozygous carriers of the variant, were typically clinically asymptomatic, with a mildly prolonged QT interval detected by EKG; although rare cases of symptomatic long QT syndrome (LQTS) with intact auditory phenotype (denoted as Romano-Ward syndrome) were also reported (Winbo 2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, demonstrating non-functional channels when the variant protein was expressed alone; while co-expression of the variant protein with the wild type channel did not indicate dominant negative effect (Mousavi Nik 2015). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic for autosomal recessive long QT syndrome.

The p.Arg518X variant in KCNQ1 was reported in the heterozygous state in 6 individuals with autosomal dominant long QT syndrome (LQTS) and in the compound heterozygous state in 2 siblings with severe autosomal recessive LQTS (Larsen 1999, Stattin 2012). It has also been reported in the compound heterozygous and homozygous state in >13 individuals with Jervell and Lange-Nielsen syndrome (JLNS) and segregated with disease in >6 individuals from 2 families (Tranebjaerg 1999, Ning 2003, Wimbo 2012, Wimbo 2014). Relatives of these individuals who were heterozygous carriers of this variant were either clinically asymptomatic for LQTS or had a modestly prolonged QT interval (Larsen 1999, Ning 2003) suggesting reduced penetrance and variable expressivity. This variant has also been reported by other clinical labs in ClinVar (Variation ID 3131) and has been identified in 0.02% (21/111682) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Please note that for diseases with late-onset, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. This nonsense variant leads to a premature termination codon at position 518, which is predicted to lead to a truncated or absent protein. In vitro functional studies provide support for an impact of the p.Arg518X variant to protein function (Harmer 2012, Harmer 2014, Slaats 2015). Loss-of-function variants in KCNQ1 are associated with autosomal recessive JLNS and autosomal dominant LQTS (also known as Romano-Ward syndrome). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant LQTS (ACMG/AMP criteria applied: PVS1, PS4_Moderate, PS3_Supporting) and autosomal recessive JLNS (ACMG/AMP criteria applied: PVS1, PM2_Supporting, PS3_Supporting, PM3_Strong).

This nonsense variant found in exon 12 of 16 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in individuals with autosomal dominant Long QT syndrome 1 (MIM: #192500) and in the homozygous/compound heterozygous state in patients with autosomal recessive Jervell and Lange-Nielsen syndrome (MIM: #220400) (PMID: 10482963, 10704188, 10737999, 18752142, 22539601, 24552659, 27451284, 28438721). Experimental evidence supports a damaging effect for this variant on protein function (PMID: 22309168, 24912595). Loss-of-function variation in KCNQ1 is an established mechanism of disease (PMID: 29532034). The c.1552C>T (p.Arg518Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.01% (26/251412). This variant is a common founder mutation in the Swedish population (PMID: 24552659). Based on the available evidence, the c.1552C>T (p.Arg518Ter) variant is classified as Pathogenic.

This sequence change creates a premature translational stop signal (p.Arg518*) in the KCNQ1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833). This variant is present in population databases (rs17215500, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and/or long QT syndrome, although the clinical manifestations of long QT syndrome for heterozygous carriers are typically mild (PMID: 10704188, 22539601, 23098067, 24552659). It is commonly reported in individuals of Swedish ancestry (PMID: 24552659). ClinVar contains an entry for this variant (Variation ID: 3131). For these reasons, this variant has been classified as Pathogenic.

The c.1552C>T (p.Arg518*) variant of the KCNQ1 gene is located in exon 12 and is predicted to cause loss of normal protein function either through abnormal, prematurely truncated protein, or by absence of protein product due to nonsense-mediated mRNA decay. The loss-of-function variants in KCNQ1 gene are known to be pathogenic for long QT syndrome (LQTS) (PMID: 9323054, 19862833). This variant has been reported in individuals affected with autosomal recessive Jervell and Lange-Nielsen syndrome and has also been reported in autosomal recessive and autosomal dominant LQTS (PMID 10482963, 10704188, 10737999, 18752142, 22539601, 24552659, 27451284, and 28438721). Reduced penetrance and variable expressivity have been observed in individuals heterozygous for this variant (10482963, 11530100, and 24552659). This variant is a founder allele in Swedish population (PMID 22539601, 24552659). This variant is present at a low frequency (26/251412) in the general population according to gnomAD. For these reasons, the variant c.1552C>T (p.Arg518*) variant in the KCNQ1 gene has been classified as pathogenic.

