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:16

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: 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_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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.477+5G>A		splice_region_variant, intron_variant	Intron 2 of 15	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.477+5G>A		splice_region_variant, intron_variant	Intron 2 of 15	1	NM_000218.3	ENSP00000155840.2		P51787-1

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Long QT syndrome 1

Pathogenic:6

May 23, 2019

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Aug 01, 2023

Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 10, 2022

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 05, 2022

Roden Lab, Vanderbilt University Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:in vitro;research

The KCNQ1 c.477+5G>A variant was observed in 7 cases of LQTS and was observed rarely in population databases (PMID: 32893267). The variant is highly predicted to alter mRNA splicing. A minigene assay provided experimental support for this prediction. Collectively, this evidence allows the classification of this variant as Pathogenic. -

Jul 01, 2025

ClinGen Potassium Channel Arrhythmia Variant Curation Expert Panel, ClinGen

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

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). -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Gain of function variants result exclusively in short QT syndrome 2 (MIM#609621), while dominant negative and loss of function variants can cause long QT syndrome 1 (LQTS, MIM#192500), familial atrial fibrillation 3 (MIM#607554) as well as Jervell and Lange-Nielsen syndrome (JLNS, MIM#220400) (OMIM, PMIDs: 19632626, 28438721). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. JLNS is characterised by congenital, bilateral deafness and variable degrees of QT prolongation, and is the only condition caused by biallelic variants (PMID: 28438721). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, PMID: 20301308). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. This splice site variant has been demonstrated across two different studies to result in aberrant mRNA splicing with each study predicting a different premature termination codon (Crehalet, H. et al. (2012)). (SP) 0251 - Variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (3 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic or pathogenic by multiple clinical diagnostic laboratories and has been reported as either compound heterozygous in JLNS individuals or heterozygous in LQTS individuals (ClinVar, VCGS, Crehalet, H. et al. (2012); PMIDs: 28438721, 10728423, 32508908, 36102233). (SP) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:4

Mar 24, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Non-canonical splice site variant demonstrated to result in loss-of-function (Crehalet et al., 2012); Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID# 53047; ClinVar); This variant is associated with the following publications: (PMID: 7446532, 25525159, 10973849, 18441444, 16922724, 10560595, 19716085, 21350584, 23124029, 15840476, 10728423, 22429796, 28438721, 23995044, 32048431, 31737537, 31447099, 34135346, 23392653, 32508908) -

Jul 20, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 14, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The KCNQ1 c.477+5G>A variant (rs397508111, ClinVar Variation ID: 53047) is reported in the literature in several individuals affected with LQTS or Jervell and Lange-Nielsen syndrome (JLNS) (Ackerman 1999, Crehalet 2012, Giudicessi 2013, Kapplinger 2009, Millat 2006, Obeyesekere 2012, Splawski 2000, Van Langen 2003). This variant is found in the general population with an overall allele frequency of 0.0012% (3/250976 alleles) in the Genome Aggregation Database (v2.1.1). This is an intronic variant, and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Additionally, in vitro assays show use of a cryptic donor site further downstream (Crehalet 2012), and other variants affecting the same splice site (c.477+5G>C and c.477+1G>A) have been reported in individuals with LQTS (Kapplinger 2009). Based on available information, the c.477+5G>A variant is considered to be pathogenic. References: Ackerman MJ et al. Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome. Mayo Clin Proc. 1999 Nov;74(11):1088-94. PMID: 10560595. Crehalet H et al. Combined use of in silico and in vitro splicing assays for interpretation of genomic variants of unknown significance in cardiomyopathies and channelopathies. Cardiogenetics. 2012; v2:e6. Giudicessi JR et al. Prevalence and potential genetic determinants of sensorineural deafness in KCNQ1 homozygosity and compound heterozygosity. Circ Cardiovasc Genet. 2013 Apr;6(2):193-200. PMID: 23392653. Kapplinger JD et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009 Sep;6(9):1297-303. PMID: 19716085. Millat G et al. Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome. Clin Genet. 2006 Sep;70(3):214-27. PMID: 16922724. Obeyesekere MN et al. End-recovery QTc: a useful metric for assessing genetic variants of unknown significance in long-QT syndrome. J Cardiovasc Electrophysiol. 2012 Jun;23(6):637-42. PMID: 22429796. Splawski I et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation. 2000 Sep 5;102(10):1178-85. PMID: 10973849. Van Langen IM et al. The use of genotype-phenotype correlations in mutation analysis for the long QT syndrome. J Med Genet. 2003 Feb;40(2):141-5. PMID: 12566525. -

