rs12720459

Positions:

• chr11-2583535-C-A
• chr11-2583535-C-G
• chr11-2583535-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_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 0.0000158 in 1,459,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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 Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 7.42

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a helix (size 19) in uniprot entity KCNQ1_HUMAN there are 35 pathogenic changes around while only 0 benign (100%) in NM_000218.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2583535-C-G is described in Lovd as [Pathogenic].
• 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	Protein	UniProt
KCNQ1	NM_000218.3	c.1022C>A	p.Ala341Glu	missense_variant	7/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1022C>A	p.Ala341Glu	missense_variant	7/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.641C>A	p.Ala214Glu	missense_variant	7/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.761C>A	p.Ala254Glu	missense_variant	8/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.578C>A	p.Ala193Glu	missense_variant	3/11			ENSP00000495806

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1459990 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 726348

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: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 21, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 01, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	KCNQ1: PS1, PM2, PS4:Moderate, PP3, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2022	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) -

Long QT syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 23, 1999

- -

Long QT syndrome 1/2, digenic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 23, 1999

- -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 28, 2023

For 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 submitter

clinical testing

Ambry Genetics

Aug 10, 2020

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. 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 submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 16, 2021

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. -

Congenital long QT syndrome Other:1

not provided, no classification provided

literature only

Cardiovascular 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
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

Other links and lift over

dbSNP: rs12720459; hg19: chr11-2604765;