11-2570740-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

This summary comes from the ClinGen Evidence Repository: NM_000218.3(KCNQ1):c.590C>T is a missense variant predicted to cause replacement of proline with leucine at position 197. This residue is conserved across the 5 human KCNQ paralogues (https://www.cardiodb.org/paralogue_annotation/gene.php?name=KCNQ1) and another missense variant in the same codon, NM_000218.3(KCNQ1):c.589C>T (p.Pro197Ser), has been investigated in connection with long QT syndrome 1 (PMID:29532034) but has been classified as a variant of uncertain significance for long QT syndrome 1 by the ClinGen Potassium Channel Arrhythmia VCEP, so PM5 is not yet met. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00004576, with 54 / 1179994 in the European non-FInnish population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004, so neither criterion is met. This variant has been reported in the cardiovascular disorder literature, however, the available clinical details are not sufficient for inclusion in PS4, so the PS4_Supporting code is not yet met. The computational predictor REVEL gives a score of 0.965, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). The variant demonstrates 60-70% of wild-type cell surface trafficking by flow cytometry (PMID:29532034), but 140-150% of wild-type peak current density (PMID:29532034, PMID:30571187), which is not compatible with a proposed role as a disease-causing variant for long QT syndrome 1, so the PS3 code is not met. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA007671/MONDO:0100316/112

Frequency

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

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:14

Conservation

PhyloP100: 7.46

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

long QT syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
long QT syndrome 1
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Jervell and Lange-Nielsen syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Jervell and Lange-Nielsen syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
atrial fibrillation, familial, 3
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
short QT syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
short QT syndrome type 2
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
familial atrial fibrillation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Jervell and Lange-Nielsen syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

KCNQ1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.590C>T	p.Pro197Leu	missense_variant	Exon 3 of 16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 link	c.590C>T	p.Pro197Leu	missense_variant	Exon 3 of 16	1	NM_000218.3	ENSP00000155840.2		P51787-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152188

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

GnomAD2 exomes

AF:

0.0000522

AC:

AN:

249032

AF XY:

0.0000740

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000350

AC:

AN:

1459126

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

726022

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50732

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000459

AC:

AN:

1111964

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000652

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:6

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Oct 03, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in a study examining the cost-effectiveness of genetic testing in inherited heart disease, although clinical information was not provided (Sabater-Molina et al., 2013); 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: 31518351, 27153395, 29197658, 30571187, 34426522, 29532034, 32048431) -

May 05, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Pro197Leu variant (rs200108320) has been previously identified in several cohorts of cardiomyopathy patients (Ng 2013, Sabater-Molina 2013, Maxwell 2016); however, no additional clinical details or segregation data were provided. This variant is also listed in the ClinVar database as a variant of uncertain significance (Variation ID: 191476). It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in non-Finnish European populations of 0.011% (identified in 12 out of 111,358 chromosomes). The proline at codon 197 is highly conserved considering 8 species up to Ciona intestinalis (Alamut software v2.9), and computational analyses suggest this variant has a significant effect on KCNQ1 protein structure/function (SIFT: damaging, PolyPhen2: probably damaging, and Mutation Taster: disease causing). However, based on the available information, the clinical significance of the p.Pro197Leu variant cannot be determined with certainty. -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KCNQ1: PP3 -

Long QT syndrome

Uncertain:3

Jan 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 197 of the KCNQ1 protein (p.Pro197Leu). This variant is present in population databases (rs200108320, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 191476). 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 with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNQ1 function (PMID: 29532034, 30571187). 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. -

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Criteria: PM1, PP3 -

Jul 29, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces proline with leucine at codon 197 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 the mutant protein exhibits partially reduced cell surface expression but normal or increased potassium channel activity, which is inconsistent with a mutation causing long QT syndrome (PMID: 29532034, 30571187). This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 13/249032 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. -

Cardiovascular phenotype

Uncertain:2

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 14, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P197L variant (also known as c.590C>T), located in coding exon 3 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 590. The proline at codon 197 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Long QT syndrome 1

Uncertain:1

Jul 01, 2025

ClinGen Potassium Channel Arrhythmia Variant Curation Expert Panel, ClinGen

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

NM_000218.3(KCNQ1):c.590C>T is a missense variant predicted to cause replacement of proline with leucine at position 197. This residue is conserved across the 5 human KCNQ paralogues (https://www.cardiodb.org/paralogue_annotation/gene.php?name=KCNQ1) and another missense variant in the same codon, NM_000218.3(KCNQ1):c.589C>T (p.Pro197Ser), has been investigated in connection with long QT syndrome 1 (PMID: 29532034) but has been classified as a variant of uncertain significance for long QT syndrome 1 by the ClinGen Potassium Channel Arrhythmia VCEP, so PM5 is not yet met. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00004576, with 54 / 1179994 in the European non-FInnish population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004, so neither criterion is met. This variant has been reported in the cardiovascular disorder literature, however, the available clinical details are not sufficient for inclusion in PS4, so the PS4_Supporting code is not yet met. The computational predictor REVEL gives a score of 0.965, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). The variant demonstrates 60-70% of wild-type cell surface trafficking by flow cytometry (PMID: 29532034), but 140-150% of wild-type peak current density (PMID: 29532034, PMID: 30571187), which is not compatible with a proposed role as a disease-causing variant for long QT syndrome 1, so the PS3 code is not met. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025). -

Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1

Uncertain:1

Aug 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiac arrhythmia

Uncertain:1

Feb 03, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces proline with leucine at codon 197 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant does not cause trafficking defects or reduction in channel current (PMID: 29532034, 30571187, 36339618). This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 13/249032 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

CardioboostArm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

.;D;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.2

.;M;.

PhyloP100

7.5

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-9.2

D;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.97, 0.95

MutPred

0.75

.;Gain of MoRF binding (P = 0.034);.;

MVP

0.97

MPC

1.1

ClinPred

0.94

GERP RS

4.4

Varity_R

0.98

gMVP

0.98

Mutation Taster

=4/96

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over