rs199472795

Positions:

chr11-2775984-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000218.3(KCNQ1):c.1615C>T(p.Arg539Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000319 in 1,567,782 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R539Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 1.69

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]

KCNQ1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a region_of_interest Interaction with KCNE1 C-terminus (size 37) in uniprot entity KCNQ1_HUMAN there are 36 pathogenic changes around while only 1 benign (97%) in NM_000218.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2775985-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

PP5

Variant 11-2775984-C-T is Pathogenic according to our data. Variant chr11-2775984-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 52998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2775984-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.1615C>T	p.Arg539Trp	missense_variant	13/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.1615C>T	p.Arg539Trp	missense_variant	13/16	1	NM_000218.3	ENSP00000155840	P1	P51787-1
KCNQ1	ENST00000335475.6 linkuse as main transcript	c.1234C>T	p.Arg412Trp	missense_variant	13/16	1		ENSP00000334497		P51787-2
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.1258C>T	p.Arg420Trp	missense_variant	13/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.1075C>T	p.Arg359Trp	missense_variant	8/11			ENSP00000495806

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000283

AC:

AN:

1415590

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

699444

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:

0.00000367

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 23, 2014	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.Arg539Trp Based on the information reviewed below, we classify it as very likely disease causing. This variant has previously been reported in at least 8 unrelated individuals with LQTS (Chouabe et al 2000, Zareba et al 2003, Choi et al 2004, Tester et al 2005, Kapplinger et al 2009, Kapa et al 2009). There is strong published segregation data in one family. There is in vitro functional data showing loss of potassium channel function. Chouabe and colleagues (2000) report the variant in a family with LQTS in which a 16 year old girl had died suddenly while riding her bicycle. Her father had a prolonged QTc of 489 msec. She had a sister who syncopized once under physical stress. This sister had one child who died suddenly at 16 years old while swimming and two sons who syncopized when they were 10. All of these family members were genotype positive (segregation in at least 5 family members-the girl who died bicycling was not herself genotyped). Zareba and colleagues (2003) report the variant in 2 individuals from the International LQTS Registry. That registry contained 294 subjects from 55 LQT1 families with pathogenic variants in KCNQ1. It is not clear if these two individuals are from the same family. No segregation data is presented. To be in the registry, subjects had to have a clinical diagnosis of LQTS. Additional phenotypic information is not presented. It’s unclear if these individuals are represented in other published studies. Kapa and colleagues (2009) of the Mayo Clinic reported the variant in 6 individuals in their cohort of 388 unrelated patients with LQTS genotyped by the Sudden Death Genomics Laboratory. No segregation data is presented. LQTS is defined by QTc > 480 msec or a Schwartz score greater than or equal to 4. Participants were assessed for variants in KCNQ1, KCNH2, and SCN5A. Mayo Clinic had published their data in other reports prior to this including Choi et al 2004, Tester et al 2005, Kapplinger et al 2009, and the individuals reported in Kapa et al likely include all previously reported individuals from this group. The LQTS patient reported in Choi et al (2004) had a first-degree family member with a swimming-triggered cardiac event. This residue is not conserved across paralogs (http://cardiodb.org/Paralogue_Annotation/gene.php?name=KCNQ1). However, residue 539 is in the cytoplasmic domain of the protein, in which missense variants are 22x more frequent in LQTS cases than in controls (Kapa et al. 2009). This is a nonconservative amino acid change, resulting in the replacement of a positively-charged Arginine with a nonpolar Tryptophan. Arginine at this location is highly conserved across mammalian species. The adjacent residues are also highly conserved. Another variant at this same codon, p.Arg539Gln, has also been reported in association with LQTS. Variation at nearby residues has been associated with LQTS, which may support the functional importance of this region of the protein: Arg533Trp, Val541Ile, Glu543Lys, Ser546Leu, Gln547Arg, Gly548Asp (HGMD professional version as of January 17, 2014). In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Probably Damaging” with a score of 1.0. SIFT predicts the variant is damaging with a score of 0.001. Mutation Taster predicts the variant is disease causing with a probability >0.9999. Functional studies show that this variant causes a positive voltage shift of channel activation (Chouabe et al 2000) and weaker stabilization of the open state of the potassium channel, decreasing the maximal current (Peroz et al 2008). The mutant channels reportedly have reduced affinity for phosphatid -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 31, 2020	- -

