chr11-2572105-G-A

Position:

chr11-2572105-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM5PP3_StrongPP5

The ENST00000155840.12(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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R259C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

KCNQ1
ENST00000155840.12 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12U:1O:1

Conservation

PhyloP100: 9.14

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in ENST00000155840.12

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2572104-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53101.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=7, Pathogenic=5, Uncertain_significance=1, not_provided=1}. Variant chr11-2572105-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.776G>A	p.Arg259His	missense_variant	5/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.776G>A	p.Arg259His	missense_variant	5/16	1	NM_000218.3	ENSP00000155840	P1	P51787-1
KCNQ1	ENST00000335475.6 linkuse as main transcript	c.395G>A	p.Arg132His	missense_variant	5/16	1		ENSP00000334497		P51787-2
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.515G>A	p.Arg172His	missense_variant	6/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.478-11330G>A		intron_variant				ENSP00000495806

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000163

AC:

AN:

244876

Hom.:

AF XY:

0.0000225

AC XY:

AN XY:

133458

show subpopulations

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 SAS 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:

AN:

1457986

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

725428

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

ExAC

AF:

0.00000827

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome 1

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jan 30, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 19, 2024	Criteria applied: PS4,PM1,PM5,PS3_SUP,PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Oct 11, 2021	Incidental finding in clinical exome sequencing. PS1, PS3, PP3 -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	KCNQ1: PM1, PM5, PS4:Moderate, PM2:Supporting, PP1, PP3, PS3:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Sep 21, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2024	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) -

Short QT syndrome type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 11, 2021

Incidental finding in clinical exome sequencing. PS1, PS3, 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

PS4_Supporting+PS3+PM2_Supporting+PM5 -

KCNQ1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Jan 05, 2022

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Jun 08, 2021

PS3, PP3, PM1 -

Long QT syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2023

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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function with a positive predictive value of 95%. 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 13, 2022

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. -

Cardiac arrhythmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 17, 2023

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 several individuals affected with or suspected of having long QT syndrome (PMID: 16922724, 34798354, ClinVar SCV000234416.14), in two individuals affected with short QT syndrome (PMID: 24291113, 26346102), in one individual suspected of having epilepsy (PMID: 31696929), and in an individual with need for cardiopulmonary resuscitation attempts (PMID: 34389451). Different missense substitutions at this codon (p.Arg259Cys, p.Arg259Leu) are known to be pathogenic (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). Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Congenital long QT syndrome

Other:1

not provided, no classification provided

literature only

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

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

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

.;D;.

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

.;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.83

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

GERP RS

4.0

Varity_R

0.85

gMVP

0.94

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over