ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1316C>T (p.Ser439Phe) (rs199472804)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046015 SCV000074028 likely pathogenic Long QT syndrome 2020-03-05 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 566 of the KCNQ1 protein (p.Ser566Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with long QT syndrome (PMID: 10973849, 14678125, 19716085, 17470695, 22949429, 23098067, 21131640, 22456477, 27231019). ClinVar contains an entry for this variant (Variation ID: 53006). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV000223686 SCV000234519 likely pathogenic not provided 2020-09-17 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; No studies have been performed to determine the functional effect of the this variant; Reported in ClinVar as likely pathogenic (ClinVar Variant ID# 53006; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 22949429, 22581653, 25525159, 17470695, 19841300, 19716085, 14678125, 22956155, 12388934, 23098067, 10973849, 22456477, 27231019, 21131640)
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 2021-01-18 criteria provided, single submitter clinical testing PS4_Moderate, PM1, PM2_Supporting, PP3
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

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