Submissions for variant NM_000218.3(KCNQ1):c.1697C>T (p.Ser566Phe)

dbSNP: rs199472804

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046015	SCV000074028	pathogenic	Long QT syndrome	2023-09-26	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 566 of the KCNQ1 protein (p.Ser566Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 10973849, 14678125, 17470695, 19716085, 21131640, 22456477, 22949429, 23098067, 27231019; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53006). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function. This variant disrupts the p.Ser566 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (PMID: 15840476, 19716085; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000223686	SCV000234519	likely pathogenic	not provided	2024-06-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22949429, 22581653, 25525159, 17470695, 19841300, 19716085, 14678125, 22956155, 12388934, 23098067, 22456477, 27231019, 21131640, 23631430, 10973849)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046015	SCV001448368	likely pathogenic	Long QT syndrome	2020-11-30	criteria provided, single submitter	clinical testing	Variant summary: KCNQ1 c.1697C>T (p.Ser566Phe) results in a non-conservative amino acid change located in the Potassium channel, voltage dependent, KCNQ, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251096 control chromosomes. c.1697C>T has been reported in the literature in multiple individuals and families affected with Long QT Syndrome (Earle_2013, Albertella_2011, Kapplinger_2009, Lieve_2013, Splawski_2000, Zareba_2003, etc). These data indicate that the variant is very likely to be associated with disease. However one clinical lab via ClinVar has reported possible non-segregation with disease observed in at least two families tested. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other variants at the same codon position have also been reported in association with LQTS in HGMD (S566P, S566Y). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likley pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000223686	SCV001714960	likely pathogenic	not provided	2022-01-12	criteria provided, single submitter	clinical testing	PP3, PM1, PM2_supporting, PS4
Ambry Genetics	RCV002399406	SCV002714048	likely pathogenic	Cardiovascular phenotype	2024-02-22	criteria provided, single submitter	clinical testing	The p.S566F variant (also known as c.1697C>T), located in coding exon 14 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1697. The serine at codon 566 is replaced by phenylalanine, an amino acid with highly dissimilar properties, located in the C-terminal cytoplasmic region. This variant has been reported in several long QT syndrome (LQTS) cohorts (Splawski I et al. Circulation. 2000;102:1178-85; Kapa S et al. Circulation. 2009;120:1752-60; Albertella L et al. Arch Dis Child. 2011;96:704-7; Giudicessi JR et al. Circ Cardiovasc Genet. 2012;5:519-28; Stattin EL et al. BMC Cardiovasc Disord. 2012;12:95). Other variants affecting this codon (p.S566Y, p.S566P) have also been detected in LQTS cohorts; however, details were limited (Kapplinger JD. Heart Rhythm. 2009 Sep;6(9):1297-303). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002504937	SCV002814449	likely pathogenic	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2021-11-18	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057619	SCV000089138	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10973849;PMID:14678125;PMID:19716085;PMID:19841300;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223686	SCV000280149	likely pathogenic	not provided	2014-12-17	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Ser566Phe This variant has been reported in at least 9 unrelated cases, with no segregation data available. The variant was first reported by Splawski et al (2000) in 3 unrelated families with long QT syndrome. The cohort was recruited from North America and Europe. They do not specifically note that these patients are from the long QT registry but several of the authors on the paper lead the registry. Phenotype, ancestry, and segregation were not reported. Kapplinger et al (2009) reported the variant in 5 unrelated individuals who had long QT genetic testing at the PGxHealth/Familion laboratory. Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). Zareba et al (2003) include two patients with this variant from the international long QT registry in a study on genotype-phenotype correlation (may overlap with the cases reported by Splawski et al). Kapa et al (2009) included one Caucasian patient with this variant in a study comparing variants in cases and controls, however that case may overlap with Kapplinger et al (2009) as the sample came from the Mayo, Familion, and Dutch cohots. Moss et al (2007) note three individuals with long QT who died suddenly and had this variant, however it is unclear whether those individuals are related. That sample was drawn from the international registry, the Dutch registry, and the Japanese registry, so these cases may overlap with Zareba et al (2003), Kapa et al (2009) and Splawski et al (2000) as well. The variant was also included in a paper by Ackerman’s group on variant classification, which likely overlaps prior reports (Guidicessi et al 2012). Albertella et al (2011) reported the variant in a child with long QT syndrome who had a water-related event. PolyPhen-2 predicts the variant to be probably damaging and mutation taster predicts it to be disease causing. While the serine at codon 566 is conserved across most species it is a phenylalanine (same as this variant) in chimps. Other variants at the same codon have been reported in association with long QT syndrome: p.Ser566Pro (Kapplinger et al 2009, Tester et al 2005), p.Ser566Tyr (Tester et al 2005). Variants at nearby codons have also been reported with long QT syndrome: p.Arg562Met (van Langen et al 2003, Moss et al 2007), p.Ile567Ser (Zareba et al 2003, Choi et al 2004, Tester et al 2005), p.Ile567Thr (Napolitano et al 2005, Kapplinger et al 2009), p.Gly568Ala (Chen et al 2003), p.Gly568Arg (Tester et al 2005, Kapplinger et al 2009), p.Lys569Glu (Kapplinger et al 2009), p.Ser571Leu (Kapplinger et al 2009). There is no variation at codon 566 in the NHLBI ESP, which currently includes variant calls from ~6500 individuals (as of Sept 30 2012). The variant is not listed in 1000 genomes (as of Sept 30 2012). The variant is listed in dbSNP (rs199472804), however the only submission is from a long QT clinical database. There is no population frequency data provided in dbSNP. The variant has not been observed in a total of 1500 published controls. Splawski et al (2000) did not observe the variant in 200 presumed healthy individuals. Kapplinger et al (2009) reported that the variant was not observed in 1,300 presumed healthy individuals (47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, and 6% unknown/other).
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477954	SCV000536891	likely pathogenic	Long QT syndrome 1	2016-03-10	no assertion criteria provided	research
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678814	SCV000805000	likely pathogenic	not specified	2016-04-18	no assertion criteria provided	clinical testing