chr11-2445250-A-ACGCGCCCAT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. BA1PM4

This summary comes from the ClinGen Evidence Repository: NM_000218.3(KCNQ1):c.160_168dup (p.Pro56_Gly57insIleAlaPro) is an in-frame insertion of nine nucleotides within a non-repeat region of KCNQ1 (PM4). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.03002, with 1,854 alleles / 61,766 total alleles in the African/African American population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BA1 threshold of >0.004 (BA1). This variant has been reported in at least one affected proband with a diagnosis of long QT syndrome, however, available reported details are not sufficiently specific for long QT syndrome 1, so the PP4 and PS4 codes are not met (PMID:28438721). This variant has been shown to disrupt KCNQ1 function in only one patch-clamp assay, so experimental evidence is not sufficient to meet PS3_Supporting (PMID 19646991). In summary, this variant meets the criteria to be classified as likely benign for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: BA1 and PM4. (VCEP specifications version 1.0.0; date of approval 03/04/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA006159/MONDO:0100316/112

Frequency

Genomes: 𝑓 0.0088 ( 21 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 12 hom. )

Consequence

KCNQ1
NM_000218.3 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign reviewed by expert panel P:1U:2B:11

Conservation

PhyloP100: -0.203

Publications

3 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: Likely_benign. The variant received -6 ACMG points.

PM4

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

BA1

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.160_168dupATCGCGCCC	p.Ile54_Pro56dup	conservative_inframe_insertion	Exon 1 of 16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9
KCNQ1	NM_001406836.1 link	c.160_168dupATCGCGCCC	p.Ile54_Pro56dup	conservative_inframe_insertion	Exon 1 of 15		NP_001393765.1
KCNQ1	NM_001406838.1 link	c.160_168dupATCGCGCCC	p.Ile54_Pro56dup	conservative_inframe_insertion	Exon 1 of 11		NP_001393767.1
KCNQ1	NM_001406837.1 link	c.-203_-195dupATCGCGCCC		5_prime_UTR_variant	Exon 1 of 17		NP_001393766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 link	c.160_168dupATCGCGCCC	p.Ile54_Pro56dup	conservative_inframe_insertion	Exon 1 of 16	1	NM_000218.3	ENSP00000155840.2		P51787-1

Frequencies

GnomAD3 genomes

AF:

0.00880

AC:

1305

AN:

148264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0308

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00201

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000135

Gnomad OTH

AF:

0.00294

GnomAD2 exomes

AF:

0.000258

AC:

AN:

7752

AF XY:

0.000207

show subpopulations

Gnomad AFR exome

AF:

0.00862

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:

0.000311

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000730

AC:

767

AN:

1051082

Hom.:

Cov.:

AF XY:

0.000659

AC XY:

332

AN XY:

503788

show subpopulations

African (AFR)

AF:

0.0285

AC:

593

AN:

20828

American (AMR)

AF:

0.00195

AC:

AN:

7692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12036

East Asian (EAS)

AF:

0.00

AC:

AN:

20844

South Asian (SAS)

AF:

0.0000409

AC:

AN:

24432

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19226

Middle Eastern (MID)

AF:

0.00152

AC:

AN:

2638

European-Non Finnish (NFE)

AF:

0.0000664

AC:

AN:

903282

Other (OTH)

AF:

0.00234

AC:

AN:

40104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

109

146

182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00881

AC:

1307

AN:

148370

Hom.:

Cov.:

AF XY:

0.00845

AC XY:

612

AN XY:

72398

show subpopulations

African (AFR)

AF:

0.0308

AC:

1261

AN:

40938

American (AMR)

AF:

0.00200

AC:

AN:

14964

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3404

East Asian (EAS)

AF:

0.00

AC:

AN:

5082

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9276

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000135

AC:

AN:

66640

Other (OTH)

AF:

0.00291

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

127

190

254

317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00

Hom.:

Asia WGS

AF:

0.00371

AC:

AN:

3244

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1Uncertain:2Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:4

