11-2587630-C-T

Position:

• chr11-2587630-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM5

The NM_000218.3(KCNQ1):​c.1189C>T​(p.Arg397Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R397Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:13 B:1 O:1
• Conservation: PhyloP100: 0.958

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 2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2587631-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1189C>T	p.Arg397Trp	missense_variant	9/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1189C>T	p.Arg397Trp	missense_variant	9/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.808C>T	p.Arg270Trp	missense_variant	9/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.832C>T	p.Arg278Trp	missense_variant	9/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.649C>T	p.Arg217Trp	missense_variant	4/11			ENSP00000495806.2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000199 AC: 50 AN: 251342 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135856

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000230 AC: 336 AN: 1461666 Hom.: 0 Cov.: 32 AF XY: 0.000237 AC XY: 172 AN XY: 727148

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000650

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000261

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74480

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000297 Hom.: 0

Bravo AF: 0.000147

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000600

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:13 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Pathogenic:2 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 397 of the KCNQ1 protein (p.Arg397Trp). This variant is present in population databases (rs199472776, gnomAD 0.08%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 17470695, 19841300). ClinVar contains an entry for this variant (Variation ID: 52970). 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. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 23571586, 24190995). 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. -
Likely benign, flagged submission	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	The c.1189C>T (p.Arg397Trp) variant has been identified in a heterozygous state in at least seven patients with clinically-diagnosed long QT syndrome, in a heterozygous state in three individuals with an unclear clinical diagnosis, and in a heterozygous state in two unaffected individuals (Moss et al. 2007; Kapa et al. 2009; Kapplinger et al. 2009; Amin et al. 2012; Ghouse et al. 2015). The p.Arg397Trp variant was absent from 2300 controls but is reported at a frequency of 0.00058 in the European American population of the Exome Sequencing Project. Functional studies of electrophysiological properties in HEK293 cells and Xenopus oocytes demonstrated that the p.Arg397Trp variant reduced the hIK currents and ATP sensitivity of the channel (Crotti et al. 2013; Li et al. 2013). Based on the evidence, the p.Arg397Trp variant is classified as likely pathogenic for long QT syndrome. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	This missense variant replaces arginine with tryptophan at codon 397 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant may result in reduced potassium ionic current (PMID: 23571586) and reduced ATP sensitivity (PMID: 24190995). This variant has been reported in individuals with a family history of long QT syndrome (PMID: 17470695), in one individual with catecholaminergic polymorphic ventricular tachycardia (PMID: 32553227), in individuals with sudden death (PMID: 23571586, 24440382), and in a stillbirth case (PMID: 30615648). This variant has also been identified in individuals with normal QTc intervals (PMID: 26159999) and showed no significant association with prolonged QTc interval in the Icelandic population (PMID: 37449562). This variant occurs at an appreciable frequency in the general population and has been identified in 53/282726 chromosomes 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. -
Likely pathogenic, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PS4_Strong, PS3_Supporting, PP3 -

Long QT syndrome 1 Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Mar 25, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 21, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Sep 04, 2023	This sequence change in KCNQ1 is predicted to replace arginine with tryptophan at codon 397, p.(Arg397Trp). The arginine residue is moderately conserved (100 vertebrates, UCSC), and is located in the cytoplasmic region. There is a large physicochemical difference between arginine and tryptophan. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.03% (39/129,098 alleles) in the European non-Finnish population. This variant has been reported in multiple probands with KCNQ1-related cardiac arrhythmias (PMID: 19841300, 31737537). An in vitro functional assay using HEK293T cells showed a decrease in current density indicating that this variant impacts protein function (PMID: 23571586). Another functional study using a patch clamp assay in Xenopus oocytes showed a partial loss of conduction in the presence of this mutant and a complete loss of conduction in combination with another mutant suggestive that this variant impacts protein function (PMID: 24190995). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.76). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3, PS3_Supporting -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 10, 2024	Variant summary: KCNQ1 c.1189C>T (p.Arg397Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251342 control chromosomes, predominantly at a frequency of 0.00032 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNQ1 causing Long QT Syndrome phenotype (8.3e-05). c.1189C>T has been reported in the literature in many individuals affected with Long QT Syndrome (e.g., Moss_2007, Kapa_2009, Kapplinger_2009, Amin_2012) as well as an in an intrauterine fetal death (e.g., Crotti_2013) and a sillbirth case (e.g., Sahlin_2019). However, co-segregation data was not provided to confirm causality in these cases and in some cases, co-occurring variants of uncertain significance were reported. Therefore, these data do not allow any conclusion about variant significance. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant reduced the slowly activating K+ channel current densities by >70% compared to wild type and reduced ATP sensitivity as well (e.g., Li_2013, Crotti_2013). The following publications have been ascertained in the context of this evaluation (PMID: 22199116, 23571586, 19841300, 25854863, 24190995, 17470695, 30615648). ClinVar contains an entry for this variant (Variation ID: 52970). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 29, 2019	The p.Arg397Trp variant in KCNQ1 has been reported in 9 individuals with LQTS (Moss 2007, Kapplinger 2009, Giudicessi 2012, Amin 2012). However, it has also been detected in asymptomatic individuals (Ghouse 2015, Taylor 2015) and in 0.03% (39/129098) of European chromosomes and 0.09% (9/10364) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar (Variation ID 52970). In vitro functional studies provide some evidence that the p.Arg397Trp variant may impact protein function (Li 2013); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis support an impact to the protein, though this information is not predictive enough to determine pathogenicity. In summary, due to the presence of conflicting evidence, the clinical significance of the p.Arg397Trp variant is uncertain. ACMG/AMP Criteria applied: BS1_Supporting, PP3. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2024	Reported in association with LQTS or sudden death and in individuals referred for LQTS genetic testing; however, the majority of these publications did not provide specific clinical details or familial segregation data (PMID: 17470695, 19841300, 19716085, 23571586, 24440382, 34505893); Identified in a patient with CPVT in published literature (PMID: 32553227); Identified in the homozygous state in a patient with neonatal diabetes (PMID: 39055936); 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: 29197658, 25637381, 25985138, 19716085, 22378279, 22949429, 19841300, 23571586, 26159999, 24440382, 32048431, 32233023, 31737537, 30615648, 31019283, 28988457, 34426522, 34398675, 35008927, 34505893, 34621001, RidaM2023[Preprint], 24190995, 35534676, 22199116, 22581653, 17470695, 39055936, 32553227, 37937776) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	KCNQ1: PS3:Supporting -