Long QT syndrome

Pathogenic:2

Sep 24, 2024

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant causes a G to A nucleotide substitution at the +5 position of intron 2 splice donor site of the KCNQ1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Functional studies using RNA samples from carriers and mini-gene assays have shown that this variant results in the complete loss of canonical splicing (PMID: 10728423, 36197721, 37821546, doi.org/10.4081/cardiogenetics.2012.e6). This variant has been reported in over ten individuals affected with long QT syndrome or prolonged QT interval (PMID: 10560595, 10728423, 10973849, 16922724, 22429796, 28438721; Crehalet et al., 2012, doi.org/10.4081/cardiogenetics.2012.e; Hofman 2013, dissertation, Univ. of Amsterdam, ISBN 9789461822116). This variant has also been identified in five biallelic individuals affected with autosomal recessive Jervell and Lange-Nielsen syndrome (PMID: 10728423, 23392653, 32508908; Amirian 2018, doi:10.4172/1747-0862.1000359), indicating that this variant contributes to disease. This variant has been identified in 3/250976 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNQ1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 2 of the KCNQ1 gene. It does not directly change the encoded amino acid sequence of the KCNQ1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs397508111, gnomAD 0.003%). This variant has been observed in individuals with Jervell and Lange-Nielsen syndrome (JLNS) and/or long QT syndrome (PMID: 10560595, 10973849, 16922724, 22429796, 23392653). This variant is also known as c.639+5G>A, IVSI+5G>A, IVS2+5G>A, and M159sp. ClinVar contains an entry for this variant (Variation ID: 53047). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Cardiac arrhythmia

Pathogenic:2

Jun 06, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 21, 2023

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: KCNQ1 c.477+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the 5 canonical splicing donor site. Two predict the variant weakens the 5' canonical splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing in Hela cells by a minigene splicing assay (Crehalet_2012). The variant allele was found at a frequency of 1.2e-05 in 250976 control chromosomes. c.477+5G>A has been reported in the literature in multiple individuals affected with features of autosomal dominant Arrhythmia including prolonged QT/QTc interval or Long-QT Syndrome (examples, Crehalet_2012, Yee_2022, Al-Hassnan_2017). This variant has also been observed at a compound heterozygous state along with second pathogenic variants in at-least two individuals diagnosed with autosomal recessive Jervell and Lange-Nielsen syndrome (examples, Chouabe_2000, Qiu_2020), which the patients present both congenital sensorineural deafness and prolonged QT intervals. These data indicate that the variant is very likely to be associated with both diseases. The following publications have been ascertained in the context of this evaluation (PMID: 28438721, 10728423, 32508908, 36102233, Crehalet_2012 without PMID). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Congenital long QT syndrome

Pathogenic:1

Apr 12, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.477+5G>A variant in KCNQ1 has been reported in the heterozygous state in >5 individuals with Long QT syndrome (LQTS), and in the compound heterozygous state in one individual with Jervell and Lange-Nielsen syndrome (JLNS; Ackerman 1999 PMID: 10560595, Chouabe 2000 PMID: 10728423, Hofman 2011 PMID: 21350584, Crehalet 2012, Obeyesekere 2012 PMID: 22429796). It segregated with prolonged QT-intervals in at least 3 relatives from 2 different families, including that of the individual with JNLS (Ackerman 1999 PMID: 10560595, Chouabe 2000 PMID: 10728423). At least two relatives who were heterozygous carriers of this variant were clinically asymptomatic for LQTS, suggesting reduced penetrance (Chouabe 2000 PMID: 10728423). The c.477+5G>A variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 53047). In addition, it has been identified in 0.0012% (1/74812) of African/African American, 0.001% (1/91002) of South Asian chromosomes and 0.0009% (10/1175974) European chromosomes by gnomAD (http://gnomad.broadinstitute.org/; v4.0.0). This variant is located in the 5' splice region. Functional studies using patient cDNA have shown that the c.477+5G>A variant impacts splicing (Chouabe 2000 PMID: 10728423, Crehalet 2012), leading to an aberrant mRNA transcript that is predicted to encode the first 159 amino acids of the protein, followed by 4 aberrant residues and a premature termination codon. This would likely result in an absent protein. Loss-of-function variants in KCNQ1 are associated with LQTS (also known as Romano-Ward syndrome) in the heterozygous state and with JLNS in the compound heterozygous or homozygous state. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant LQTS (ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Moderate, PP1) and autosomal recessive JLNS (ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3). -

Cardiovascular phenotype

Pathogenic:1

Mar 31, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.477+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 2 in the KCNQ1 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. This variant (also known as IVS2+5G>A, IVS1+5G>A and c.639+5G>A) was identified in one or more individuals with features consistent with long QT syndrome (LQTS) and segregated with disease in at least one family (Ackerman MJ et al. Mayo Clin. Proc. 1999;74:1088-94; Chouabe C et al. Cardiovasc. Res. 2000;45:971-80; Millat G et al. Clin. Genet. 2006;70:214-27; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Hofman N et al. Neth Heart J. 2011;19:10-16; Crehalet H et al. Cardiogenetics. 2012;2:e6; Obeyesekere MN et al. J. Cardiovasc. Electrophysiol. 2012;23:637-42; Cuneo BF et al. Circ Arrhythm Electrophysiol. 2013;6:946-51; Al-Hassnan ZN et al. Heart Rhythm. 2017;14:1191-1199). This variant has been identified in the homozygous state and/or in conjunction with other KCNQ1 variant(s) in individual(s) with features consistent with Jervell and Lange-Nielson syndrome (JLNS); in at least one instance, the variants were identified in trans (Chouabe C et al. Cardiovasc. Res. 2000;45:971-80; Giudicessi JR et al. Circ Cardiovasc Genet. 2013;6:193-200; Amirian A et al. J Mol Genet med. 2018;12:(3); Qiu Y et al. Neural Plast. 2020 May;2020:3569359). A minigene assay indicated that this mutation leads to the utilization of a cryptic donor, resulting in a frameshift and premature truncation (Crehalet H et al. Cardiogenetics. 2012;2:e6). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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