ClinVar Miner

Submissions for variant NM_000218.3(KCNQ1):c.674C>T (p.Ser225Leu)

gnomAD frequency: 0.00001  dbSNP: rs199473456
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046103 SCV000074116 pathogenic Long QT syndrome 2021-11-11 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 225 of the KCNQ1 protein (p.Ser225Leu). This variant is present in population databases (rs199473456, gnomAD 0.003%). This missense change has been observed in individuals with long QT syndrome (PMID: 9927399, 10973849, 15840476, 17470695, 19716085, 22727609, 22949429, 23130128, 24606995). ClinVar contains an entry for this variant (Variation ID: 53083). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 11087258, 19590188, 21451124, 22456477). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000057730 SCV000731736 likely pathogenic Congenital long QT syndrome 2018-09-25 criteria provided, single submitter clinical testing The p.Ser225Leu variant in KCNQ1 has been reported in >15 individuals with long QT syndrome (Priori 1999, Splawski 2000, Tester 2005, Kapplinger 2009, Andrsova 2012, Giudicessi 2012, Christiansen 2014). This variant has also been reported b y other clinical laboratories in ClinVar (Variation ID: 53083) and has been iden tified in 2/110780 of European chromosomes by the Genome Aggregation Database (g nomAD, In vitro functional studies provide s ome evidence that the p.Ser225Leu variant may impact protein function, potential ly in a dominant negative mechanism (Henrion 2009, Barsheshet 2012, Bianchi 2000 ) and computational prediction tools and conservation analysis suggest that the p.Ser225Leu variant may impact the protein. In summary, although additional stud ies are required to fully establish its clinical significance, the p.Ser225Leu v ariant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PM2, PS3_Supporting , PP3.
Color Health, Inc RCV001841649 SCV001357885 likely pathogenic Cardiac arrhythmia 2019-11-20 criteria provided, single submitter clinical testing This missense variant replaces serine with leucine at codon 225 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown this variant has a dominant-negative effect on potassium channel current and changes the activation and deactivation rates of the channel (PMID: 11087258, 19590188, 21451124, 22456477). This variant has been reported in many individuals affected with long QT syndrome or referred for long QT syndrome genetic testing (PMID: 9927399, 10973849, 14678125, 15466642, 15840476, 17470695, 19716085, 19841300, 21451124, 22456477, 22727609, 22949429, 23130128, 24606995, 29925740). This variant has been identified in 3/248308 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256914 SCV001433432 pathogenic Long QT syndrome 1 2019-05-02 criteria provided, single submitter clinical testing
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV001256914 SCV001435329 pathogenic Long QT syndrome 1 2020-06-20 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057730 SCV000089249 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:9927399;PMID:10973849;PMID:14678125;PMID:15466642;PMID:15840476;PMID:19590188;PMID:19716085;PMID:19841300;PMID:17999538;PMID:17470695;PMID:22456477). 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 RCV000182302 SCV000280160 likely pathogenic not provided 2014-10-13 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.Ser225Leu This variant has been reported in at least 11 unrelated individuals with LQTS and as many as 13 total subjects. There is no segregation data available on the variant. Priori et al (1999) first identified the variant in an Italian family where 1 member had a LQTS diagnosis and 2 first degree relatives were found to be carriers but did not have a clinical diagnosis. Splawski et al (2000) reported 2 families with p.S225L and LQTS. One family is from the US and the other is from Italy, thus we cannot assume that this family is a separate new case from the Priori et al family. Three years later the same author group reports the presence of the variant in 2/294 cases derived from the International Long QT Registry (Zareba et al). Based on the sample source and author group it is highly likely that these 2 cases are the same as the cases in Splawskis paper. Choi et al (2004) report that the variant was identified in 1/388 unrelated patients sent to Mayo for LQTS genetic testing between August 1997 and May 2003. The average QTc of the cohort was 482ms. The individual was a 12 yo male whose arrhythmic event was triggered by swimming. Tester et al (2005) reported the variant in 3/541 unrelated cases sent to Mayo for testing between August 1997 and July 2004. One of these cases likely overlaps with Choi et al. Moss et al (2007) reported the variant in 13/600 individuals with LQT. It cannot be assumed that these 13 subjects are not related. Kapplinger et al (2009) reported 8 unrelated cases with the variant out of 2500 patients referred to Familion for LQTS genetic testing between May 2004 and October 2008. Recently Medlock et al (2012) re-tested all LQTS subjects who were found to be genotype negative in previous studies (n=269) and identified 1 additional new case with p.S225L variant. Thus bringing the total to 11 unrelated cases. The Couderc et al (2012) publication mentions p.S225L variant but the patient population had previously been genotyped thus no new cases can be added. This is a non conservative amino acid change with a polar Serine replaced with a nonpolar Leucine. In silico analysis predict the amino acid replacement to be damaging /possibly damaging to resulting protein function (SIFT/PolyPhen). Additional variants (R231C, R231H) in nearby codons have been reported in association with LQTS thus indicating a functional significance of this region of the KCNQ1 gene. Henrion et al (2009) demonstrated that xenopus oocytes with the p.S225L variant in KCNQ1 had altered voltage dependencies for activation and deactivation compared to wildtype oocytes. Priori et al (1999) did not identify the variant in 100 presumably healthy controls. Kapplinger et al (2009) report that the variant was absent in 1300 presumably healthy controls (47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, and 6% unknown/other). In total the variant is absent if 1400 presumably healthy individuals. The variant is listed in dbSNP with the rs # 199473456; however there is no allele frequency data available. It is not listed in 1000Genomes. There is no variation at codon 225 in the NHLBI ESP, which currently includes variant calls from ~6500 individuals (as of November 29th 2012).
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000046103 SCV000804995 likely pathogenic Long QT syndrome 2016-04-21 no assertion criteria provided clinical testing

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