Long QT syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 539 of the KCNQ1 protein (p.Arg539Trp). 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 individuals with long QT syndrome (PMID: 10728423, 14678125, 15840476, 23098067, 23631430). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52998). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 10728423, 15746441, 16556866, 21576493, 23251633, 24681627, 25559286). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 13, 2017	Variant summary: The KCNQ1 c.1615C>T (p.Arg539Trp) variant located in the C-terminal domain involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. Multiple functional studies, Chouabe_2000 and Yamashita_2001, indicate the variant has a dominant-negative effect. This variant was found in 1/30938 control chromosomes (gnomAD) at a frequency of 0.0000323, which does not exceed the estimated maximal expected allele frequency of a pathogenic KCNQ1 variant (0.0000833). Multiple publications have cited the variant in individuals diagnosed with LQTS including one family, which the variant segregate with diseases including two affected family members dying suddenly at 16 and 18 years old (Chouabe_200). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Long QT syndrome 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Nov 08, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	Aug 01, 2023	- -

Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 05, 2021

- -

KCNQ1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2024

The KCNQ1 c.1615C>T variant is predicted to result in the amino acid substitution p.Arg539Trp. This variant has been reported in multiple individuals with long QT syndrome type 1 (Chouabe et al. 2000. PubMed ID: 10728423; Tester et al. 2005. PubMed ID: 15840476; Stattin et al. 2012. PubMed ID: 23098067; Table S1, Lieve et al. 2013. PubMed ID: 23631430; Table S1, Westphal et al. 2020. PubMed ID: 32383558; Table S1, Schwartz et al. 2021. PubMed ID: 34505893) and has been shown to co-segregate with disease in a large family (Chouabe et al. 2000. PubMed ID: 10728423). In vitro functional studies have demonstrated that this variant negatively impacts potassium channel function (Chouabe et al. 2000. PubMed ID: 10728423; Park et al. 2005. PubMed ID: 15746441; Coyan et al. 2014. PubMed ID: 24681627). This variant is reported in 0.0022% of alleles in individuals of European (non-Finnish) descent in gnomAD. Other missense variants at the same amino acid residue (p.Arg539Leu, p.Arg539Gln) have been reported in individuals with long QT syndrome, at least one of which (p.Arg539Leu) was shown to be functionally damaging (Table S1, Kapplinger et al. 2009. PubMed ID: 19716085; Rinné et al. 2023. PubMed ID: 36674868). Taken together, we interpret the p.Arg539Trp variant as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2024

The p.R539W pathogenic mutation (also known as c.1615C>T), located in coding exon 13 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1615. The arginine at codon 539 is replaced by tryptophan, an amino acid with dissimilar properties, and is located in the C-terminal region of the protein. This alteration has been previously detected in unrelated individuals with reported or suspected long QT syndrome (Chouabe C et al. Cardiovasc Res. 2000;45(4):971-80; Zareba W et al. J Cardiovasc Electrophysiol. 2003;14(11):1149-53; Tester DJ et al. Heart Rhythm. 2005;2(5):507-17; Kapa S et al. Circulation. 2009;120(18):1752-60; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Choi G et al. Circulation. 2004;110(15):2119-24). This alteration was also reported to co-segregate with prolonged QTc interval, syncope and sudden death in one family in the literature (Chouabe C et al. Cardiovasc Res. 2000;45(4):971-80). Furthermore, functional studies have reported this alteration to result in abnormal ion channel function (Park KH et al. Circ Res. 2005;96(7):730-9; Peroz D et al. J Physiol (Lond). 2008;586(7):1785-9; Coyan FC et al. PLoS ONE. 2014;9(3):e93255). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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:9312006;PMID:14678125;PMID:15466642;PMID:15840476;PMID:18174212;PMID:19716085;PMID:19841300;PMID:10728423;PMID:15746441). 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

0.98

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.83

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.5

M;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-6.6

D;.;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;.;D

Sift4G

Uncertain

0.0020

D;.;D

Polyphen

1.0

D;.;D

Vest4

0.92

MutPred

0.80

Loss of catalytic residue at R539 (P = 0.0326);.;.;

MVP

0.98

MPC

1.2

ClinPred

1.0

GERP RS

3.8

Varity_R

0.75

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over