rs120074190

Positions:

chr11-2778009-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong

The NM_000218.3(KCNQ1):c.1766G>A(p.Gly589Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,613,604 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 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 5.82

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 12 ACMG points.

PM1

In a helix (size 21) in uniprot entity KCNQ1_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_000218.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.886

PP5

Variant 11-2778009-G-A is Pathogenic according to our data. Variant chr11-2778009-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2778009-G-A 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.1766G>A	p.Gly589Asp	missense_variant	15/16	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.1766G>A	p.Gly589Asp	missense_variant	15/16	1	NM_000218.3	ENSP00000155840	P1	P51787-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

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:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

250966

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.000560

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461412

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727038

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:

0.000510

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74334

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:

0.000753

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2001

- -

Jervell and Lange-Nielsen syndrome 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2001

- -

Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Dec 31, 2019

The c.1766G>A (p.Gly589Asp) variant in the exon 15 of KCNQ1 gene has been reported in heterozygous form in multiple unrelated individuals with long QT syndrome (LQTS) and in homozygous form in individuals with Jervell and Lange-Nielsen syndrome (PMID: 10483966, 11216980, 12477631, 12690509, 17329209, 19160088, 19716085, 20659946, 12402336, 23098067, 17467628, 17329207, 11799244, 22095730, 28619993). It is a founder mutation in the Finnish and Swedish populations (PMID: 11216980, 23098067). This variant is present at a frequency of 14/282342 in the gnomAD population database. Multiple lines of in silico algorithms predict the p.Gly589Asp change to be deleterious. Functional studies show that Gly589Asp affects the normal function of KCNQ1 potassium channel (PMID: 11216980, 15528464, 25344363, 22095730, 28785673, 28619993). In addition, multiple missense variants present in nearby residues (T587M, I588F, I588T, A590T, R591H, R591C, R591L, R594P, R594Q) have also been reported in affected individuals with LQTS. Therefore, this c.1766G>A (p.Gly589Asp) variant in the KCNQ1 gene is classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 22, 2016

The G589D pathogenic variant in the KCNQ1 gene has been reported multiple times in association with both LQTS and JLNS (Swan et al., 1999; Piippo et al., 2001; Saucerman et al., 2004; Marjamma et al., 2009; Kapplinger et al., 2009; Hintsa et al., 2010; Stattin et al., 2012). Several studies have reported G589D is a founder mutation in the Finnish population, with one study identifying the pathogenic G589D variant in 34 out of 114 Finnish individuals with autosomal dominant LQTS (Piippo et al., 2001; Marjamma et al., 2009). Furthermore, the G89D variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and was not observed with any significant frequency in the Exome Aggregation Consortium (ExAC). G589D is a non-conservative amino acid substitution that is conserved across species. Multiple functional studies have demonstrated that G589D disrupts normal KCNQ1 channel function (Piippo et al., 2001; Saucerman et al., 2004; Heijman et al., 2012; Aromolaran et al., 2014). In addition, Kiviaho et al. (2015) reported that cardiomyocytes harboring G489D exhibited abnormal mechanical beating behavior with a prolonged phase of contracted state before relaxation. Finally, multiple pathogenic missense variants in nearby residues (T587M, A590T, R591H, R594P, R594Q) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), supporting the functional importance of this region of the protein.In summary, G589D in the KCNQ1 gene is interpreted as a pathogenic variant. -

Long QT syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 25, 2023

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. ClinVar contains an entry for this variant (Variation ID: 3140). This missense change has been observed in individuals with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 10483966, 11216980, 19160088, 20659946, 22629021, 23098067, 28619993). It is commonly reported in individuals of Finland and Sweden ancestry (PMID: 10483966, 11216980, 19160088, 20659946, 22629021, 23098067, 28619993). This variant is present in population databases (rs120074190, gnomAD 0.05%). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 589 of the KCNQ1 protein (p.Gly589Asp). Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 22095730, 25344363). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2023

The p.G589D pathogenic mutation (also known as c.1766G>A), located in coding exon 15 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1766. The glycine at codon 589 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been described in numerous patients with long QT syndrome and autosomal recessive Jervell and Lange-Nielsen syndrome, has been reported to segregate with disease in two large Finnish families, and is considered to be a founder mutation in the Finnish population (Piippo K et al. J Am Coll Cardiol. 2001;37(2):562-8). In several functional in vitro studies, this alteration adversely affected the voltage-gated potassium ion channel, resulting in decreased current amplitude, prolongation of the channel activation threshold, and trafficking defects (Piippo K et al. J Am Coll Cardiol. 2001;37(2):562-8; Marx SO et al. Science. 2002;295(5554):496-9). 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. -

Cardiac arrhythmia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 28, 2019

This missense variant (also known as KCNQ1-Fin) replaces glycine with aspartic acid at codon 589 of the KCNQ1 protein. This variant is located in the C-terminal cytoplasmic coiled-coil domain that mediates tetramerization and formation of a functional channel. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental functional studies have shown that this variant alters KCNQ1 channel function and hinders the channel complex transportation to the plasma membrane (PMID: 11216980, 22095730, 25344363, 28619993, 28785673). This variant is a well-known founder mutation in the Finnish population and occurs in 30% of Finnish individuals with long QT syndrome (PMID: 11216980, 27531917, 29622001, 29740400). Heterozygous carriers show a relatively benign clinical course, as only 10% of the carriers experiencing cardiac symptoms and their mean QTc was only moderately prolonged (PMID: 27531917). This variant has been reported in homozygosity in individuals affected with Jervell and Lange-Nielsen syndrome (PMID: 11216980, 29740400). This variant has been identified in 14/282342 chromosomes (14/24888 Finnish European chromosomes) in general populations by the Genome Aggregation Database (gnomAD). Based on 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:10483966;PMID:11216980;PMID:12477631;PMID:12690509;PMID:17329209;PMID:19160088;PMID:19716085;PMID:20659946;PMID:12402336;PMID:17467628;PMID:17329207;PMID:11799244;PMID:22095730). 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

0.99

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;.;.;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

D;D;D;T

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

M;.;.;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-4.0

D;.;D;.

REVEL

Pathogenic

0.86

Sift

Benign

0.20

T;.;T;.

Sift4G

Benign

0.090

T;.;T;.

Polyphen

1.0

D;.;D;.

Vest4

0.95

MVP

0.98

MPC

1.3

ClinPred

0.83

GERP RS

3.1

Varity_R

0.50

gMVP

0.99

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