ClinVar Genomic variation as it relates to human health

The p.Glu449ArgfsX14 variant in KCNQ1 has been reported in at least 2 individuals with long QT syndrome (LQTS; Chen 2003 PMID: 12702160, Itoh 2016 PMID: 26669661). This variant has also been reported in in 2 individuals with Jervell and Lange-Nielsen syndrome (JLNS): in 1 homozygote (Adadi 2017 PMID: 28364778) and 1 heterozygote in whom a variant affecting the other copy of KCNQ1 was not identified (Chang 2014 PMID: 24388587). This variant has also been reported by other clinical laboratories in Clinvar (Variation ID: 52978) and has been identified in 0.003% (1/34524) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 449 and leads to a premature termination codon 14 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the KCNQ1 gene is an established disease mechanism in autosomal dominant LQTS and in autosomal recessive JLNS. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant LQTS (ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Supporting) and in autosomal recessive JLNS (ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Supporting).

The c.1343dupC pathogenic mutation, located in coding exon 10 of the KCNQ1 gene, results from a duplication of C at nucleotide position 1343, causing a translational frameshift with a predicted alternate stop codon (p.E449Rfs*14). This alteration has been reported in subjects with long QT syndrome (LQTS) (Chen S et al. Clin Genet, 2003 Apr;63:273-82; Kapa S et al. Circulation, 2009 Nov;120:1752-60; Chang RK et al. J Pediatr, 2014 Mar;164:590-5.e1-3). This alteration was also reported as homozygous in a subject with congenital hearing loss and prolonged QT interval (Adadi N et al. J Med Case Rep, 2017 Apr;11:88). 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.

This sequence change creates a premature translational stop signal (p.Glu449Argfs*14) 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 (rs397508088, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with long QT syndrome or suspected long QT syndrome (PMID: 12702160, 24388587, 26669661). This variant is also known as c.1338insC. ClinVar contains an entry for this variant (Variation ID: 52978). For these reasons, this variant has been classified as Pathogenic.

The c.1343dup (p.Glu449Argfs*14) variant is located in exon 10 of the KCNQ1 gene. This 1bp duplication is predicted to shift the reading frame such that it introduces a premature translation termination codon. It is expected to result in an absent or disrupted protein product. This variant has been reported in individuals with long QT syndrome in heterozygosity (PMID: 36102233, 32383558, 24388587, 15840476, 12702160), and in individuals with Jervell and Lange-Nielsen Syndrome in homozygosity or compound heterozygosity (PMID: 26669661, 28364778). Loss-of-function variants in KCNQ1 gene are known to be pathogenic (PMID: 9323054, 19862833). ClinVar contains an entry for this variant (ID: 52978). This variant is rare (1/250342 chromosomes) in the general population database (gnomAD). Based on the available evidence, this variant is classified as pathogenic.

Identified in patients with long QT syndrome (LQTS) (PMID: 12702160, 24388587, 15913580); Frameshift 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15913580, 26669661, 32470535, 24388587, 12702160, 28364778)