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rs12720459

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000218.3(KCNQ1):c.1022C>A(p.Ala341Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000277 in 831,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A341G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

16
3
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 7.42
Variant links:
Genes affected
KCNQ1 (HGNC:6294): (potassium voltage-gated channel subfamily Q member 1) This gene encodes a voltage-gated potassium channel required for repolarization phase of the cardiac action potential. This protein can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. Mutations in this gene are associated with hereditary long QT syndrome 1 (also known as Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation. This gene exhibits tissue-specific imprinting, with preferential expression from the maternal allele in some tissues, and biallelic expression in others. This gene is located in a region of chromosome 11 amongst other imprinted genes that are associated with Beckwith-Wiedemann syndrome (BWS), and itself has been shown to be disrupted by chromosomal rearrangements in patients with BWS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1
In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000218.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-2583535-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
Variant 11-2583535-C-A is Pathogenic according to our data. Variant chr11-2583535-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 3120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2583535-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNQ1NM_000218.3 linkuse as main transcriptc.1022C>A p.Ala341Glu missense_variant 7/16 ENST00000155840.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNQ1ENST00000155840.12 linkuse as main transcriptc.1022C>A p.Ala341Glu missense_variant 7/161 NM_000218.3 P1P51787-1
KCNQ1ENST00000335475.6 linkuse as main transcriptc.641C>A p.Ala214Glu missense_variant 7/161 P51787-2
KCNQ1ENST00000496887.7 linkuse as main transcriptc.761C>A p.Ala254Glu missense_variant 8/165
KCNQ1ENST00000646564.2 linkuse as main transcriptc.578C>A p.Ala193Glu missense_variant 3/11

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.0000277
AC:
23
AN:
831338
Hom.:
0
Cov.:
31
AF XY:
0.0000313
AC XY:
12
AN XY:
383892
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000303
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJun 01, 2020The 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. -
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 10, 2022Reported 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) -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJan 21, 2021- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2022KCNQ1: PS1, PM2, PS4:Moderate, PP3, PP4 -
Long QT syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 23, 1999- -
Long QT syndrome 1/2, digenic Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 23, 1999- -
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeAug 28, 2023For these reasons, this variant has been classified as Pathogenic. 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. 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 10376919, 20368164, 22095730). -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsAug 10, 2020The 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. Located in the S6 transmembrane domain, this alteration (also reported as A212E) has been detected in multiple unrelated individuals with confirmed or suspected long QT syndrome (LQTS) and has been reported to segregate with disease in families (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). One in vitro functional study reported this alteration to result in dominant-negative suppression of IKs, and an in vivo knock-in mouse model exhibited repolarization defects with prolonged QTc (Wang Z et al. J. Cardiovasc Electrophysiol. 1999;10:817-26; Casimiro MC et al. Genomics, 2004 Sep;84:555-64). Other alterations affecting this amino acid position (p.A341V and p.A341G) have also been reported in association with LQTS (Wang Q et al. Nat Genet. 1996;12:17-23; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Cardiac arrhythmia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthNov 16, 2021This 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. -
Congenital long QT syndrome Other:1
not provided, no classification providedliterature onlyCardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust-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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
CardioboostArm
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.59
Cadd
Pathogenic
31
Dann
Uncertain
0.99
DEOGEN2
Pathogenic
0.99
D;.;.
Eigen
Pathogenic
0.73
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Pathogenic
0.93
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.0
H;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-4.7
D;.;D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;.;D
Sift4G
Pathogenic
0.0010
D;.;D
Polyphen
1.0
D;.;D
Vest4
0.99
MutPred
0.93
Loss of glycosylation at S338 (P = 0.2445);.;.;
MVP
0.99
MPC
1.3
ClinPred
1.0
D
GERP RS
3.9
Varity_R
0.98
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs12720459; hg19: chr11-2604765; API