11-2768881-C-T

Variant names:

• chr11-2768881-C-T
• rs17215500
• NM_000218.3:c.1552C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

This summary comes from the ClinGen Evidence Repository: NM_000218.3(KCNQ1):c.1552C>T (p.Arg518Ter) is a nonsense variant in exon 12 of 16 that introduces a premature stop codon at codon 518 and is predicted to trigger nonsense-mediated decay (PVS1). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0001737, with 205/1179992 alleles in the European (non-Finnish) population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP BS1 threshold of >0.0004 and higher than the PM2_Supporting threshold of <0.00001, so neither criterion is met. This variant has been detected in at least 2 apparently unrelated individuals with Jervell and Lange-Nielsen syndrome who had both a long QT interval and congenital deafness and harbored the variant in the homozygous state (1 pt, PMID:29922582, PMID:28438721, PM3), however PM3 is not met since this code requires the variant to be sufficiently rare (meeting PM2_Supporting). Additional individuals harbored the variant in the compound heterozygous state, some with autosomal recessive long QT syndrome (without congenital deafness) and others with Jervell and Lange-Nielsen syndrome (PMID:24912595, PMID:23392653). One individual harbored the variant in the compound heterozygous state, confirmed in trans with the NM_000218.3(KCNQ1):c.1573G>A (p.Ala525Thr) variant, which has not yet been classified by the ClinGen Potassium Channel Arrhythmia VCEP (PMID:24912595). This variant has been shown to disrupt KCNQ1 function in at least four experimental assays, including manual patch-clamp and KCNQ1 mislocalization by immunofluorescence (PMID:24912595, PMID:25705178), however, PS3_Supporting is not met since the variant has already met PVS1. In summary, this variant meets the criteria to be classified as likely pathogenic for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PVS1. (VCEP specifications version 1.0.0; date of approval 03/04/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA005894/MONDO:0100316/112

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 stop_gained
• Clinical Significance: Likely pathogenic reviewed by expert panel P:29 U:1 O:1
• Conservation: PhyloP100: 1.83
• Publications: 62 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: G2P, Labcorp Genetics (formerly Invitae)
• 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

Specifications for KCNQ1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000218.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.1552C>T	p.Arg518*	stop_gained	Exon 12 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.1456C>T	p.Arg486*	stop_gained	Exon 11 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.1282C>T	p.Arg428*	stop_gained	Exon 13 of 17	NP_001393766.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1552C>T	p.Arg518*	stop_gained	Exon 12 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.1171C>T	p.Arg391*	stop_gained	Exon 12 of 16	ENSP00000334497.5	P51787-2
	KCNQ1	ENST00000910997.1		c.1549C>T	p.Arg517*	stop_gained	Exon 12 of 16	ENSP00000581056.1

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

GnomAD2 exomes AF: 0.000103 AC: 26 AN: 251412 AF XY: 0.0000957

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

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

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53392

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

European-Non Finnish (NFE) AF: 0.000183 AC: 203 AN: 1111976

Other (OTH) AF: 0.000281 AC: 17 AN: 60392

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000102 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

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	Long QT syndrome 1 (7)
7	-	-	not provided (7)
4	1	-	Long QT syndrome (5)
3	-	-	KCNQ1-related disorder (3)
2	-	-	Cardiovascular phenotype (2)
1	-	-	Cardiac arrhythmia (1)
1	-	-	Congenital long QT syndrome (1)
1	-	-	Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 (1)
1	-	-	Long QT syndrome 1, recessive (1)
1	-	-	Monogenic hearing loss (1)
1	-	-	not specified (1)
-	-	-	Jervell and Lange-Nielsen syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.8
Vest4		0.97
GERP RS		-0.65
Mutation Taster		=3/197	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: rs17215500; hg19: chr11-2790111; COSMIC: COSV99326725; COSMIC: COSV99326725;