rs199472737

chr11-2572942-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 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 Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:9 O:1
• Conservation: PhyloP100: 1.21

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000218.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.877C>T	p.Arg293Cys	missense_variant	6/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.877C>T	p.Arg293Cys	missense_variant	6/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.496C>T	p.Arg166Cys	missense_variant	6/16	1
KCNQ1	ENST00000496887.7	c.616C>T	p.Arg206Cys	missense_variant	7/16	5
KCNQ1	ENST00000646564.2	c.478-10493C>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152204 Hom.: 0 Cov.: 33

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: 9 AN: 250250 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135604

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: 81 AN: 1461470 Hom.: 0 Cov.: 32 AF XY: 0.0000646 AC XY: 47 AN XY: 727048

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: 3 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

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.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:9 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
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	- -

Long QT syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	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	- -

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]. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 26, 2021

Reported in association with LQTS (Choi et al., 2004; Tester et al., 2005; Bdier et al., 2017); 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: 22581653, 28438721, 29197658, 31737537, 28944242, 27884173, 25637381, 25985138, 26077850, 19716085, 15840476, 15466642) -

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
CardioboostArm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.
Eigen	Benign	-0.055
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	0.93	D;D
PrimateAI	Benign	0.32	T
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	D
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

Other links and lift over

dbSNP: rs199472737; hg19: chr11-2594172; COSMIC: COSV50116237; COSMIC: COSV50116237;