rs151344631

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_000218.3(KCNQ1):c.613G>A(p.Val205Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,162 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 (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11O:2

Conservation

PhyloP100: 7.36

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 10 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.913

PP5

Variant 11-2571333-G-A is Pathogenic according to our data. Variant chr11-2571333-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 37255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2571333-G-A is described in Lovd as [Pathogenic]. Variant chr11-2571333-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.613G>A	p.Val205Met	missense_variant	Exon 4 of 16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNQ1	ENST00000155840.12 link	c.613G>A	p.Val205Met	missense_variant	Exon 4 of 16	1	NM_000218.3	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6 link	c.232G>A	p.Val78Met	missense_variant	Exon 4 of 16	1		ENSP00000334497.5	P51787-2
KCNQ1	ENST00000496887.7 link	c.352G>A	p.Val118Met	missense_variant	Exon 5 of 16	5		ENSP00000434560.2	E9PPZ0
KCNQ1	ENST00000646564.2 link	c.478-12102G>A		intron_variant	Intron 2 of 10			ENSP00000495806.2	A0A2R8YEQ9

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250528

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135708

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461010

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726838

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.000121

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 1

Pathogenic:3

Mar 02, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 04, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KCNQ1 c.613G>A (p.Val205Met) variant has been reported in the medical literature in individuals affected with long QT syndrome (Arbour L et al., PMID: 18580685; Eldstrom J et al., PMID: 25444851; Jackson H et al., PMID: 23844633; Natarajan P et al., PMID: 27831900). This variant is only observed on 3/281,894 total alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to KCNQ1 protein function. Functional studies suggest that this variant reduces KCNQ1 channel activity, indicating impact to protein function (Arbour L et al., PMID: 18580685; Eldstrom J et al., PMID: 25444851). This variant has been submitted to ClinVar as pathogenic by seven laboratories (variation ID: 37255). Based on available information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -

Jul 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Long QT syndrome

Pathogenic:3

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Sep 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 205 of the KCNQ1 protein (p.Val205Met). This variant is present in population databases (rs151344631, gnomAD 0.008%). This missense change has been observed in individuals with long QT syndrome in members of First Nation communities in British Columbia. It has been observed in the heterozygous and homozygous state in numerous affected individuals, though the severity of the symptoms was variable. In addition, this variant has been observed in unrelated individuals with long QT syndrome (PMID: 18580685, 23844633, 26669661, 27831900). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37255). 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: 18580685, 25444851). For these reasons, this variant has been classified as Pathogenic. -

Jul 31, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KCNQ1 c.613G>A (p.Val205Met) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 276590 control chromosomes. c.613G>A has been reported in the literature in multiple heterozygous individuals of whom several were affected with Long QT syndrome, as well as in four homozygous patients presenting with a more severe cardiac phenotype, and occasionally with symptoms suggestive of Jervell and Lange-Nielsen syndrome (Jackson 2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Arbour 2008). The most pronounced variant effect results in approximately 30%-50% of the normal channel activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2Other:1

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNQ1: PP1:Strong, PM1, PS3:Moderate, PS4:Moderate, PM2:Supporting, PP3 -

Community Genetics, University of British Columbia

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 10, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate marked alteration of channel activity (Arbour et al., 2008; Eldstrom et al., 2010; Eldstrom et al., 2015); 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: 25637381, 22378279, 18580685, 20421371, 25525159, 23844633, 31447099, 31589614, 31737537, 28264985, 34319147, 27831900, 25444851, Sanatani2022[Article], RidaM2023[Preprint], 26669661, 32009526, 36725074) -

Congenital long QT syndrome

Pathogenic:1Other:1

Aug 07, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val205Met variant in KCNQ1 has been reported in 2 individuals with long QT syndrome and segregated with disease in at least 10 affected relatives from bot h families (Arbour 2008). Additionally, four individuals have been reported to b e homozygous for this variant and present with a clinically more severe phenotyp e that did not include hearing loss (Jackson 2014). This variant has also been r eported by other clinical laboratories in ClinVar (variation ID: 3725) and has b een identified in 1/126300 European chromosomes by the Genome Aggregation Databa se (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs151344631). In vitro func tional studies provide evidence that the p.Val205Met variant may impact protein function (Arbour 2008, Eldstrom 2010, Eldstrom 2015). In summary, this variant m eets criteria to be classified as pathogenic for long QT syndrome in an autosoma l dominant manner based upon segregation studies and functional evidence. -

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:18580685;PMID:20421371;PMID:22378279). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

KCNQ1-related disorder

Pathogenic:1

Nov 25, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4, PM2, PP3, PP1_Moderate -

Cardiovascular phenotype

Pathogenic:1

Apr 05, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V205M pathogenic mutation (also known as c.613G>A), located in coding exon 4 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 613. The valine at codon 205 is replaced by methionine, an amino acid with highly similar properties. This mutation has been reported in multiple families with long QT syndrome and has been observed with an elevated prevalence in an isolated Northern Canadian population (Arbour L, Genet. Med. 2008 Jul; 10(7):545-50; Kapplinger JD et al. J. Med. Genet., 2017 Mar; Pottinger TD et al. J Am Heart Assoc, 2020 Feb;9:e013808). Additionally, in vitro studies have shown this mutant exhibits altered channel gating kinetics and currents in transfected cells (Arbour L et al. Genet. Med., 2008 Jul;10:545-50; Jackson HA, Clin. Genet. 2014 Jul; 86(1):85-90; Eldstrom J, Heart Rhythm 2015 Feb; 12(2):386-94). Based on the supporting evidence, p.V205M is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

.;D;.

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

.;M;.

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-2.8

D;D;N

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.92, 0.90

MVP

0.97

MPC

1.2

ClinPred

0.99

GERP RS

4.5

Varity_R

0.92

gMVP

0.96

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.

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