11-2588804-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. BA1BP5PP1

This summary comes from the ClinGen Evidence Repository: NM_000218.3(KCNQ1):c.1343C>G (p.Pro448Arg) is a missense variant predicted to cause substitution of proline by arginine at amino acid 448 (p.Pro448Arg). This variant has been reported as a polymorphism that is present in approximately 20% of Asian individuals (PMID:11997281). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.09851, with 4408 alleles / 44746 total alleles and 203 homozygotes in the East Asian population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BA1 threshold of >0.004 (BA1). The variant has been reported to segregate with long QT syndrome 1 through the proband and 3 affected family members from one family (PP1; PMID:17597962). This variant has been observed in 1 patient with an alternate molecular basis for disease with a phenotype that is not sufficiently specific (BP5; PMID 15242738). Functional studies have been performed on this variant (PMIDs: 15051636, 15242738), but it does not yet meet the criteria for PS3/BS3. In summary, this variant meets the criteria to be classified as benign for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: BA1, BP5, and PP1. (VCEP specifications version 1.0.0; date of approval 03/04/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA005620/MONDO:0100316/112

Frequency

Genomes: 𝑓 0.0035 ( 17 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 195 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:19O:1

Conservation

PhyloP100: -0.179

Publications

48 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: G2P, Labcorp Genetics (formerly Invitae)
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:

ENSG00000296223 (HGNC:):

ENSG00000296223 links:

Genome browser will be placed here

ACMG classification

Specifications for KCNQ1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PP1

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

BP5

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

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000218.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNQ1	NM_000218.3	MANE Select	c.1343C>G	p.Pro448Arg	missense	Exon 10 of 16	NP_000209.2
KCNQ1	NM_001406836.1		c.1247C>G	p.Pro416Arg	missense	Exon 9 of 15	NP_001393765.1
KCNQ1	NM_001406837.1		c.1073C>G	p.Pro358Arg	missense	Exon 11 of 17	NP_001393766.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1343C>G	p.Pro448Arg	missense	Exon 10 of 16	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6	TSL:1	c.962C>G	p.Pro321Arg	missense	Exon 10 of 16	ENSP00000334497.5	P51787-2
KCNQ1	ENST00000910997.1		c.1340C>G	p.Pro447Arg	missense	Exon 10 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes

AF:

0.00350

AC:

532

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0908

Gnomad SAS

AF:

0.00415

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00754

AC:

1888

AN:

250376

AF XY:

0.00701

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0972

Gnomad FIN exome

AF:

0.000373

Gnomad NFE exome

AF:

0.000247

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00315

AC:

4599

AN:

1461090

Hom.:

195

Cov.:

AF XY:

0.00306

AC XY:

2225

AN XY:

726826

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33472

American (AMR)

AF:

0.0000895

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0995

AC:

3941

AN:

39606

South Asian (SAS)

AF:

0.00217

AC:

187

AN:

86190

European-Finnish (FIN)

AF:

0.000395

AC:

AN:

53130

Middle Eastern (MID)

AF:

0.00108

AC:

AN:

5566

European-Non Finnish (NFE)

AF:

0.000101

AC:

112

AN:

1111936

Other (OTH)

AF:

0.00542

AC:

327

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

Heterozygous variant carriers

238

475

713

950

1188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<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:

0.00348

AC:

529

AN:

152198

Hom.:

Cov.:

AF XY:

0.00411

AC XY:

306

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41548

American (AMR)

AF:

0.000196

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.0909

AC:

467

AN:

5140

South Asian (SAS)

AF:

0.00394

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

67998

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000213

Hom.:

Bravo

AF:

0.00440

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00749

AC:

909

Asia WGS

AF:

0.0400

AC:

139

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (5)

Long QT syndrome (2)

Long QT syndrome 1 (2)

Atrial fibrillation, familial, 3 (1)

Cardiac arrhythmia (1)

Cardiovascular phenotype (1)

Jervell and Lange-Nielsen syndrome 1 (1)

Short QT syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

1.7

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.48

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0026

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

0.69

PhyloP100

-0.18

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.59

Sift

Benign

0.097

Sift4G

Benign

0.61

Polyphen

0.0

Vest4

0.22

MVP

0.91

MPC

0.39

ClinPred

0.014

GERP RS

4.1

Varity_R

0.035

gMVP

0.33

Mutation Taster

=89/11

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over