11-2570718-C-T

Variant summary

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

The NM_000218.3(KCNQ1):c.568C>T(p.Arg190Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,078 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. R190L) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.544

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 16 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000218.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2570719-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

PP5

Variant 11-2570718-C-T is Pathogenic according to our data. Variant chr11-2570718-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2570718-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.568C>T	p.Arg190Trp	missense_variant	3/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.568C>T	p.Arg190Trp	missense_variant	3/16	1	NM_000218.3	P1	P51787-1
KCNQ1	ENST00000335475.6 linkuse as main transcript	c.187C>T	p.Arg63Trp	missense_variant	3/16	1			P51787-2
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.307C>T	p.Arg103Trp	missense_variant	4/16	5
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.478-12717C>T		intron_variant

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

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249344

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135224

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1459886

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726380

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000135

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:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2022	Not observed at a significant frequency in large population cohorts (gnomAD); 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: 20660394, 28438721, 31518351, 27251404, 24218437, 23158531, 23281414, 24552659, 22581653, 20541041, 22882672, 25825456, 26813553, 29677589, 19490272, 31009818, 34319147, 32421437, 23995044, 19841298, 31729605, 35205365, 16414944, 22539601) -

Long QT syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 06, 2023	This missense change has been observed in individuals with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 16414944, 19841298, 22456477, 22539601, 24218437, 25825456). ClinVar contains an entry for this variant (Variation ID: 53070). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg190 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8528244, 10728423, 20660394, 22629021). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. 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 sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 190 of the KCNQ1 protein (p.Arg190Trp). -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 15, 2023	The c.568C>T (p.Arg190Trp) variant in KCNQ1 gene, that encodes for potassium voltage-gated channel subfamily Q member 1, has been identified in multiple unrelated individuals (>30) affected with Long QT syndrome (LQTS) (PMID: 16414944, 19841298, 22456477, 24218437, 25825456, 19490272, 23158531, 28438721, 26813553, 32893267) and in a young individual with sudden unexpected death (PMID: 22882672). This variant has been observed in seven individuals in a family and two individuals in another family including the proband; however, phenotypes of the carrier relatives are not given (PMID: 19841298). This variant has also been observed in heterozygous state in one individual, and compound heterozygous state (with another pathogenic variant p.Arg518*) in one individual with Jervell and Lange-Nielsen syndrome (PMID: 22539601). In-silico computational prediction tools suggest that the p.Arg190Trp variant may have deleterious effect on protein function (REVEL score: 0.895). This variant is found to be rare (1/249344; 0.000004) in the general population database (gnomAD) and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 53070). Other missense variants substituting the same amino acid (p.Arg190Gln, p.Arg190Leu, p.Arg190Pro) are known disease-causing variants reported in multiple individuals with LQTS (PMID: 19716085, 20138589, 31737537, 32383558, 17470695, 32893267) and classified as likely pathogenic/pathogenic by several submitters in ClinVar (ID: 67084, 3117, 237228). Therefore, the c.568C>T (p.Arg190Trp) variant in the KCNQ1 gene is classified as pathogenic. -

Long QT syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Laan Lab, Human Genetics Research Group, University of Tartu

May 01, 2021

- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2023

The p.R190W variant (also known as c.568C>T), located in coding exon 3 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 568. The arginine at codon 190 is replaced by tryptophan, an amino acid with dissimilar properties, and is located in the S2/S3 transmembrane spanning region of the protein. This alteration has been reported in individuals with long QT syndrome (LQTS) and in a sudden unexplained death victim (Napolitano C et al. JAMA. 2005;294(23):2975-80; Jons C et al. J. Cardiovasc Electrophysiol. 2009;20(8):859-65; Winkel BG et al. J. Cardiovasc Electrophysiol. 2012; 23(10):1092-8; Crotti L et al. J Am Coll Cardiol. 2012; 60(24):2515-24; Cuneo BF et al. Circ Arrhythm Electrophysiol. 2013;6(5):946-51). This variant has also been detected in the homozygous and compound heterozygous (with p.R518* and p.R594Q) states in individuals with autosomal recessive Jervell and Lange-Nielsen syndrome (Winbo A et al. Europace. 2012; 14(12):1799-806; Al-Hassnan ZN et al. Heart Rhythm. 2017;14:1191-1199; Mura M et al. Stem Cell Res. 2018;29:157-161). This alteration showed moderate segregation with disease in a family with a dual phenotype of hypertrophic cardiomyopathy and LQTS and who also had alterations in other cardiac-related genes (Wang L et al. Europace. 2016;18(4):602-9). Another alteration at the same codon, p.R190Q (c.569G>A), have also been reported in association with LQTS (Kapplinger JD, Heart Rhythm 2009;6(9):1297-303). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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:16414944;PMID:22539601). 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

0.94

CardioboostArm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Benign

0.050

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.093

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-7.5

D;D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.98, 0.98

MutPred

0.89

.;Loss of methylation at R190 (P = 0.0273);.;

MVP

0.98

MPC

1.2

ClinPred

1.0

GERP RS

1.2

Varity_R

0.91

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.24

Position offset: -20

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