11-2768881-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000218.3(KCNQ1):c.1552C>T(p.Arg518Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,613,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:23 U:1 O:1
• Conservation: PhyloP100: 1.83

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]

ACMG classification

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 11-2768881-C-T is Pathogenic according to our data. Variant chr11-2768881-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2768881-C-T is described in Lovd as [Pathogenic]. Variant chr11-2768881-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.1552C>T	p.Arg518Ter	stop_gained	12/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1552C>T	p.Arg518Ter	stop_gained	12/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.1171C>T	p.Arg391Ter	stop_gained	12/16	1
KCNQ1	ENST00000496887.7	c.1195C>T	p.Arg399Ter	stop_gained	12/16	5
KCNQ1	ENST00000646564.2	c.1012C>T	p.Arg338Ter	stop_gained	7/11

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000103 AC: 26 AN: 251412 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135890

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000155 AC: 226 AN: 1461822 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 98 AN XY: 727208

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000183

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152090 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74278

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000842 Hom.: 0

Bravo AF: 0.0000302

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 03, 2023	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	May 08, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Region Ostergotland	Feb 22, 2021	PVS1, PS3, PP5, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Feb 24, 2018	This c.1552C>T (p.Arg518*) variant in exon 12 of the KCNQ1 gene creates a premature translation stop codon and is predicted to result in an absent or disrupted protein product. This variant is well-described in association with autosomal recessive Jervell and Lange-Nielsen syndrome and has also been reported in autosomal recessive and autosomal dominant LQTS (PMID 10482963, 10704188, 10737999, 18752142, 22539601, 24552659, 27451284, and 28438721). Reduced penetrance and variable expressivity have been observed in individuals heterozygous for this variant (10482963, 11530100, and 24552659). This variant is a founder allele in Swedish population (PMID 22539601). Based on these data the p.Arg518* variant in the KCNQ1 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Jul 21, 2017	- -
Pathogenic, criteria provided, single submitter	research	Cavalleri Lab, Royal College of Surgeons in Ireland	Dec 11, 2019	ACMG evidence PVS1, PS2, PP5 -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2020	Nonsense 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; Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 3131; Landrum et al., 2016); Published functional studies demonstrate a damaging effect (Ghosh et al., 2006; Harmer et al., 2014); This variant is associated with the following publications: (PMID: 16556866, 24912595, 23392653, 10737999, 25236808, 10482963, 11530100, 10704188, 24552659, 19716085, 24052033, 27286732, 31447099, 31737537, 28988457, 28438721, 22309168, 19841300, 26318259, 26669661, 27831900, 27816319, 19940153, 15840476, 18752142, 17905336, 29740400, 27451284, 15935335, 26187847, 24080067, 26019114, 14510661, 14678125, 25637381, 25525159, 29922582, 29247119, 29379719, 15176425, 22539601, 24631775, 23098067, 10973849, 26546361) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 30, 2020	PVS1, PS4, PS3, PP4 -
Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 11, 2017	- -

