rs397508077

Variant names:

• chr11-2585299-CTCAT-C
• rs397508077
• NM_000218.3:c.1124_1127delTTCA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.1124_1127delTTCA​(p.Ile375ArgfsTer43) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,440 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 8.70
• Publications: 2 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-2585299-CTCAT-C is Pathogenic according to our data. Variant chr11-2585299-CTCAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 52962.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.1124_1127delTTCA	p.Ile375ArgfsTer43	frameshift_variant, splice_region_variant	Exon 8 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1124_1127delTTCA	p.Ile375ArgfsTer43	frameshift_variant, splice_region_variant	Exon 8 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251100 AF XY: 0.00000736

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461440 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727066

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111846

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Mar 04, 2022

AiLife Diagnostics, AiLife Diagnostics

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

- -

-

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 30, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 30291343, 26669661, 28532774, 28341588, 36721196, 15840476) -

Long QT syndrome Pathogenic:3

Nov 13, 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.Ile375Argfs*43) 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 (rs397508077, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 15840476, 28532774). This variant is also known as del 1124–1127 L374/fs43*, L375RfsX43. ClinVar contains an entry for this variant (Variation ID: 52962). 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. -

Nov 09, 2023

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 24, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1124_1127del (p.Ile375Argfs*43) variant in the KCNQ1 gene is located in exon 8 and introduces a reading frameshift resulting in premature translational termination codon. This variant is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ1 gene are known to be pathogenic (PMID: 9323054, 19862833). This variant has been reported in multiple individuals with either autosomal dominant long QT syndrome or autosomal recessive Jervell Lange-Nielsen syndrome (PMID: 36721196,15840476, 26669661). This variant is rare (1/251100 chromosomes) in the general population database, gnomAD. ClinVar contains an entry for this variant (ID:52962). Based on the evidence, the c.1124_1127del (p.Ile375Argfs*43) variant in the KCNQ1 gene variant is classified as pathogenic. -

Cardiovascular phenotype Pathogenic:3

Mar 27, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.1124_1127delTTCA (p.Ile375Argfs) variant in KCNQ1 gene is a frameshift change that results in the loss of the 780 amino acids of CPT (~35%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is absent from the large control population datasets of ExAC and gnomAD (120414 and 246038 chrs, respectively). The variant has been reported in at least two LQTS families with maternal lineage of inheritance (Itah, 2016) and another unrelated affected individual (Tester, 2005). In addition, it has been cited as Pathogenic by a reputable databases/clinical laboratories. Taking together, the variant was classified as Pathogenic. -

Dec 20, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PP5; This variant identified in exon 8 of KCNQ1 involves the deletion of four coding bases (c.1124_1127delTTCA) that results in a shift in the reading frame and introduces a premature termination of the protein 43 amino acids downstream (p.Ile375Ter43). This alteration is absent from healthy populations, and has been classified as a pathogenic alteration by other clinical testing laboratories (SCV000234581.12; SCV000695982.1). No evidence was found to support any of the ACMG Benign criteria; therefore, this alteration meets ACMG guidelines for classification as a pathogenic variant. -

May 28, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1124_1127delTTCA (p.I375Rfs*43) alteration, located in exon 8 (coding exon 8) of the KCNQ1 gene, consists of a deletion of 4 nucleotides from position 1124 to 1127, causing a translational frameshift with a predicted alternate stop codon after 43 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of <0.001% (1/251100) total alleles studied. The highest observed frequency was 0.001% (1/113510) of European (non-Finnish) alleles. This variant has been detected in long QT syndrome cohorts and has been reported as L374/fs43 and L375RfsX43 (Tester, 2005; Itoh, 2016; Ebrahim, 2017). Based on the available evidence, this alteration is classified as pathogenic. -

Long QT syndrome 1 Pathogenic:2

Oct 19, 2020

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_v1.1.1, 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 mutations result exclusively in Short QT syndrome (MIM#609621), while dominant negative and loss of function mutations can cause Long QT syndrome (LQTS, MIM#192500), atrial fibrillation (MIM#607554) and Jervell and Lange-Nielson syndrome (JLNS, MIM#220400) (OMIM, PMID: 19632626, PMID: 28438721). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. JLNS is a more severe form of LQTS, and is the only condition caused by biallelic mutations (PMID: 28438721). (N) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 20301308, OMIM). (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 8 of 16). (P) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic (ClinVar, Decipher). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in patients with LQTS (ClinVar, PMID: 19862833). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Jan 12, 2022

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiac arrhythmia Pathogenic:1

Apr 30, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes the deletion of 4 nucleotides in exon 8 of the KCNQ1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has shown that this variant leads to reduced channel current density in transfected CHO cells. Additionally, there was a complete lack of expression of the variant allele in iPSC-CMs (induced pluripotent stem cell-derived cardiomyocytes) from a heterozygous carrier, although RNA expression was maintained in whole-blood derived cDNA from the same individual (PMID: 36721196). This variant has been reported in nine Belgian families presenting with either Jervell-Lange-Nielsen syndrome (JLNS) or long QT syndrome. Among them, two homozygotes were affected with JLNS, four symptomatic heterozygotes experienced syncopes or sudden cardiac death, and six out of 40 heterozygotes exhibited a resting QTc greater than 500 ms (PMID: 36721196). In one of these families, the variant was identified in an individual with Brugada syndrome, but was absent in his children who were also diagnosed with the condition, suggesting other genetic factors might be involved (PMID: 36721196). Additionally, this variant has been observed in several individuals affected with or suspected of having long QT syndrome in other cohorts (PMIDs: 15840476, 26669661, 28532774, 32893267, 36721196) and in a healthy individual (PMID: 30291343). This variant has been identified in 1/251100 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs397508077; hg19: chr11-2606529;