Submissions for variant NM_000218.3(KCNQ1):c.1022C>A (p.Ala341Glu)

dbSNP: rs12720459

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045932	SCV000073945	pathogenic	Long QT syndrome	2024-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 341 of the KCNQ1 protein (p.Ala341Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 8528244, 10086971, 16627448, 19716085, 22949429). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3120). 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: 10376919, 20368164, 22095730). This variant disrupts the p.Ala341 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15028050, 17984373). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000182154	SCV000234457	pathogenic	not provided	2022-02-10	criteria provided, single submitter	clinical testing	Reported in multiple individuals with Long QT syndrome referred for genetic testing at GeneDx and in published literature (Wang et al., 1996; Berthet et al., 1999; Splawksi et al., 2000; Chen et al., 2003; Kapplinger et al., 2009; Hedley et al., 2013; Laksman et al., 2014; Choi et al., 2021; Schwartz et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as voltage clamp studies in Xenopus oocytes co-expressing both wild-type and mutant KCNQ1 channels have shown that A341E causes a dominant negative suppression of the delayed rectifier potassium current (Wang et al., 1999); 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: 20368164, 10086971, 8528244, 12702160, 14678125, 19716085, 22677073, 24217263, 24861447, 22949429, 29265344, 17470695, 27535533, 10973849, 10376919, 26582918, 12388934, 33087929, 34135346, 34319147, 34505893)
Ambry Genetics	RCV000621485	SCV000738058	pathogenic	Cardiovascular phenotype	2024-12-27	criteria provided, single submitter	clinical testing	The p.A341E pathogenic mutation (also known as c.1022C>A), located in coding exon 7 of the KCNQ1 gene, results from a C to A substitution at nucleotide position 1022. The alanine at codon 341 is replaced by glutamic acid, an amino acid with dissimilar properties. This variant (also referred to as A212E) was identified in one or more individuals with features consistent with long QT syndrome (LQTS) and segregated with disease in at least one family (Wang Q et al. Nat Genet. 1996;12:17-23; Berthet M et al. Circulation. 1999;99:1464-70; Splawski I et al. Circulation. 2000;102:1178-85; Chen S et al. Clin Genet. 2003;63:273-82; Giudicessi JR et al. Circ Cardiovasc Genet. 2012;5:519-28; Hedley PL et al. Cardiovasc J Afr. 2013;24:231-7; Laksman ZW et al. Heart Rhythm. 2014;11:1632-8). In an assay testing KCNQ1 function, this variant showed a functionally abnormal result (Wang Z et al. J. Cardiovasc Electrophysiol. 1999;10:817-26). An animal model expressing this equivalent variant exhibited phenotype(s) consistent with KCNQ1-related disease (Casimiro MC et al. Genomics, 2004 Sep;84:555-64). Other variant(s) at the same codon, p.A341V (c.1022C>T) have been identified in individual(s) with features consistent with LQTS (Wang Q et al. Nat Genet. 1996;12:17-23). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000182154	SCV001474275	pathogenic	not provided	2020-06-01	criteria provided, single submitter	clinical testing	The KCNQ1 c.1022C>A; p.Ala341Glu variant (rs12720459) is reported in the literature in multiple individuals and families affected with long QT syndrome (LQTS) and co-segregates with disease in at least three different families (Berthet 1999, Laksman 2014, Splawski 2000, Wang 1996). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The alanine at codon 341 is highly conserved, and functional studies demonstrate that this variant causes loss of ion channel activity and exerts a dominant negative effect on wildtype protein (Wang 1999). Further, a transgenic mouse model expressing a murine variant orthologous to the human p.Ala341Glu exhibits arrhythmias and cardiac dysfunction similar to human patients (Goldman 2009). Another amino acid substitution at this codon (p.Ala341Val) has also been reported in multiple individuals and families with LQTS and is considered disease-causing (Splawski 2000, Wang 1996). Based on available information, the p.Ala341Glu variant is considered to be pathogenic. References: Berthet M et al. C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence. Circulation. 1999 Mar 23;99(11):1464-70. Goldman AM et al. Arrhythmia in heart and brain: KCNQ1 mutations link epilepsy and sudden unexplained death. Sci Transl Med. 2009 Oct 14;1(2):2ra6. Laksman ZW et al. Early repolarization is associated with symptoms in patients with type 1 and type 2 long QT syndrome. Heart Rhythm. 2014 Sep;11(9):1632-8. 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. Wang Q et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet. 1996 Jan;12(1):17-23. Wang Z et al. Functional effects of mutations in KvLQT1 that cause long QT syndrome. J Cardiovasc Electrophysiol. 1999 Jun;10(6):817-26.