Long QT syndrome Pathogenic:4 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Feb 05, 2024	This sequence change in KCNQ1 is a nonsense variant predicted to cause a premature stop codon, p.(Arg518*), in biologically relevant exon 12/16 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.02% (205/1,179,992 alleles) in the European (non-Finnish) population. This variant is a Swedish founder mutation associated with a milder long QT syndrome (LQTS) phenotype in heterozygous individuals and a more severe phenotype consistent with Jervell Lange-Nielsen syndrome (JLNS) in biallelic individuals (PMID: 24552659, 34135346, 36310718). The variant has been reported to segregate with JLNS and LQTS (with incomplete penetrance) in multiple families (PMID: 24552659). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Strong. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	The c.1552C>T (p.Arg518*) variant of the KCNQ1 gene is located in exon 12 and is predicted to cause loss of normal protein function either through abnormal, prematurely truncated protein, or by absence of protein product due to nonsense-mediated mRNA decay. The loss-of-function variants in KCNQ1 gene are known to be pathogenic for long QT syndrome (LQTS) (PMID: 9323054, 19862833). This variant has been reported in individuals affected with autosomal recessive Jervell and Lange-Nielsen syndrome and has also been reported in autosomal recessive and autosomal dominant LQTS (PMID 10482963, 10704188, 10737999, 18752142, 22539601, 24552659, 27451284, and 28438721). Reduced penetrance and variable expressivity have been observed in individuals heterozygous for this variant (10482963, 11530100, and 24552659). This variant is a founder allele in Swedish population (PMID 22539601, 24552659). This variant is present at a low frequency (26/251412) in the general population according to gnomAD. For these reasons, the variant c.1552C>T (p.Arg518*) variant in the KCNQ1 gene has been classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Arg518*) 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 (rs17215500, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and/or long QT syndrome, although the clinical manifestations of long QT syndrome for heterozygous carriers are typically mild (PMID: 10704188, 22539601, 23098067, 24552659). It is commonly reported in individuals of Swedish ancestry (PMID: 24552659). ClinVar contains an entry for this variant (Variation ID: 3131). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, flagged submission	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 16, 2018	Variant summary: KCNQ1 c.1552C>T (p.Arg518X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00011 in 246226 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in KCNQ1 causing autosomal recessive LQTS (0.00011 vs 0.013), allowing no conclusion about variant significance. The variant, c.1552C>T, has been reported in the literature as a founder mutation in the Swedish population, in several homozygous and compound heterozygous individuals, who were affected with autosomal recessive long QT syndrome (LQTS) with intact auditory phenotype or with deafness (later designated as Jervell and Lange-Nielsen syndrome) (Larsen 1999, Giudicessi 2013, Winbo 2012). In these reports, family members, who were heterozygous carriers of the variant, were typically clinically asymptomatic, with a mildly prolonged QT interval detected by EKG; although rare cases of symptomatic long QT syndrome (LQTS) with intact auditory phenotype (denoted as Romano-Ward syndrome) were also reported (Winbo 2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, demonstrating non-functional channels when the variant protein was expressed alone; while co-expression of the variant protein with the wild type channel did not indicate dominant negative effect (Mousavi Nik 2015). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic for autosomal recessive long QT syndrome. -

KCNQ1-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This nonsense variant found in exon 12 of 16 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in individuals with autosomal dominant Long QT syndrome 1 (MIM: #192500) and in the homozygous/compound heterozygous state in patients with autosomal recessive Jervell and Lange-Nielsen syndrome (MIM: #220400) (PMID: 10482963, 10704188, 10737999, 18752142, 22539601, 24552659, 27451284, 28438721). Experimental evidence supports a damaging effect for this variant on protein function (PMID: 22309168, 24912595). Loss-of-function variation in KCNQ1 is an established mechanism of disease (PMID: 29532034). The c.1552C>T (p.Arg518Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.01% (26/251412). This variant is a common founder mutation in the Swedish population (PMID: 24552659). Based on the available evidence, the c.1552C>T (p.Arg518Ter) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 23, 2018	The KCNQ1 c.1552C>T (p.Arg518Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. Across a selection of available literature, the p.Arg518Ter variant has been identified in at least 111 individuals with KCNQ1-related disorders including at least eight in a homozygous state, at least 10 in a compound heterozygous state, and 93 in a heterozygous state (Larsen et al. 1999; Wei et al. 2000; Stattin et al. 2012; Giudicessi et al. 2013; Winbo et al. 2014). The variant was also found in two unaffected individuals in a heterozygous state (Larsen et al. 1999; Wei et al. 2000). The p.Arg518Ter variant was absent from 200 control chromosomes and is reported at a frequency of 0.00024 in the European (non-Finnish) population of the Exome Aggregation Consortium. This variant has been classified as a founder variant from a specific region of Sweden (Winbo et al. 2015) but has also been detected in other populations (Larsen et al. 1999; Wei et al. 2000; Giudicessi et al. 2013). Individuals carrying the variant in a compound heterozygous or homozygous state have a more severe phenotype compared to those with the variant in a heterozygous state (Winbo et al. 2015). To assess the functional effects of the p.Arg518Ter variant, fluorescently labelled KCNQ1 variant constructs were transfected in CHO-K1 cells and confocal microscopy was used to visualize localization of channel complexes. Two studies demonstrated that channel trafficking was disrupted in the presence of the variant whereby a high concentration of the complexes was retained in the endoplasmic reticulum (Wilson et al. 2005; Harmer et al. 2014). In addition, whole-cell patch clamp experiments were used to evaluate current flow and demonstrated that the p.Arg518Ter variant did not produce any current (Ghosh et al. 2006). Based on the collective evidence, the p.Arg518Ter variant is classified as pathogenic for KCNQ1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 12, 2018

