rs199472720

Variant names:

• chr11-2572105-G-A
• rs199472720
• NM_000218.3:c.776G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-2572105-G-A
• chr11-2572105-G-C
• chr11-2572105-G-T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.776G>A​(p.Arg259His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,610,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R259L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 9.14
• Publications: 32 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 17 ACMG points.

• PM1: In a hotspot region, there are 22 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000218.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2572105-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 53102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.8321 (below the threshold of 3.09). Trascript score misZ: 0.90233 (below the threshold of 3.09). GenCC associations: The gene is linked to short QT syndrome type 2, long QT syndrome 1, Jervell and Lange-Nielsen syndrome 1, long QT syndrome, short QT syndrome, Jervell and Lange-Nielsen syndrome, hypertrophic cardiomyopathy, familial atrial fibrillation, atrial fibrillation, familial, 3.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 11-2572105-G-A is Pathogenic according to our data. Variant chr11-2572105-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 53101.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.776G>A	p.Arg259His	missense_variant	Exon 5 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.776G>A	p.Arg259His	missense_variant	Exon 5 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000163 AC: 4 AN: 244876 AF XY: 0.0000225

Gnomad AFR exome AF: 0.0000645

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: 0.0000272

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 24 AN: 1457986 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 725428

African (AFR) AF: 0.0000299 AC: 1 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1110220

Other (OTH) AF: 0.0000332 AC: 2 AN: 60278

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74466

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000827 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:3

Nov 19, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS4,PM1,PM5,PS3_SUP,PP3 -

Jan 30, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.776G>A (p.Arg259His) variant in the KCNQ1 gene has been reported in multiple LQTS/SQTS patients with significantly higher prevalence than that observed as extremely low in general population according to gnomad database. Arginine at amino acid position 259 is highly conserved during evolution. Arg259Cys, Arg259Gly and Arg259Leu have been reported in multiple LQTS/SQTS patients as deleterious mutations [PMID: 11021476, 15840476, 19716085, 27868350, 21350584]. Multiple in silico predictions suggest this arginine to histidine change is deleterious. Based upon above evidences, this c.776G>A (p.Arg259His) variant in the KCNQ1 gene is classified as likely pathogenic. -

Oct 11, 2021

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Incidental finding in clinical exome sequencing. PS1, PS3, PP3 -

not provided Pathogenic:3

Sep 21, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in individuals with short (SQTS) or long QT syndrome (LQTS) and suspected or witnessed sudden cardiac arrest/death referred for genetic testing at GeneDx and in published literature (PMID: 16922724, 24291113, 26346102, 26370830, 29241489, 34076677, 34389451); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest that p.(R259H) may have a gain-of-function effect associated with QT interval shortening; however, further studies are needed to clarify the functional impact of this variant and its potential role in SQTS or LQTS (PMID: 26346102); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28814790, 29759541, 31315195, 19862833, 25974115, 26370830, 30337886, 29021305, 29241489, 26346102, 31447099, 31589614, 34505893, 24291113, 34389451, 16922724, 34076677) -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNQ1: PM5, PS4:Moderate, PM2:Supporting, PP3 -

Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 Pathogenic:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4_Supporting+PS3+PM5 -

Short QT syndrome type 2 Pathogenic:1

Oct 11, 2021

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Incidental finding in clinical exome sequencing. PS1, PS3, PP3 -

KCNQ1-related disorder Pathogenic:1

Jan 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.776G>A;p.(Arg259His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID 53101; PMID: 16922724; 24291113; 26346102) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 26346102) - PS3_supporting. The variant is located in a mutational hot spot and/or critical and well-established functional domain (S4-S5 domain; PMID: 16922724) - PM1. The variant is present at low allele frequencies population databases (rs199472720 – gnomAD 0.0001314%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Pathogenic missense variant in this residue have been reported (ClinVar 53102; 53100; PMID: 11021476, 21350584, 23158531) - PM5. In summary, the currently available evidence indicates that the variant is pathogenic. -

Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551647:Long QT syndrome 1 Pathogenic:1

Jun 08, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PP3, PM1 -

Long QT syndrome Pathogenic:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 259 of the KCNQ1 protein (p.Arg259His). This variant is present in population databases (rs199472720, gnomAD 0.004%). This missense change has been observed in individuals with long QT syndrome and short QT syndrome (PMID: 16922724, 24291113, 26346102). ClinVar contains an entry for this variant (Variation ID: 53101). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 26346102). This variant disrupts the p.Arg259 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11021476, 21350584, 23158531). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

May 05, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R259H variant (also known as c.776G>A), located in coding exon 5 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 776. The arginine at codon 259 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in individuals with short QT syndrome (Mazzanti A et al. J Am Coll Cardiol. 2014;63:1300-8; Wu ZJ et al. J Geriatr Cardiol. 2015;12:394-401; Mazzanti A et al. J Am Coll Cardiol. 2017;70(24):3010-3015), in an asymptomatic individual with QTc prolongation and family history of sudden death (Millat G et al. Clin Genet. 2006;70:214-27), and a case with cardiac arrest who was reported to have long QT syndrome (Tiesmeier J et al. Resuscitation. 2021 11;168:176-185). This variant has also been detected in cohorts not selected for the presence of arrhythmia; however, clinical details were limited (Capalbo A et al. PLoS Genet. 2019 10;15(10):e1008409; Zouk H et al. Am J Hum Genet. 2019 09;105(3):588-605). An in vitro assay indicated this variant to impact channel function, resulting in a gain-of-function effect (Wu ZJ et al. J Geriatr Cardiol. 2015;12:394-401). Internal structural analysis indicates this alteration lies in the S4-S5 linking region and may impact modulation of channel gating (Eckey K et al. J Biol Chem. 2014;289(33):22749-58). In addition, other alterations affecting this amino acid (p.R259C (c.775C>T) p.R259L (c.776G>T), and p.R259G (c.775C>G)) have also been reported in association with LQTS (Kapa S et al. Circulation. 2009;120(18):1752-60; Coto E et al. Am J Med Genet A. 2017;173(3):749-752). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Short QT syndrome type 2;C4551647:Long QT syndrome 1 Pathogenic:1

Mar 18, 2024

Institute of Human Genetics, Heidelberg University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiac arrhythmia Pathogenic:1

Feb 18, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with histidine at codon 259 of the KCNQ1 protein. This variant is found within a highly conserved region of the cytoplasmic linker. Rare nontruncating variants in this region (a.a. 249-261) have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant alters the channel electrophysiological properties by significantly decreasing current density and peak current (PMID: 34798354), which are inconsistent with the findings from another study (PMID: 26346102). This variant has been reported in over five individuals affected with long QT syndrome (PMID: 16922724, 34798354, 39073097; ClinVar SCV000234416.14), in two individuals affected with short QT syndrome (PMID: 24291113, 26346102) and in one individual suspected of having epilepsy (PMID: 31696929). Different missense substitutions at this codon (p.Arg259Cys, p.Arg259Leu) are reported to be disease-causing (ClinVar variation ID 53100, 53102), indicating that arginine at this position is important for KCNQ1 protein function. This variant has been identified in 5/271834 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Congenital long QT syndrome Other:1

-

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16922724). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	.;M;.
PhyloP100		9.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.9	D;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.91, 0.91
MutPred		0.91		.;Gain of catalytic residue at I257 (P = 0.1169);.;
MVP		0.99
MPC		1.3
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.85
gMVP		0.94
Mutation Taster		=7/93	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: rs199472720; hg19: chr11-2593335; COSMIC: COSV99325916;