11-2588798-AC-ACC

Variant names:

• chr11-2588798-A-AC
• rs397508087
• NM_000218.3:c.1343dupC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 0.0710
• Publications: 8 publications found

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

ENSG00000296223 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId 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	c.1343dupC	p.Glu449ArgfsTer14	frameshift_variant	Exon 10 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1343dupC	p.Glu449ArgfsTer14	frameshift_variant	Exon 10 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151480 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250342 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461234 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 726892

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000447 AC: 2 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53142

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5590

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111948

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151480 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 73970

African (AFR) AF: 0.0000243 AC: 1 AN: 41138

American (AMR) AF: 0.00 AC: 0 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67908

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

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)

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 15, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Long QT syndrome Pathogenic:3

Feb 08, 2024

All of Us Research Program, National Institutes of Health

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.

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.

Long QT syndrome 1 Pathogenic:2

Aug 01, 2023

Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 26, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction); Variant is present in gnomAD <0.01 (v4: 10 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar; Other NMD-predicted variant(s) comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). Additional information: This variant is heterozygous; 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); 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); The condition associated with this gene has incomplete penetrance (OMIM, PMID: 20301308); Inheritance information for this variant is not currently available in this individual.

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 protein’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
PhyloP100		0.071
Mutation Taster		=4/196	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397508087; hg19: chr11-2610028;