rs120074179

Variant names:

• chr11-2572089-G-A
• rs120074179
• NM_000218.3:c.760G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-2572089-G-A
• chr11-2572089-G-C
• chr11-2572089-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2_Supporting PS4_Moderate PP1_Strong PS3_Supporting PP3 PP4

This summary comes from the ClinGen Evidence Repository: NM_000218.3(KCNQ1):c.760G>A (p.Val254Met)‌ is a missense variant in KCNQ1 predicted to replace valine with methionine at amino acid 254. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in affected probands exhibiting QTc prolongation above 480 milliseconds and an exercise-associated event, which together are highly specific for long QT syndrome 1 (PP4, PMID:29439887). This variant has been reported in at least 4 additional probands affected with long QT syndrome 1 (PS4_Moderate; PMID:29439887). The variant segregates with long QT syndrome through 10 affected family members of the 5 probands confirmed to be similarly affected by exhibiting QTc prolongation above 480 milliseconds and/or syncope and/or Schwartz score above 3.5 (PP1_Strong, PMID:29439887). An additional family has been reported but has not been described in sufficient detail to be considered for family segregation (PMID:8528244). The computational predictor REVEL gives a score of 0.918, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). The variant has been shown to disrupt KCNQ1 function in two required experimental assays, both of them manual patch-clamp studies reporting a dominant negative electrophysiological defect (PS3_Supporting; PMID:10376919, PMID:14756674). In summary, this variant meets the criterion to be classified as pathogenic for long QT syndrome 1, as specified by the ClinGen Potassium Channel Arrhythmia VCEP; PS3_Supporting, PS4_Moderate PM2_Supporting, PP1_Strong, PP3, PP4. (VCEP specifications version 1.0.0; date of approval 03/04/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA008122/MONDO:0100316/112

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9 O:2
• Conservation: PhyloP100: 7.58
• Publications: 41 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: Pathogenic. The variant received 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.760G>A	p.Val254Met	missense	Exon 5 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.760G>A	p.Val254Met	missense	Exon 5 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.490G>A	p.Val164Met	missense	Exon 6 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.760G>A	p.Val254Met	missense	Exon 5 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.379G>A	p.Val127Met	missense	Exon 5 of 16	ENSP00000334497.5	P51787-2
	KCNQ1	ENST00000910997.1		c.757G>A	p.Val253Met	missense	Exon 5 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460076 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726386

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52084

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111690

Other (OTH) AF: 0.00 AC: 0 AN: 60338

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Long QT syndrome 1 (3)
3	-	-	not provided (3)
2	-	-	Long QT syndrome (2)
1	-	-	Cardiovascular phenotype (1)
-	-	-	Congenital long QT syndrome (1)
-	-	-	Jervell and Lange-Nielsen syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551647:Long QT syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.90		Loss of helix (P = 0.0376)
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.90
gMVP		0.95
Mutation Taster		=6/94	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: rs120074179; hg19: chr11-2593319; COSMIC: COSV50102167;