The KCNQ1: p.Arg518Ter variant (rs17215500) has been reported in association with Jervell and Lange-Nielsen syndrome, an autosomal recessive disorder that includes long QT intervals and sensorineural hearing loss (Larsen 1999, Giudicessi 2013 and Wei 2000). It is common in the northern Swedish population due to a founder effect (Winbo 2014). Some carriers have been reported to have long QT intervals and related symptoms. Functional analysis, though, suggests that this variant is loss of function and does not act in the dominant negative manner of missense variants typically associated with Romano Ward syndrome (Huang 2001). In addition, this variant may be associated with digenic LQTS; for example, a symptomatic female patient with a resting QTc of 520ms harbored one copy each of this variant and a pathogenic SCN5A variant (Tan 2014). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.02 percent in the European Non-Finnish population (identified on 21 out of 116,682 chromosomes) and has been reported to the ClinVar database as pathogenic by multiple clinical laboratories. This variant induces a termination codon in exon 12 (of 16 exons), and functional studies demonstrate reduced plasma membrane ion channel localization and activity (Harmer 2014). Overall, the p.Arg518Ter variant is considered to be pathogenic. -

Conduction disorder of the heart Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jun 10, 2019

- -

Congenital long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 02, 2019

The p.Arg518X variant in KCNQ1 was reported in the heterozygous state in 6 individuals with autosomal dominant long QT syndrome (LQTS) and in the compound heterozygous state in 2 siblings with severe autosomal recessive LQTS (Larsen 1999, Stattin 2012). It has also been reported in the compound heterozygous and homozygous state in >13 individuals with Jervell and Lange-Nielsen syndrome (JLNS) and segregated with disease in >6 individuals from 2 families (Tranebjaerg 1999, Ning 2003, Wimbo 2012, Wimbo 2014). Relatives of these individuals who were heterozygous carriers of this variant were either clinically asymptomatic for LQTS or had a modestly prolonged QT interval (Larsen 1999, Ning 2003) suggesting reduced penetrance and variable expressivity. This variant has also been reported by other clinical labs in ClinVar (Variation ID 3131) and has been identified in 0.02% (21/111682) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Please note that for diseases with late-onset, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. This nonsense variant leads to a premature termination codon at position 518, which is predicted to lead to a truncated or absent protein. In vitro functional studies provide support for an impact of the p.Arg518X variant to protein function (Harmer 2012, Harmer 2014, Slaats 2015). Loss-of-function variants in KCNQ1 are associated with autosomal recessive JLNS and autosomal dominant LQTS (also known as Romano-Ward syndrome). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant LQTS (ACMG/AMP criteria applied: PVS1, PS4_Moderate, PS3_Supporting) and autosomal recessive JLNS (ACMG/AMP criteria applied: PVS1, PM2_Supporting, PS3_Supporting, PM3_Strong). -

Long QT syndrome 1, recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 08, 2003

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 15, 2021

The p.R518* pathogenic mutation (also known as c.1552C>T), located in coding exon 12 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1552. This changes the amino acid from an arginine to a stop codon within coding exon 12. This mutation, considered to be a Swedish founder mutation, has been described frequently in patients with autosomal recessive Jervell and Lange-Nielsen syndrome and in patients with autosomal dominant long QT syndrome, although some heterozygotes may exhibit mild phenotype or reduced penetrance (Larsen LA et al. Eur J Hum Genet. 1999;7(6):724-8; Tester DJ et al. Heart Rhythm. 2005;2(5):507-17; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Winbo A et al. Europace. 2012;14(12):1799-806; Winbo A et al. BMC Cardiovasc Disord. 2014;14:22). In one study, individuals heterozygous for R518* had a prolonged QTc compared with genotype negative individuals (average QTc of 462 ms vs 433ms) (Winbo A et al. BMC Med. Genet. 2017;18:74). 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. -

Cardiac arrhythmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 18, 2023

This variant changes 1 nucleotide in exon 12 of the KCNQ1 gene, creating a premature translation stop signal. It is expected to result in an absent or non-functional protein product. This variant has been reported in over 90 heterozygous individuals with mild long QT syndrome (PMID: 23098067, 24552659), as well as in over 30 compound heterozygous or homozygous individuals affected with Jervell and Lange-Nielsen syndrome (PMID: 10704188, 22539601, 24552659). This variant is thought to be a Swedish founder mutation (PMID: 24552659). This variant has been identified in 26/251412 chromosomes (20/113712 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNQ1 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. -

Jervell and Lange-Nielsen syndrome 1 Other:1

not provided, no classification provided

literature only

GeneReviews

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Uncertain	0.20
Eigen_PC	Benign	-0.082
FATHMM_MKL	Benign	0.49	N
MutationTaster	Benign	1.0	A;A
Vest4		0.97
GERP RS		-0.65

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

Other links and lift over

dbSNP: rs17215500; hg19: chr11-2790111; COSMIC: COSV99326725; COSMIC: COSV99326725;