Congenital long QT syndrome Uncertain:1 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:17470695;PMID:19716085;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Wolff-Parkinson-White pattern Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Jul 14, 2017

This variant was identified in an individual with Wolff-Parkinson-White syndrome -

Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jun 19, 2020

The c.1189C>T (p.Arg397Trp) variant identified in the KCNQ1 gene substitutes a well conserved Arginine for Tryptophan at amino acid 397/677 (exon 9/16), and is also referred to asp.Arg270Trp annotated from transcript NM_181798.1. This variant is reported in gnomAD with an allele frequency of 1.26e-4 (v3.0; 18 heterozygotes, 0 homozygotes)and 1.88e-4 (v2.1.1; 53 heterozygotes, 0 homozygotes). In silico algorithms predict this variant to be Deleterious (SIFT; score: 0.001), Damaging (Provean; score: -3.32),and Pathogenic (REVEL; score: 0.7599) to the function of the canonical transcript. The p.Arg397 residue is in the intracellular C-terminal domain of KCNQ1 (UniProtKB:P51787). This variant has been reported many times in ClinVar with varying interpretations including Likely Pathogenic, Benign, and a Variant of Uncertain Significance (VarID:52970). The c.1189C>T (p.Arg397Trp) variant identified here has been reported in several affected individuals in the literature [PMID:17470695;PMID:19841300;PMID:22199116;PMID:22456477;PMID:24440382], however many of these studies were panel based and examined only a small number of potentially causative genes. Functional studies suggest the p.Arg397Trp variant leads to reduced current densities [PMID:23571586;PMID:24190995], and may be involved in coordination of ATP binding [PMID:24190995]. While it has been observed in several affected individuals and in vitro functional studies suggest an effect on current density, the presence of this variant at an allele frequency higher than expected in control databases leave some uncertainty regarding its pathogenicity. Given that, the c.1189C>T (p.Arg397Trp) variant identified in the KCNQ1 gene is reported as a Variant of Uncertain Significance. -

Familial atrial fibrillation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 2024

The p.R397W variant (also known as c.1189C>T), located in coding exon 9 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1189. The arginine at codon 397 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been previously reported in individuals with suspicion of long QT syndrome or unexplained fetal death (Moss AJ et al. Circulation. 2007;115(19):2481-9; Kapa S et al. Circulation. 2009;120(18):1752-60; Crotti L et al. JAMA. 2013;309(14):1473-82; Sahlin E et al. PLoS ONE, 2019 Jan;14:e0210017). In vitro functional studies have reported this alteration to result in altered ion channel function, but these experiments may not accurately reflect physiological conditions in vivo (Crotti L et al. JAMA. 2013;309(14):1473-82; Li Y et al. Proc Natl Acad Sci U.S.A. 2013;110(47):18922-7). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Jervell and Lange-Nielsen syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 17, 2024

This missense variant replaces arginine with tryptophan at codon 397 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant may result in reduced potassium ionic current (PMID: 23571586) and reduced ATP sensitivity (PMID: 24190995). This variant has been reported in individuals with a family history of long QT syndrome (PMID: 17470695), in one individual with catecholaminergic polymorphic ventricular tachycardia (PMID: 32553227), in individuals with sudden death (PMID: 23571586, 24440382), and in a stillbirth case (PMID: 30615648). This variant has also been identified in individuals with normal QTc intervals (PMID: 26159999) and showed no significant association with prolonged QTc interval in the Icelandic population (PMID: 37449562). This variant occurs at an appreciable frequency in the general population and has been identified in 53/282726 chromosomes 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;.;.
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.3	D;.;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0070	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.89
MVP		0.98
MPC		1.1
ClinPred		0.27	T
GERP RS		4.7
Varity_R		0.43
gMVP		0.85

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: rs199472776; hg19: chr11-2608860;