rs1435990592

Variant names:

• chr11-2445294-TCCCCGGCCGCG-T
• rs1435990592
• NM_000218.3:c.200_210delCGGCCGCGCCC

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.200_210delCGGCCGCGCCC​(p.Pro67ArgfsTer214) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ1 NM_000218.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.827
• Publications: 1 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

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 11-2445294-TCCCCGGCCGCG-T is Pathogenic according to our data. Variant chr11-2445294-TCCCCGGCCGCG-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 449221.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.200_210delCGGCCGCGCCC	p.Pro67ArgfsTer214	frameshift_variant	Exon 1 of 16	ENST00000155840.12	NP_000209.2
KCNQ1	NM_001406836.1	c.200_210delCGGCCGCGCCC	p.Pro67ArgfsTer214	frameshift_variant	Exon 1 of 15		NP_001393765.1
KCNQ1	NM_001406838.1	c.200_210delCGGCCGCGCCC	p.Pro67ArgfsTer212	frameshift_variant	Exon 1 of 11		NP_001393767.1
KCNQ1	NM_001406837.1	c.-163_-153delCGGCCGCGCCC		5_prime_UTR_variant	Exon 1 of 17		NP_001393766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.200_210delCGGCCGCGCCC	p.Pro67ArgfsTer214	frameshift_variant	Exon 1 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.03e-7 AC: 1 AN: 1244822 Hom.: 0 AF XY: 0.00000164 AC XY: 1 AN XY: 610262

African (AFR) AF: 0.00 AC: 0 AN: 25680

American (AMR) AF: 0.00 AC: 0 AN: 20336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19314

East Asian (EAS) AF: 0.00 AC: 0 AN: 28580

South Asian (SAS) AF: 0.00 AC: 0 AN: 57184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3788

European-Non Finnish (NFE) AF: 9.90e-7 AC: 1 AN: 1010542

Other (OTH) AF: 0.00 AC: 0 AN: 50798

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Oct 12, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Dec 30, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 23, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with Long QT syndrome referred for testing at GeneDx and in the published literature (PMID: 19716085); 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: 19716085) -

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

- -

Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 Pathogenic:1

Dec 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

KCNQ1-related disorder Pathogenic:1

Jan 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The KCNQ1 c.200_210del11 variant is predicted to result in a frameshift and premature protein termination (p.Pro67Argfs*214). This variant has been reported to be causative for long QT syndrome (described as 200_210delCGGCCGCGCCC (S66fs+213X) in Table S1, Kapplinger et al. 2009. PubMed ID: 19716085). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in KCNQ1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Long QT syndrome Pathogenic:1

Jan 23, 2025

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.Pro67Argfs*214) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 449221). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Jun 13, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.200_210del11 pathogenic mutation, located in coding exon 1 of the KCNQ1 gene, results from a deletion of 11 nucleotides at nucleotide positions 200 to 210, causing a translational frameshift with a predicted alternate stop codon (p.P67Rfs*214). This variant (also described as S66fs+213X) was reported in individual(s) with features consistent with long QT syndrome (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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		0.83
Mutation Taster		=8/192	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1435990592; hg19: chr11-2466524;