This c.1552C>T (p.Arg518*) variant in exon 12 of the KCNQ1 gene creates a premature translation stop codon and is predicted to result in an absent or disrupted protein product. This variant is well-described in association with autosomal recessive Jervell and Lange-Nielsen syndrome and has also been reported in autosomal recessive and autosomal dominant LQTS (PMID 10482963, 10704188, 10737999, 18752142, 22539601, 24552659, 27451284, and 28438721). Reduced penetrance and variable expressivity have been observed in individuals heterozygous for this variant (10482963, 11530100, and 24552659). This variant is a founder allele in Swedish population (PMID 22539601). Based on these data the p.Arg518* variant in the KCNQ1 gene is classified as pathogenic.

The KCNQ1 c.1552C>T (p.Arg518Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. Across a selection of available literature, the p.Arg518Ter variant has been identified in at least 111 individuals with KCNQ1-related disorders including at least eight in a homozygous state, at least 10 in a compound heterozygous state, and 93 in a heterozygous state (Larsen et al. 1999; Wei et al. 2000; Stattin et al. 2012; Giudicessi et al. 2013; Winbo et al. 2014). The variant was also found in two unaffected individuals in a heterozygous state (Larsen et al. 1999; Wei et al. 2000). The p.Arg518Ter variant was absent from 200 control chromosomes and is reported at a frequency of 0.00024 in the European (non-Finnish) population of the Exome Aggregation Consortium. This variant has been classified as a founder variant from a specific region of Sweden (Winbo et al. 2015) but has also been detected in other populations (Larsen et al. 1999; Wei et al. 2000; Giudicessi et al. 2013). Individuals carrying the variant in a compound heterozygous or homozygous state have a more severe phenotype compared to those with the variant in a heterozygous state (Winbo et al. 2015). To assess the functional effects of the p.Arg518Ter variant, fluorescently labelled KCNQ1 variant constructs were transfected in CHO-K1 cells and confocal microscopy was used to visualize localization of channel complexes. Two studies demonstrated that channel trafficking was disrupted in the presence of the variant whereby a high concentration of the complexes was retained in the endoplasmic reticulum (Wilson et al. 2005; Harmer et al. 2014). In addition, whole-cell patch clamp experiments were used to evaluate current flow and demonstrated that the p.Arg518Ter variant did not produce any current (Ghosh et al. 2006). Based on the collective evidence, the p.Arg518Ter variant is classified as pathogenic for KCNQ1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The KCNQ1: p.Arg518Ter variant (rs17215500) has been reported in association with Jervell and Lange-Nielsen syndrome, an autosomal recessive disorder that includes long QT intervals and sensorineural hearing loss (Larsen 1999, Giudicessi 2013 and Wei 2000). It is common in the northern Swedish population due to a founder effect (Winbo 2014). Some carriers have been reported to have long QT intervals and related symptoms. Functional analysis, though, suggests that this variant is loss of function and does not act in the dominant negative manner of missense variants typically associated with Romano Ward syndrome (Huang 2001). In addition, this variant may be associated with digenic LQTS; for example, a symptomatic female patient with a resting QTc of 520ms harbored one copy each of this variant and a pathogenic SCN5A variant (Tan 2014). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.02 percent in the European Non-Finnish population (identified on 21 out of 116,682 chromosomes) and has been reported to the ClinVar database as pathogenic by multiple clinical laboratories. This variant induces a termination codon in exon 12 (of 16 exons), and functional studies demonstrate reduced plasma membrane ion channel localization and activity (Harmer 2014). Overall, the p.Arg518Ter variant is considered to be pathogenic.

