11-2570652-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 27 ACMG points: 27P and 0B. PS1_Very_StrongPM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000218.3(KCNQ1):c.502G>C(p.Gly168Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G168E) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 9.44

Publications

24 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: Pathogenic. The variant received 27 ACMG points.

PS1

Transcript NM_000218.3 (KCNQ1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_000218.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2570653-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2720466.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.8321 (below the threshold of 3.09). Trascript score misZ: 0.90233 (below the threshold of 3.09). GenCC associations: The gene is linked to short QT syndrome type 2, long QT syndrome 1, Jervell and Lange-Nielsen syndrome 1, long QT syndrome, short QT syndrome, Jervell and Lange-Nielsen syndrome, hypertrophic cardiomyopathy, familial atrial fibrillation, atrial fibrillation, familial, 3.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 11-2570652-G-C is Pathogenic according to our data. Variant chr11-2570652-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 53053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.502G>C	p.Gly168Arg	missense_variant	Exon 3 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 link	c.502G>C	p.Gly168Arg	missense_variant	Exon 3 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249646

AF XY:

0.00000739

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:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460328

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726574

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51996

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111932

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Dec 01, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 07, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in multiple unrelated individuals with LQTS referred for genetic testing at GeneDx and in published literature (Donger et al., 1997; Kapplinger et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that p.(G168R) (nucleotide change not specified) results in lost or reduced channel function (Westenskow et al., 2004; Jons et al., 2011); This variant is associated with the following publications: (PMID: 19716085, 26681611, 28749187, 17091796, 20186784, 27041150, 24103226, 12566525, 14678125, 19490272, 23995044, 21185501, 26318259, 25479336, 9693036, 14531214, 27485560, 10973849, 22949429, 17470695, 22456477, 21451124, 27921062, 33256261, 15051636, 9386136)

Long QT syndrome

Pathogenic:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 168 of the KCNQ1 protein (p.Gly168Arg). This variant is present in population databases (rs179489, gnomAD 0.0009%). This missense change has been observed in individuals with long QT syndrome (PMID: 9386136, 9693036, 10973849, 17905336, 19841300; internal data). ClinVar contains an entry for this variant (Variation ID: 53053). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KCNQ1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 15051636, 22456477). For these reasons, this variant has been classified as Pathogenic.

Nov 08, 2023

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.502G>C (p.Gly168Arg) variant in the KCNQ1 gene has been identified in multiple individuals affected with Long QT syndrome (LQTS) (PMID:9386136, 36102233, 33256261, 27921062, 26743238, 24103226, 23995044). This variant, and another variant resulting in the same amino acid substitution c.502G>A (p.Gly168Arg), has been observed in multiple individuals referred for the long QT syndrome genetic testing (PMID: 19716085), and reported to segregate with disease in three families with more than ten affected individuals (PMID: 9693036). The other variant resulting in the same amino acid substitution, c.502G>A (p.Gly168Arg), is a well-known disease-causing variant reported in multiple individuals (>15) with LQTS (PMID: 9693036, 20186784, 10973849, 29952348, 12402336, 17905336, 27485560, 19841300, 22949429). In vitro functional studies on HEK293 cells and X. laevis oocytes have demonstrated that this missense substitution p.Gly168Arg affects KCNQ1 channel function and cause reduced channel current (PMID: 22456477, 15051636). In-silico computational prediction tools suggest that the p.Gly168Arg variant may have deleterious effect on the protein function (REVEL score: 0.937). This variant is found to be rare (1/249646; 0.000004) in the general population database (gnomAD) and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 53053). Therefore, the c.502G>C (p.Gly168Arg) variant in the KCNQ1 gene is classified as pathogenic.

Cardiovascular phenotype

Pathogenic:2

Oct 21, 2024

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS1;PS3_mod;PS4_mod;PM1_strong;PM2;PM5; PP1_strong,PP2,PP3,PP5

Sep 02, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.502G>C (p.G168R) alteration is located in exon 3 (coding exon 3) of the KCNQ1 gene. This alteration results from a G to C substitution at nucleotide position 502, causing the glycine (G) at amino acid position 168 to be replaced by an arginine (R). Based on data from gnomAD, the C allele has an overall frequency of <0.001% (1/249646) total alleles studied. The highest observed frequency was 0.001% (1/112848) of European (non-Finnish) alleles. This variant, and another nucleotide substitution resulting in the same amino acid change (c.502G>A), has been detected in multiple unrelated heterozygous individuals reported to have long QT syndrome (LQTS), has been reported to segregate with LQTS in multiple families, and has been reported in the homozygous state in association with Jervell and Lange-Nielsen syndrome (Donger, 1997; Splawski, 1998; Splawski, 2000; Márquez, 2006; Kapplinger, 2009; Summers, 2010; Vyas, 2016; Yoshinaga, 2018). This amino acid position is highly conserved in available vertebrate species. This variant has been reported to result in loss of ion channel function in vitro (Westenskow, 2004). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Congenital long QT syndrome

Other:1

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:9386136;PMID:19716085;PMID:9693036;PMID:12402336;PMID:14531214;PMID:12566525;PMID:17091796;PMID:17470695;PMID:15051636). 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

1.0

CardioboostArm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0

.;D;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.0

.;M;.

PhyloP100

9.4

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-6.0

D;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.021

D;D;D

Vest4

0.0

ClinPred

1.0

GERP RS

4.4

Varity_R

0.96

gMVP

0.99

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over