ClinVar Genomic variation as it relates to human health

The c.1066C>T (p.Gln356Ter) variant of KCNQ1 gene results in an early stop codon at amino acid 356 and is predicted to cause a truncated or absent protein product via NMD. This variant is not reported in the gnomAD population database and has been previously reported in individuals with LQTS (PMID: 10973849, 18239739, 19716085, 21350584). Loss of function variants in KCNQ1 are known to cause LQTS (PMID: 18774102, 18774102, 15840476). Based on the currently available information, the KCNQ1 c.1066C>T variant is considered pathogenic.

This sequence change creates a premature translational stop signal (p.Gln356*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 10973849, 18239739, 19716085, 19862833, 21350584). ClinVar contains an entry for this variant (Variation ID: 52946). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

The p.Q356* pathogenic mutation (also known as c.1066C>T), located in coding exon 8 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1066. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This mutation has been reported in several individuals with long QT syndrome (LQTS) as well as in multiple LQTS cohorts (Splawski I et al. Circulation. 2000;102:1178-85; Chung SK et al. Heart Rhythm. 2007;4:1306-14; Udo EO et al. Neth Heart J. 2007;15:418-21; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Hofman N et al. Neth Heart J. 2011;19:10-16; Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Rohatgi RK et al. Heart Rhythm. 2015;12(8):1807-12). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 23631430, 19716085, 21350584, 17905336, 10973849, 19862833, 18239739, 28212739, 25956966, 26669661, 36007526, 30291343, 33087929, 31737537, 32383558, 32686758, 34505893)

This variant changes 1 nucleotide in exon 8 of the KCNQ1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with or suspected of having long QT syndrome (PMID: 10973849, 17905336, 19716085, 21350584, 23631430, 25956966). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNQ1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

proposed classification - variant undergoing re-assessment, contact laboratory

Variant summary: KCNQ1 c.1066C>T (p.Gln356X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251356 control chromosomes (gnomAD). c.1066C>T has been reported in the literature in multiple individuals affected with Long QT Syndrome (e.g. Splawski_2000, Hofman_2011, Robyns_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: all five classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant changes 1 nucleotide in exon 8 of the KCNQ1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with or suspected of having long QT syndrome (PMID: 10973849, 17905336, 19716085, 21350584, 23631430, 25956966). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNQ1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.