Submissions for variant NM_000218.3(KCNQ1):c.585del (p.Lys196fs)

dbSNP: rs397508120

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182269	SCV000234572	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 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: 22629021, 19716085, 18441444, 25649125, 31229680, 31447099, 34411974, 12051962)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196205	SCV000253782	pathogenic	Long QT syndrome	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys196Serfs*41) 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 individuals with Jervell and Lange-Nielsen Syndrome (PMID: 12051962, 19716085). ClinVar contains an entry for this variant (Variation ID: 53076). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000599840	SCV000711687	pathogenic	Congenital long QT syndrome	2019-04-10	criteria provided, single submitter	clinical testing	The p.Lys196fs variant has been previously reported in the heterozygous state in 4 individuals referred for genetic testing for long QT syndrome (LQTS; Kapplinger 2009) and in the compound heterozygous state in 1 individual with Jervell and Lange-Nielsen syndrome (JLNS; Wang 2002). It has also been reported by other clinical laboratories in ClinVar (Variant ID# 53076) and is absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 196 and leads to a premature stop codon 41 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Dominant-negative and loss-of-function variants in KCNQ1 cause autosomal dominant LQTS, also known as Romano-Ward syndrome (RWS). In addition, loss of function variants in KCNQ1 also cause autosomal recessive Jervell and Lange-Nielsen syndrome (JLNS). In summary, the p.Lys196fs variant meets criteria to be classified as pathogenic for dominant LQTS and recessive JLNS. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting, PM3_Supporting
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000182269	SCV002049175	pathogenic	not provided	2020-12-08	criteria provided, single submitter	clinical testing	The KCNQ1 c.585delG; p.Lys196SerfsTer41 variant (rs397508120) is reported in the literature in multiple individuals affected with long QT syndrome (Kapplinger 2009), as well as a proband with Jervell and Lange-Nielsen syndrome in trans to a second pathogenic variant (Wang 2002). The c.585delG variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Kapplinger et al., Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009 Sep;6(9):1297-303. Wang et al., Compound heterozygous mutations in KvLQT1 cause Jervell and Lange-Nielsen syndrome. Mol Genet Metab. 2002 Apr;75(4):308-16.
Ambry Genetics	RCV002354240	SCV002647670	pathogenic	Cardiovascular phenotype	2024-11-25	criteria provided, single submitter	clinical testing	The c.585delG pathogenic mutation, located in coding exon 3 of the KCNQ1 gene, results from a deletion of one nucleotide at nucleotide position 585, causing a translational frameshift with a predicted alternate stop codon (p.K196Sfs*41). This variant was reported in individual(s) with features consistent with long QT syndrome (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). This variant has been identified in the homozygous state and/or in conjunction with other KCNQ1 variant(s) in individual(s) with features consistent with Jervell and Lange-Nielsen syndrome (Wang Z et al. Mol. Genet. Metab., 2002 Apr;75:308-16). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000182269	SCV004226838	pathogenic	not provided	2022-05-04	criteria provided, single submitter	clinical testing	PM2, PM3, PVS1
Color Diagnostics, LLC DBA Color Health	RCV003591644	SCV004358377	pathogenic	Cardiac arrhythmia	2025-02-03	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 3 of the cytoplasmic linker of the KCNQ1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals with suspected long QT syndrome (PMID: 19716085, 31229680). It has also been reported in a biallelic individual with severe phenotype (PMID: 12051962). 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.
All of Us Research Program, National Institutes of Health	RCV000196205	SCV004838763	pathogenic	Long QT syndrome	2023-08-23	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 3 of the cytoplasmic linker of the KCNQ1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals with suspected long QT syndrome (PMID: 19716085, 31229680). It has also been reported in a biallelic individual with severe phenotype (PMID: 12051962). 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000182269	SCV000924831	pathogenic	not provided	2012-09-12	no assertion criteria provided	provider interpretation