11-2588798-AC-ACC

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000218.3(KCNQ1):c.1343dupC(p.Glu449ArgfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,714 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 0.0710

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 11-2588798-A-AC is Pathogenic according to our data. Variant chr11-2588798-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 52978.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.1343dupC	p.Glu449ArgfsTer14	frameshift_variant	Exon 10 of 16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNQ1	ENST00000155840.12 link	c.1343dupC	p.Glu449ArgfsTer14	frameshift_variant	Exon 10 of 16	1	NM_000218.3	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6 link	c.962dupC	p.Glu322ArgfsTer14	frameshift_variant	Exon 10 of 16	1		ENSP00000334497.5	P51787-2
KCNQ1	ENST00000496887.7 link	c.986dupC	p.Glu330ArgfsTer14	frameshift_variant	Exon 10 of 16	5		ENSP00000434560.2	E9PPZ0
KCNQ1	ENST00000646564.2 link	c.803dupC	p.Glu269ArgfsTer14	frameshift_variant	Exon 5 of 11			ENSP00000495806.2	A0A2R8YEQ9

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151480

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

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

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250342

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135466

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461234

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726892

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151480

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73970

show subpopulations

Gnomad4 AFR

AF:

0.0000243

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Jan 15, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 12, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with long QT syndrome (LQTS) (PMID: 12702160, 24388587, 15913580); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15913580, 26669661, 32470535, 24388587, 12702160, 28364778) -

Long QT syndrome

Pathogenic:3

Sep 28, 2023

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1343dup (p.Glu449Argfs*14) variant is located in exon 10 of the KCNQ1 gene. This 1bp duplication is predicted to shift the reading frame such that it introduces a premature translation termination codon. It is expected to result in an absent or disrupted protein product. This variant has been reported in individuals with long QT syndrome in heterozygosity (PMID: 36102233, 32383558, 24388587, 15840476, 12702160), and in individuals with Jervell and Lange-Nielsen Syndrome in homozygosity or compound heterozygosity (PMID: 26669661, 28364778). Loss-of-function variants in KCNQ1 gene are known to be pathogenic (PMID: 9323054, 19862833). ClinVar contains an entry for this variant (ID: 52978). This variant is rare (1/250342 chromosomes) in the general population database (gnomAD). Based on the available evidence, this variant is classified as pathogenic. -

Mar 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu449Argfs*14) in the KCNQ1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833). This variant is present in population databases (rs397508088, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with long QT syndrome or suspected long QT syndrome (PMID: 12702160, 24388587, 26669661). This variant is also known as c.1338insC. ClinVar contains an entry for this variant (Variation ID: 52978). For these reasons, this variant has been classified as Pathogenic. -

Feb 08, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Long QT syndrome 1

Pathogenic:1

Aug 01, 2023

Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1

Pathogenic:1

Jan 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital long QT syndrome

Pathogenic:1

Mar 18, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu449ArgfsX14 variant in KCNQ1 has been reported in at least 2 individuals with long QT syndrome (LQTS; Chen 2003 PMID: 12702160, Itoh 2016 PMID: 26669661). This variant has also been reported in in 2 individuals with Jervell and Lange-Nielsen syndrome (JLNS): in 1 homozygote (Adadi 2017 PMID: 28364778) and 1 heterozygote in whom a variant affecting the other copy of KCNQ1 was not identified (Chang 2014 PMID: 24388587). This variant has also been reported by other clinical laboratories in Clinvar (Variation ID: 52978) and has been identified in 0.003% (1/34524) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the proteinâ€™s amino acid sequence beginning at position 449 and leads to a premature termination codon 14 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the KCNQ1 gene is an established disease mechanism in autosomal dominant LQTS and in autosomal recessive JLNS. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant LQTS (ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Supporting) and in autosomal recessive JLNS (ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Supporting). -

Cardiovascular phenotype

Pathogenic:1

Jan 17, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1343dupC pathogenic mutation, located in coding exon 10 of the KCNQ1 gene, results from a duplication of C at nucleotide position 1343, causing a translational frameshift with a predicted alternate stop codon (p.E449Rfs*14). This alteration has been reported in subjects with long QT syndrome (LQTS) (Chen S et al. Clin Genet, 2003 Apr;63:273-82; Kapa S et al. Circulation, 2009 Nov;120:1752-60; Chang RK et al. J Pediatr, 2014 Mar;164:590-5.e1-3). This alteration was also reported as homozygous in a subject with congenital hearing loss and prolonged QT interval (Adadi N et al. J Med Case Rep, 2017 Apr;11:88). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over