Submissions for variant NM_000218.3(KCNQ1):c.1686del

dbSNP: rs794728562

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182285	SCV000234588	likely pathogenic	not provided	2022-10-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation, as the last 115 amino acids are replaced with 30 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 23631430)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704132	SCV000833069	pathogenic	Long QT syndrome	2024-03-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg562Serfs*31) in the KCNQ1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 115 amino acid(s) of the KCNQ1 protein. 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: 23631430). ClinVar contains an entry for this variant (Variation ID: 200888). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the KCNQ1 protein in which other variant(s) (p.Arg632Glnfs*20) have been determined to be pathogenic (PMID: 10024302, 23098067, 23631430, 25187895). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001449794	SCV001653076	likely pathogenic	Congenital long QT syndrome	2020-02-07	criteria provided, single submitter	clinical testing	The p.Arg562SerfsX31 variant in KCNQ1 has been reported in 1 individual with suspected long QT syndrome (LQTS; Lieve 2013) was absent from large population studies. It has also been reported by other clinical laboratories in ClinVar (Variation ID# 200888). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 562 and leads to a premature termination codon 31 amino acids downstream. The location of this premature termination codon is within the terminal 50 bases of the second to last exon and is therefore more likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing ~13% of the coding region, with 85 amino acids removed. Truncating variants in KCNQ1 downstream of this position have been reported in individuals with LQTS. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant LQTS. ACMG/AMP Criteria applied: PVS1_Strong, PM2.
Ambry Genetics	RCV002399652	SCV002712557	pathogenic	Cardiovascular phenotype	2023-09-14	criteria provided, single submitter	clinical testing	The c.1686delG pathogenic mutation, located in coding exon 14 of the KCNQ1 gene, results from a deletion of one nucleotide at nucleotide position 1686, causing a translational frameshift with a predicted alternate stop codon (p.R562Sfs*31). This alteration occurs at the 3' terminus of theKCNQ1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 12% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been reported in a long QT syndrome genetic testing cohort (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV003591703	SCV004358435	likely pathogenic	Cardiac arrhythmia	2023-04-05	criteria provided, single submitter	clinical testing	This variant causes a deletion of 1 nucleotide in exon 16 of the KCNQ1 gene, creating a frameshift and premature translation stop signal in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product with the last 115 amino acids replaced with 30 different amino acids. The variant is expected to alter the sequence of C-terminal cytoplasmic domain (a.a. 588-622), which is important for protein function (PMID: 10654932, 18165683, 19693805, 19825999). This variant has been reported in an individual affected with long QT syndrome (PMID: 23631430). 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. Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000704132	SCV005426380	likely pathogenic	Long QT syndrome	2024-09-27	criteria provided, single submitter	clinical testing	This variant causes a deletion of 1 nucleotide in exon 16 of the KCNQ1 gene, creating a frameshift and premature translation stop signal in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product with the last 115 amino acids replaced with 30 different amino acids. The variant is expected to alter the sequence of C-terminal cytoplasmic domain (a.a. 588-622), which is important for protein function (PMID: 10654932, 18165683, 19693805, 19825999). This variant has been reported in an individual affected with long QT syndrome (PMID: 23631430). 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. Based on the available evidence, this variant is classified as Likely Pathogenic.