Submissions for variant NM_000218.3(KCNQ1):c.905C>T (p.Ala302Val)

gnomAD frequency: 0.00001  dbSNP: rs193922365

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000618395	SCV000738185	pathogenic	Cardiovascular phenotype	2024-04-17	criteria provided, single submitter	clinical testing	The c.905C>T (p.A302V) alteration is located in exon 6 (coding exon 6) of the KCNQ1 gene. This alteration results from a C to T substitution at nucleotide position 905, causing the alanine (A) at amino acid position 302 to be replaced by a valine (V). Based on data from gnomAD, the T allele has an overall frequency of <0.001% (1/249650) total alleles studied. The highest observed frequency was 0.003% (1/34488) of Latino alleles. This alteration has been identified in trans with a KCNQ1 pathogenic alteration in an individual with Jervell and Lange-Nielsen syndrome, as well as in her asymptomatic father (Wang, 2017). This variant has also been detected in an individual with a history of arrhythmia events while swimming, who also harbored an additional KCNQ1 alteration, but information about phase was not provided (Choi, 2004). In addition, this alteration has been reported in individuals with lone atrial fibrillation and long QT syndrome (LQTS), as well as in LQTS clinical genetic testing cohorts; however, clinical details were limited (Tester, 2005; Chung, 2007; Kapplinger, 2009; Olesen, 2014). This amino acid position is highly conserved in available vertebrate species. Functional studies have demonstrated reduced IKs current and abnormal trafficking (Yang, 2009; Steffensen, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000709734	SCV000839972	likely pathogenic	Long QT syndrome 1	2018-05-01	criteria provided, single submitter	clinical testing	A heterozygous c.905C>T (p.Ala302Val) likely pathogenic variant in the KCNQ1 gene was detected in this individual. This variant has been previously described in multiple individuals with long QT syndrome and atrial fibrillation (PMID 15840476, 19716085, 17905336, 24144883, 25786344). In addition, experimental studies have shown that this variant result in altered biophysical properties of the KCNQ1 protein (PMID 19808498, 25786344). Therefore, we consider this variant to be likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000030111	SCV001224616	pathogenic	Long QT syndrome	2024-11-12	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 302 of the KCNQ1 protein (p.Ala302Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 17905336, 25786344, 27917693). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 36439). 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) indicates that this missense variant is expected to disrupt KCNQ1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 19808498, 25786344). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001532623	SCV001748268	likely pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	KCNQ1: PM1, PM5, PS4:Moderate, PM2:Supporting, PS3:Supporting
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000709734	SCV004177043	pathogenic	Long QT syndrome 1	2023-09-22	criteria provided, single submitter	clinical testing	The KCNQ1 c.905C>T (p.Ala302Val) variant has been reported in several individuals affected with long QT syndrome or atrial fibrillation (Choi G et al., PMID: 15466642; Chung SK et al., PMID: 17905336; Kapplinger JD et al., PMID: 19716085; Olesen MS et al., PMID: 24144883, Steffensen AB et al., PMID: 25786344; Tester DJ et al., PMID: 15840476; Yang T et al., PMID: 19808498). At least one individual with Lange-Nielsen syndrome was compound heterozygous for this variant and a different pathogenic variant confirmed in trans (Wang C et al., PMID: 27917693). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by seven submitters. This variant is only observed on 1/249,650 alleles in the general population (gnomAD v.2.1.1), indicating it is not a comm on variant. This variant is located in the P loop of the protein and computational predictors indicate that the variant is damaging, evidence that correlates with impact to KCNQ1 function. In support of this prediction, functional studies have shown that this variant result in altered channel kinetics and protein trafficking of the KCNQ1 protein (Steffensen AB et al., PMID: 25786344; Yang T et al., PMID: 19808498). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000030111	SCV004814315	likely pathogenic	Long QT syndrome	2024-07-23	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 302 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). This variant is found within a highly conserved pore-forming region. Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant causes a significant reduction in channel currents (PMID: 19808498). This variant has been observed in compound heterozygous state with a known pathogenic KCNQ1 variant in an individual affected with autosomal recessive Jervell and Lange-Nielsen syndrome (PMID: 27917693), indicating that this variant contributes to disease. This variant has also been reported in heterozygous state in several individuals affected with or suspected of having Long QT syndrome (PMID: 15840476, 17905336, 22456477, 24606995), in an individual affected with sudden explained death (PMID: 15466642), Addisons disease with prolonged QTc interval (PMID: 22311567), or atrial fibrillation case (PMID: 24144883). This variant has been identified in 1/249650 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
GeneDx	RCV001532623	SCV005080441	pathogenic	not provided	2024-01-05	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: 29876285, 34505893, 15466642, 15840476, 19716085, 19490272, 19808498, 27409154, 22581653, 31447099, RidaM2023[Preprint], 32431610, 33332384, 35486589, 27917693, 24144883, 25786344, 17905336)
Institute of Human Genetics, University of Leipzig Medical Center	RCV000709734	SCV005368144	pathogenic	Long QT syndrome 1	2024-04-29	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PS4,PM5_STR,PM1,PM2_SUP,PP3
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001532623	SCV005878884	pathogenic	not provided	2024-02-05	criteria provided, single submitter	clinical testing	The KCNQ1 c.905C>T; p.Ala302Val variant (rs193922365) is reported in the literature in individuals affected with long QT or atrial fibrillation (Choi 2004, Chung 2007, Kapplinger 2009, Olesen 2014, Schwartz 2021, Tester 2005). This variant is also reported in one compound heterozygous individual with a different pathogenic variant confirmed in trans in Jervell and Lange-Nielson syndrome (Wang 2017). This variant is also reported in ClinVar (Variation ID: 36439) and is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, other variants at this codon (c.904G>A, p.Ala302Thr; c.905C>A; p.Ala302Glu) have been reported in individuals with long QT and are considered disease-causing (Kapplinger 2009, Napolitano 2005, Schwartz 2021). Computational analyses predict that this variant is deleterious (REVEL: 0.932), and in vitro functional analyses demonstrate reduced IK currents and abnormal protein trafficking (Steffensen 2015, Yang 2009). Based on available information, this variant is considered to be pathogenic. References: Choi G et al. Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes. Circulation. 2004 Oct 12;110(15):2119-24. PMID: 15466642. Chung SK et al. Long QT and Brugada syndrome gene mutations in New Zealand. Heart Rhythm. 2007 Oct;4(10):1306-14. PMID: 17905336. Kapplinger JD 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. PMID: 19716085. Olesen MS et al. Very early-onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation. Heart Rhythm. 2014 Feb;11(2):246-51. PMID: 24144883. Napolitano C et al. Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. JAMA. 2005 Dec 21;294(23):2975-80. PMID: 16414944. Schwartz PJ et al. Mutation location and IKs regulation in the arrhythmic risk of long QT syndrome type 1: the importance of the KCNQ1 S6 region. Eur Heart J. 2021 Dec 7;42(46):4743-4755. PMID: 34505893. Steffensen AB et al. IKs Gain- and Loss-of-Function in Early-Onset Lone Atrial Fibrillation. J Cardiovasc Electrophysiol. 2015 Jul;26(7):715-23. PMID: 25786344. 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. Wang C et al. Identification of KCNQ1 compound heterozygous mutations in three Chinese families with Jervell and Lange-Nielsen Syndrome. Acta Otolaryngol. 2017 May;137(5):522-528. PMID: 27917693. Yang T et al. Biophysical properties of 9 KCNQ1 mutations associated with long-QT syndrome. Circ Arrhythm Electrophysiol. 2009 Aug;2(4):417-26. PMID: 19808498.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030111	SCV000052766	pathogenic	Long QT syndrome	2015-04-03	no assertion criteria provided	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057792	SCV000089311	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:15466642;PMID:15840476;PMID:17905336;PMID:19716085;PMID:19808498). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Clinical Genetics, Academic Medical Center	RCV001532623	SCV001917112	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001532623	SCV001954798	likely pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Brain Gene Registry	RCV000030111	SCV003931250	not provided	Long QT syndrome		no assertion provided	phenotyping only	Variant classified as not provided and reported on 05-21-2020 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.