chr11-2528023-G-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4PP3PP4

This summary comes from the ClinGen Evidence Repository: NM_000218.3(KCNQ1):c.477+5G>A is a variant in intron 2. The computational splicing predictor SpliceAI gives a score of 0.64 for donor gain (Threshold is > 0.5), predicting that the variant disrupts the donor splice site of intron 2 of KCNQ1 (PP3). A minigene assay showed that the variant disrupts splicing resulting in stop codon, indicating that this variant impacts protein function (PMID:36197721), however at least two functional studies are needed for PS3_Supporting, so this criterion is not met. Another variant disrupting this splice site, NM_000218.3(KCNQ1):c.477+1G>A, has been classified as pathogenic for long QT syndrome 1 by the ClinGen Potassium Channel Arrhythmia VCEP, however, PS1 is not considered applicable for intronic variants. This variant has been reported in at least 13 probands with long QT syndrome (PS4; PMID:19716085, PMID:21350584, PMID:23995044, PMID:15840476, PMID:10973849, PMID:10728423). At least one affected proband exhibited QTc prolongation above 480 milliseconds and swimming-associated events, which together are highly specific for long QT syndrome 1 (PP4, PMID:10560595). This variant has been reported to segregate with LQTS in 2 mother/child relationships, as well as one proband with JLNS and aunt affected with LQTS with QTc>480, which are not sufficient to meet the PP1 code (PMID:23124029, PMID:10728423). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.00001337, with 1/74812 in the African / African-American 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 detected in at least 2 individuals with a diagnosis of Jervell and Lange-Nielsen syndrome, one of whom harbored the variant confirmed in trans with the NM_000218.3(KCNQ1):c.1741A>T (p.Lys581Ter) variant, which was previously classified pathogenic by the ClinGen Potassium Channel Arrhythmia VCEP (PMID:32508908), however PM3 is not met since this code requires the variant to be sufficiently rare (meeting PM2_Supporting). The other patient harbored the variant confirmed in trans with the p.Tyr171Ter variant, which was not specifically described at the DNA level and has not been previously classified by the ClinGen Potassium Channel Arrhythmia VCEP (PMID:23392653). In summary, this variant meets the criteria to be classified as likely pathogenic for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PS4, PP3, and PP4. (VCEP specifications version 1.0.0; date of approval 03/04/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA007174/MONDO:0100316/112

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 splice_region, intron

Scores

Splicing: ADA: 0.9981

Clinical Significance

Likely pathogenic reviewed by expert panel P:16O:1

Conservation

PhyloP100: 5.96

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PS4

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

PP3

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

PP4

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	Effect	Exon Rank	Protein
KCNQ1	NM_000218.3	MANE Select	c.477+5G>A	splice_region intron	N/A	NP_000209.2
KCNQ1	NM_001406836.1		c.477+5G>A	splice_region intron	N/A	NP_001393765.1
KCNQ1	NM_001406837.1		c.207+5G>A	splice_region intron	N/A	NP_001393766.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.477+5G>A	splice_region intron	N/A	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6	TSL:1	c.96+5G>A	splice_region intron	N/A	ENSP00000334497.5	P51787-2
KCNQ1	ENST00000910997.1		c.477+5G>A	splice_region intron	N/A	ENSP00000581056.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250976

AF XY:

0.0000221

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000824

AC:

AN:

1456644

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

725038

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33358

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86168

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52654

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000812

AC:

AN:

1107938

Other (OTH)

AF:

0.0000166

AC:

AN:

60260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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:

0.0000331

Hom.:

Bravo

AF:

0.0000113

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Long QT syndrome 1 (6)

not provided (4)

Cardiac arrhythmia (2)

Long QT syndrome (2)

Cardiovascular phenotype (1)

Congenital long QT syndrome (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.59

PhyloP100

6.0

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

Splicevardb

3.0

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.23

Position offset: -5

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