ACMG evidence PVS1, PS2, PP5

PVS1, PS4, PS3, PP4

PVS1, PS3, PP5, PS4

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 3131; Landrum et al., 2016); Published functional studies demonstrate a damaging effect (Ghosh et al., 2006; Harmer et al., 2014); This variant is associated with the following publications: (PMID: 16556866, 24912595, 23392653, 10737999, 25236808, 10482963, 11530100, 10704188, 24552659, 19716085, 24052033, 27286732, 31447099, 31737537, 28988457, 28438721, 22309168, 19841300, 26318259, 26669661, 27831900, 27816319, 19940153, 15840476, 18752142, 17905336, 29740400, 27451284, 15935335, 26187847, 24080067, 26019114, 14510661, 14678125, 25637381, 25525159, 29922582, 29247119, 29379719, 15176425, 22539601, 24631775, 23098067, 10973849, 26546361)

This variant changes 1 nucleotide in exon 12 of the KCNQ1 gene, creating a premature translation stop signal. It is expected to result in an absent or non-functional protein product. This variant has been reported in over 90 heterozygous individuals with mild long QT syndrome (PMID: 23098067, 24552659), as well as in over 30 compound heterozygous or homozygous individuals affected with Jervell and Lange-Nielsen syndrome (PMID: 10704188, 22539601, 24552659). This variant is thought to be a Swedish founder mutation (PMID: 24552659). This variant has been identified in 26/251412 chromosomes (20/113712 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNQ1 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.

This sequence change in KCNQ1 is a nonsense variant predicted to cause a premature stop codon, p.(Arg518*), in biologically relevant exon 12/16 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.02% (205/1,179,992 alleles) in the European (non-Finnish) population. This variant is a Swedish founder mutation associated with a milder long QT syndrome (LQTS) phenotype in heterozygous individuals and a more severe phenotype consistent with Jervell Lange-Nielsen syndrome (JLNS) in biallelic individuals (PMID: 24552659, 34135346, 36310718). The variant has been reported to segregate with JLNS and LQTS (with incomplete penetrance) in multiple families (PMID: 24552659). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Strong.

The c.1552C>T (p.R518*) alteration, located in exon 12 (coding exon 12) of the KCNQ1 gene, consists of a C to T substitution at nucleotide position 1552. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 518. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.01% (26/251412) total alleles studied. The highest observed frequency was 0.018% (20/113712) of European (non-Finnish) alleles. This mutation, considered to be a Swedish founder mutation, has been described frequently in patients with autosomal recessive Jervell and Lange-Nielsen syndrome and in patients with autosomal dominant long QT syndrome, although some heterozygotes may exhibit mild phenotype or reduced penetrance (Larsen, 1999; Tester, 2005; Kapplinger, 2009; Winbo, 2012; Winbo, 2014). In one study, individuals heterozygous for R518* had a prolonged QTc compared with genotype negative individuals (average QTc of 462 ms vs 433ms) (Winbo, 2017). Based on the available evidence, this alteration is classified as pathogenic.

The KCNQ1 c.1552C>T variant is predicted to result in premature protein termination (p.Arg518*). This variant has been reported to be associated with autosomal recessive Jervell and Lange-Nielsen syndrome and autosomal dominant long QT syndrome (Larsen et al. 1999. PubMed ID: 10482963; Tranebjaerg et al. 1999. PubMed ID: 10704188; Wei et al. 2000. PubMed ID: 10737999; Winbo et al. 2012. PubMed ID: 22539601). Reduced penetrance and variable expressivity have been reported for this variant (Winbo et al. 2012. PubMed ID: 22539601; Winbo et al. 2014. PubMed ID: 24552659). This variant is reported in 0.018% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic by the majority of submitters in ClinVar (www.ncbi.nlm.nih.gov/clinvar/variation/3131/). Nonsense KCNQ1 variants are expected to be pathogenic. This variant is interpreted as pathogenic.