Submissions for variant NM_000218.3(KCNQ1):c.1792_1793del (p.Lys598fs)

dbSNP: rs2133992401

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001842086	SCV001734380	likely pathogenic	Cardiac arrhythmia	2020-10-13	criteria provided, single submitter	clinical testing	This variant deletes two nucleotides in exon 15 of the KCNQ1 gene, creating a frameshift in the penultimate exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing an altered C-terminal sequence in the cytoplasmic coiled-coil domain (a.a. 588-622). The C-terminal cytoplasmic coiled-coil domain mediates tetramerization (PMID: 18165683, 19693805, 19825999) and formation of a functional channel (PMID: 10654932). This variant has not been reported in individuals affected with cardiovascular disorders in the literature. 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
Ambry Genetics	RCV002405214	SCV002713005	pathogenic	Cardiovascular phenotype	2016-06-21	criteria provided, single submitter	clinical testing	The c.1792_1793delAA pathogenic mutation, located in coding exon 15 of the KCNQ1 gene, results from a deletion of two nucleotides at nucleotide positions 1792 and 1793, causing a translational frameshift with a predicted alternate stop codon (p.K598Gfs*53). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003771586	SCV004616869	pathogenic	Long QT syndrome	2022-12-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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, 16981927, 19825999, 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1171410). This premature translational stop signal has been observed in individual(s) with Long QT syndrome (PMID: 34505893). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys598Glyfs*53) in the KCNQ1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 79 amino acid(s) of the KCNQ1 protein.