Revvity Omics, Revvity	RCV000182154	SCV002023223	pathogenic	not provided	2021-01-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000182154	SCV002821563	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	KCNQ1: PS1, PM2, PS4:Moderate, PP3, PP4
Color Diagnostics, LLC DBA Color Health	RCV003591617	SCV004358400	pathogenic	Cardiac arrhythmia	2021-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glutamic acid at codon 341 in the transmembrane domain segment S6 of the KCNQ1 protein. This variant is also known as p.Ala212Glu in literature based on GeneBank accession number U40990 (PMID: 8528244). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes a dominant-negative suppression of potassium current in vitro (PMID: 10376919). Transgenic mice expressing a murine variant orthologous to the human variant display cardiac arrhythmias in ECG recordings (PMID: 20368164). This variant has been reported in over twenty individuals affected with long QT syndrome (PMID: 8528244, 10973849, 8528244, 10973849, 26318259, 23124029, 24217263, 24861447, 32893267, 33900377). It has been shown that this variant segregates with long QT syndrome in two families (PMID: 8528244, 10973849). A different missense variant occurring at the same codon, p.Ala341Val, is known to be pathogenic (Clinvar variation ID 3121), indicating that alanine at this position is important for KCNQ1 protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000003267	SCV005398846	pathogenic	Long QT syndrome 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Gain of function mutations result exclusively in Short QT syndrome (MIM#609621), while dominant negative and loss of function mutations can cause Long QT syndrome (LQTS, MIM#192500), atrial fibrillation (MIM#607554) and Jervell and Lange-Nielsen syndrome (JLNS, MIM#220400) (OMIM, PMIDs: 19632626, 28438721). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. JLNS is characterized by congenital, bilateral deafness and variable degrees of QT prolongation, and is the only condition caused by biallelic mutations (PMID: 28438721). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, PMID: 20301308). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated S6 transmembrane domain (UniProt). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. The p.(Ala341Val) variant has been reported as a South African founder mutation and has multiple pathogenic entries in ClinVar (PMID: 24217263). Additionally, the p.(Ala341Gly) variant has been identified in a LQTS proband and has a pathogenic entry in ClinVar (PMID: 19716085). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in multiple unrelated LQTS probands and has pathogenic entries in ClinVar (PMIDs: 19716085, 22677073, 24861447, 24217263, VCGS). (SP) 0903 - This variant has evidence for segregation with disease. This variant has been shown to segregate with LQTS in a 13-year-old proband and three affected relatives (PMID: 24861447). (SP) 1002 - Moderate functional evidence supporting abnormal protein function. Patch clamp functional analysis indicates that this variant has a dominant negative effect on channel function (PMID: 10376919). However, patch clamp assays have been shown to be unreliable, therefore results from these studies are used with caution during variant classification. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000003267	SCV000023425	pathogenic	Long QT syndrome 1	1999-03-23	no assertion criteria provided	literature only
OMIM	RCV000003268	SCV000023426	pathogenic	Long QT syndrome 1/2, digenic	1999-03-23	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057526	SCV000089045	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:8528244;PMID:10086971;PMID:10973849;PMID:12702160;PMID:14678125;PMID:17984373;PMID:19716085;PMID:19841300;PMID:20368164;PMID:10376919;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.