rs199472737

Positions:

chr11-2572942-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000218.3(KCNQ1):c.877C>T(p.Arg293Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000521 in 1,613,674 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R293H) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:10O:1

Conservation

PhyloP100: 1.21

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 Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.877C>T	p.Arg293Cys	missense_variant	6/16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.877C>T	p.Arg293Cys	missense_variant	6/16	1	NM_000218.3	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6 linkuse as main transcript	c.496C>T	p.Arg166Cys	missense_variant	6/16	1		ENSP00000334497.5	P51787-2
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.616C>T	p.Arg206Cys	missense_variant	7/16	5		ENSP00000434560.2	E9PPZ0
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.478-10493C>T		intron_variant				ENSP00000495806.2	A0A2R8YEQ9

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152204

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000360

AC:

AN:

250250

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000554

AC:

AN:

1461470

Hom.:

Cov.:

AF XY:

0.0000646

AC XY:

AN XY:

727048

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000540

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000471

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:10Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome 1

Pathogenic:1Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Feb 19, 2024	This variant has been observed in multiple patients with Long QT Syndrome (Choi et al., 2004, Circulation 110:2119; Moss et al., 2007, Circulation 115:2481; Taylor et al., 2015, Nat Genet 47:717). Furthermore, it has been detected in two independant LQTS patients within our in-house cohort. Segregation analysis in one of the two patients revealed that the variant co-segregated with a mild LQTS phenotype and a marginally prolonged QTc interval (3 family members: 2 affected carriers, 1 unaffected WT). Given its sporadic occurrence in the general population (gnomAD allelfrequency: 0.005%), it is reasonable to infer that it represents a mild variant with reduced penetrance. CardioBoost, an in-silico prediction tool tailored for arrhythmias, predicts the variant to be pathogenic. Moreover, the variant is localized within the functionally relevant S5-S6 loop of the channel (Walsh et al., 2021, Genet Med). Variant classified as likely pathogenic: PM1, PS4_Supporting, PP3, PP4, PP1 -
Uncertain significance, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 10, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -

Long QT syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 06, 2024	This missense variant replaces arginine with cysteine at codon 293 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant did not show a deleterious phenotype in cellular electrophysiology study in HEK293T cells (PMID: 33876311). This variant has been reported in individuals affected with long QT syndrome, including ten individuals from four Saudi Arabian families (PMID: 28438721, 28944242, 29033053, 35703482). It has also been observed in two individuals with exercise-induced paradoxical QT prolongation (PMID: 30919684), in an individual affected with sudden death (PMID: 15466642), and in at least five Saudi homozygotes with no arrhythmia phenotype (communication with an external laboratory, PMID: 27884173). This variant has been identified in 10/281640 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The Saudi Human Genome Project has reported this variant to occur at 1.29% allele frequency among over 20,000 individuals tested (PMID: 36973604). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 15, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 293 of the KCNQ1 protein (p.Arg293Cys). This variant is present in population databases (rs199472737, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of KCNQ1-related conditions and/or clinical features of long QT syndrome (PMID: 15466642, 28944242, 31737537, 33876311, 34495297, 35703482; Invitae). This variant is also known as c.496C>T (p.Arg166Cys). ClinVar contains an entry for this variant (Variation ID: 67117). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. Experimental studies have shown that this missense change does not substantially affect KCNQ1 function (PMID: 33876311). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2024	Reported in association with LQTS (PMID: 15466642, 15840476, 28944242, 28438721); 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: 28944242, 15466642, 15840476, 19716085, 25985138, 25637381, 27884173, 31737537, 34426522, 36291626, 35703482, 34495297, 33876311, 29197658, 22581653, 28438721, 17470695, 29033053, 35534676, 30919684, 26077850) -

Atrial fibrillation, familial, 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 06, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2020

The c.877C>T (p.R293C) alteration is located in exon 6 (coding exon 6) of the KCNQ1 gene. This alteration results from a C to T substitution at nucleotide position 877, causing the arginine (R) at amino acid position 293 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 12, 2022

This missense variant replaces arginine with cysteine at codon 293 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant did not show a deleterious phenotype in cellular electrophysiology study in HEK293T cells (PMID: 33876311). This variant has been reported in individuals affected with long QT syndrome, including ten individuals from four Saudi Arabian families (PMID: 28438721, 28944242, 29033053, 35703482). It has also been observed in two individuals with exercise-induced paradoxical QT prolongation (PMID: 30919684), in an individual affected with sudden death (PMID: 15466642), and in at least five Saudi homozygotes with no arrhythmia phenotype (communication with an external laboratory, PMID: 27884173). This variant has been identified in 10/281640 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

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:15466642;PMID:15840476;PMID:19716085). 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

Benign

0.14

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;.

Eigen

Benign

-0.055

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

1.6

L;.

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-4.1

D;D

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

0.97

D;P

Vest4

0.82

MVP

0.93

MPC

1.2

ClinPred

0.50

GERP RS

3.9

Varity_R

0.36

gMVP

0.95

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