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

dbSNP: rs199472804

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046015	SCV000074028	pathogenic	Long QT syndrome	2024-12-06	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; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53006). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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; internal data), 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
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000477954	SCV005399121	pathogenic	Long QT syndrome 1	2020-05-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene (OMIM). (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0112 - Variants in this gene are known to have reduced penetrance (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from serine to phenylalanine (exon 14). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and moderate conservation. (N) 0600 - Variant is located in an annotated domain or motif (C-terminal domain which interacts with KCNE1 C-termius; UnitProt, PDB). (N) 0703 - Comparable variants have moderate previous evidence for pathogenicity. Two different variants in the same codon resulting in a change to a tyrosine and a proline have been shown to cause long QT (Cardiac Family Database, PMID: 19716085). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in multiple patients with long QT (ClinVar, Cardiac Family Database, PMID: 10973849, 14678125, 17470695, 19716085, 23098067). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000223686	SCV005877048	likely pathogenic	not provided	2023-12-04	criteria provided, single submitter	clinical testing	The KCNQ1 c.1697C>T; p.Ser566Phe variant (rs199472804) is reported in the literature in numerous individuals affected with or suspected of long QT syndrome (Avari Silva 2016, Giudicessi 2012, Kapa 2009, Lieve 2013, Splawski 2000, Stattin 2012, Walsh 2021). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, other variants at this codon (c.1697C>A; p.Ser566Tyr) have been reported in individuals with long QT syndrome (Lieve 2013, Strand 2020, Tester 2005). Computational analyses predict that this variant is deleterious (REVEL: 0.83). Based on available information, this variant is considered to be likely pathogenic. References: Avari Silva JN et al. Implantable Loop Recorder Monitoring for Refining Management of Children With Inherited Arrhythmia Syndromes. J Am Heart Assoc. 2016 May 26;5(6):e003632. PMID: 27231019. Giudicessi JR et al. Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome. Circ Cardiovasc Genet. 2012 Oct 1;5(5):519-28. PMID: 22949429. Kapa S et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 Nov 3;120(18):1752-60. PMID: 19841300. Lieve KV et al. Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. Genet Test Mol Biomarkers. 2013 Jul;17(7):553-61. PMID: 23631430. Splawski I et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation. 2000 Sep 5;102(10):1178-85. PMID: 10973849. Stattin EL et al. Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing. BMC Cardiovasc Disord. 2012 Oct 25;12:95. PMID: 23098067. Strand S et al. Complex and Novel Arrhythmias Precede Stillbirth in Fetuses With De Novo Long QT Syndrome. Circ Arrhythm Electrophysiol. 2020 May;13(5):e008082. PMID: 32421437. Tester DJ et al. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005 May;2(5):507-17. PMID: 15840476. Walsh R et al. Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls. Genet Med. 2021 Jan;23(1):47-58. PMID: 32893267.
Molecular Genetics, Royal Melbourne Hospital	RCV000046015	SCV005900379	pathogenic	Long QT syndrome	2025-02-06	criteria provided, single submitter	clinical testing	This sequence change in KCNQ1 is predicted to replace serine with phenylalanine at codon 566, p.(Ser566Phe). The serine residue is highly conserved (100 vertebrates, Multiz Alignments) and is located in the C-terminus in an region that interacts with KCNE1. This region (amino acids 509-575) is defined as a mutational hotspot (PMID: 32893267). There is a large physicochemical difference between serine and phenylalanine. The highest population minor allele frequency in the population database gnomAD v4.1 is 0.001% (12/1,179,990 alleles) in the European (non-Finnish) population. This variant has been reported in multiple probands with long QT syndrome and segregates with disease in one family (PMID: 19841300, 27231019, 32893267, 37445499; ClinVar: SCV000074028.14, SCV001714960.2, SCV000234519.9, SCV005399121.1). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.830). Another missense variant, c.1697C>A, p.(Ser566Tyr) in the same codon has been classified as likely pathogenic/pathogenic (ClinVar ID: 53005). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PM1_Strong, PM2_Supporting, PP1.
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