Aug 17, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 18, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ile54_Pro56dup in Exon 1 of KCNQ1: This variant is not expected to have clinic al significance because it has been identified in 2.9% (250/8370) of African ch romosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitu te.org; dbSNP rs561562768). It has been reported in two individuals with cardia c arrhythmias (1/182 LQTS, Berge 2008; 1/231 AF, Abraham 2010) and segregated in three affected individuals in one family, though phenotypes were unknown in 2 o ther mutation carriers (Abraham 2010). In addition, one study demonstrated some alteration of channel properties (Abraham 2010) although this study was only in vitro such that correlation to a clinical phenotype was not possible. This varia nt was also identified in several healthy control cohorts (0.3% 4/1488 chromosom es, Ackerman 2003; 1/364 chromosomes, Arnestad 2007; 2.1% (2/94) African-America n control chromosomes, Abraham 2010) and is now listed in the KCNQ1 database as a benign variant (http://www.fsm.it/cardmoc/kvlqt1poly.htm). In summary, given t he high frequency of the variant in spite of the reports in the literature, this variant is benign for a reasonably penetrant disease variant and insufficient b iological evidence for a clinically relevant impact to protein function, we have classified this variant as likely benign. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 24, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: KCNQ1 c.160_168dupATCGCGCCC (p.Ile54_Pro56dup) results in an in-frame duplication that is predicted to duplicate three amino acids into the encoded protein. The variant allele was found at a frequency of 0.0017 in 1200626 control chromosomes, predominantly at a frequency of 0.03 within the African or African-American subpopulation in the gnomAD database (v4), including 31 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 300 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNQ1 causing Arrhythmia phenotype (0.0001). c.160_168dupATCGCGCCC has been reported in the literature in individuals affected with Arrhythmia as well as in control population (e.g. Abraham_2010, Berge_2008, Ackerman_2003, Tester_2005_01, Kapa_2009, Hassnan_2017, Millat_2014). In a family with familial atrial fibrillation, this variant was reported with inconclusive co-segregation of this variant with disease (Abraham_2010). This family however, was not comprehensively screened for mutations in all susceptibility genes. Co-occurrences with other pathogenic variants have been reported (KCNQ1 c.674C>T, p.Ser225Leu; KCNH2 c.1841C>T, p.Ala614Val) in our internal database. In vitro functional study detected partial defect of the channel properties (Abraham_2010), suggesting that it could be a functional polymorphism.. The following publications have been ascertained in the context of this evaluation (PMID: 14661677, 17210839, 15913580, 19841300, 19646991, 18752142, 22947121, 22818067, 24687331, 28438721). ClinVar contains an entry for this variant (Variation ID: 42487). Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:3

Jul 17, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 18752142, 14661677, 17210839, 19646991, 28438721, 32048431, 30847666) -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KCNQ1: BS1, BS2 -

Sep 21, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Uncertain:2

Feb 27, 2013

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 02, 2013

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Atrial fibrillation, familial, 3

Pathogenic:1

Jan 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Long QT syndrome 1

Benign:1

Jul 01, 2025

ClinGen Potassium Channel Arrhythmia Variant Curation Expert Panel, ClinGen

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

NM_000218.3(KCNQ1):c.160_168dup (p.Pro56_Gly57insIleAlaPro) is an in-frame insertion of nine nucleotides within a non-repeat region of KCNQ1 (PM4). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.03002, with 1,854 alleles / 61,766 total alleles in the African/African American population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BA1 threshold of >0.004 (BA1). This variant has been reported in at least one affected proband with a diagnosis of long QT syndrome, however, available reported details are not sufficiently specific for long QT syndrome 1, so the PP4 and PS4 codes are not met (PMID: 28438721). This variant has been shown to disrupt KCNQ1 function in only one patch-clamp assay, so experimental evidence is not sufficient to meet PS3_Supporting (PMID 19646991). In summary, this variant meets the criteria to be classified as likely benign for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: BA1 and PM4. (VCEP specifications version 1.0.0; date of approval 03/04/2025). -

KCNQ1-related disorder

Benign:1

Mar 09, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Ventricular fibrillation

Benign:1

May 20, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.20

Mutation Taster

=34/66

disease causing

(source)

Splicing

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