rs397508112

Variant names:

• chr11-2570637-CT-C
• rs397508112
• NM_000218.3:c.488delT

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.488delT​(p.Leu163ArgfsTer74) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000548 in 1,460,366 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.81
• Publications: 4 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 11-2570637-CT-C is Pathogenic according to our data. Variant chr11-2570637-CT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 53050.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.488delT	p.Leu163ArgfsTer74	frameshift_variant	Exon 3 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.488delT	p.Leu163ArgfsTer74	frameshift_variant	Exon 3 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460366 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 726592

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Feb 08, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 15466642, 15840476, 19716085, 19841300, 22677073, 31447099, 30122538, 33087929, 34319147) -

Dec 01, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Pathogenic:2

Oct 12, 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.Leu163Argfs*74) 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 individuals with sudden unexplained death (PMID: 22677073). This variant is also known as L163FS/X236. ClinVar contains an entry for this variant (Variation ID: 53050). For these reasons, this variant has been classified as Pathogenic. -

Jul 10, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 1 nucleotide in exon 3 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. This variant has been reported in two individuals affected with or suspected of having long QT syndrome (PMID: 19716085, 32893267) and in another two individuals affected with sudden unexplained death (PMID: 15840476, 22677073). This variant has not been identified 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. -

Long QT syndrome 1 Pathogenic:1

May 24, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.488del (p.Leu163Argfs*74) variant in the KCNE1 gene has been reported in a patient from a cohort of 388 patients referred for LQTS genetic testing with a family history of a first degree relative with a cardiac event during swimming [reported as V162fs in PMID 15840476, 15840476]. This variant has not been observed in the ExAC database but has been assessed in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/53050). This one bp deletion in exon 3 results in a frameshift and the creation of a premature stop codon, and is predicted to result in a loss of function of KCNQ1. This variant is thus classified as pathogenic -

Jervell and Lange-Nielsen syndrome;C1141890:Congenital long QT syndrome;C5680250:Rare genetic deafness Pathogenic:1

Feb 02, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu163fs variant in KCNQ1 has been previously reported in at least 1 indiv idual with long QT syndrome and is absent from large population databases (Choi 2004, Tester 2005, Kapplinger 2009). This variant is predicted to cause a frames hift, which alters the protein's amino acid sequence beginning at codon 163 and leads to a premature stop codon 74 amino acids downstream. This alteration is th en predicted to lead to a truncated or absent protein. Loss of function variants in KCNQ1 lead to Jervell and Lange-Nielsen syndrome (JLNS) in compound heterozy gous and homozygous individuals, while dominant-negative and loss-of-function va riants in KCNQ1 have been shown to cause dominantly inherited long QT syndrome 1 (also known as Romano-Ward syndrome)in heterozygous individuals. In summary, al though additional studies are required to fully establish its clinical significa nce, this variant meets our criteria to be classified as likely pathogenic (http ://www.partners.org/personalizedmedicine/LMM) based upon its impact to the prote in. -

KCNQ1-related disorder Pathogenic:1

Sep 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The KCNQ1 c.488delT variant is predicted to result in a frameshift and premature protein termination (p.Leu163Argfs*74). This variant has been reported to be causative for long QT syndrome or sudden unexplained death (Table S1, Kapplinger et al. 2009. PubMed ID: 19716085; Tester et al. 2012. PubMed ID: 22677073). 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. -

Cardiovascular phenotype Pathogenic:1

Aug 28, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.488delT pathogenic mutation, located in coding exon 3 of the KCNQ1 gene, results from a deletion of one nucleotide at position 488, causing a translational frameshift with a predicted alternate stop codon (p.L163Rfs*74). This mutation has been reported in patients referred for long QT syndrome clinical genetic testing; however, clinical details are limited (Tester DJ et al. Heart Rhythm. 2005;2:507-17; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). 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		5.8
Mutation Taster		=0/200	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: rs397508112; hg19: chr11-2591867;