rs199472697

chr11-2570671-G-Achr11-2570671-G-Cchr11-2570671-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000218.3(KCNQ1):c.521G>A(p.Arg174His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,612,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 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. R174C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 9.42

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 Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000218.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2570670-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 11-2570671-G-A is Pathogenic according to our data. Variant chr11-2570671-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2570671-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.521G>A	p.Arg174His	missense_variant	3/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.521G>A	p.Arg174His	missense_variant	3/16	1	NM_000218.3	P1	P51787-1
KCNQ1	ENST00000335475.6 linkuse as main transcript	c.140G>A	p.Arg47His	missense_variant	3/16	1			P51787-2
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.260G>A	p.Arg87His	missense_variant	4/16	5
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.478-12764G>A		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

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:

0.00

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249456

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135338

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460212

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726504

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

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:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 1

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Nov 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub	Sep 29, 2017	This variant has been reported in multiple patients with LQTS (1. Denjoy et al. (1999) Arch Mal Coeur Vaiss. 92(5):557-63; Splawski et al. (2000) Circulation. 102(10):1178-85; Shimizu et al. (2004) J Am Coll Cardiol. 44(1):117-25; Moss et al. (2007) Circulation. 115(19):2481-9; Kapplinger et al. (2009) Heart Rhythm. 6(9):1297-303Í¾ Lupoglazoff et al J Am Coll Cardiol. 2004 Mar 3Í¾43(5):82630; ClinVar variation ID 53059), and has been detected in a single individual in control populations (ExAC database 1/16484 alleles). Other variants at the same amino acid residue have also been reported in association with LQTS: p.Arg174Cys (pubmed: 9386136, 15840476, 19716085, 19934648, 9312006, 11668638); p.Arg174Leu (pubmed: 21956039); p.Arg174Pro (pubmed: 16414944). This variant occurs in the Transmembrane/Linker/Pore region of KCNQ1. Variants found in this region have been shown to have a high probability of pathogenicity (Kapa et al. Circulation. 2009 Nov 3Í¾ 120(18): 1752â€“1760). In silico analysis predicts pathogenicity (SIFT; PolyPhen; Mutation Taster; LRT, FATHMM; MutationAssessor) but these predictions have not been confirmed by published functional studies. The affected amino acid residue is highly conserved across species. -

not provided

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Feb 08, 2012	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Arg174His Based on the information reviewed below, we classify it as likely disease causing. This variant has previously been reported multiple times, in ~7 unrelated individuals with LQTS (it is unclear if there is any overlap in individuals reported in the following papers). Splawski et al. (2000) reported it for the first time in a proband with LQTS. Shimizu et al. (2004) described its effects in 1 Japanese family. Lupoglazoff et al. (2004) reported it in a neonate with sinus bradycardia and prolonged QT of 500 msec. Moss et al. (2007) reported it in 2 unrelated families in the U.S. International/Netherlands/Japanese LQTS Registries. Kapplinger et al. (2009) reported it in one individual tested for LQTS at Familion. In 2009, clinicians from Kaiser San Diego and UCSD reported it in an abstract at ASHG as a homozygous mutation in a neonate with Jervell and Lange-Nielsen syndrome, whose family members (maternal and paternal) had LQTS. There is no known published segregation data. We do have segregation data within a family at our center, however, and the variant tracks with disease. Other variants at this same amino acid residue have also been reported in association with LQTS according to HGMD: p.Arg174Cys, p.Arg174Leu, p.Arg174Pro. This is a conservative amino acid change, resulting in the replacement of a positively charged arginine with a positively charged histidine, but the side chains are very different in shape. According to cardiodb.org, Arg174 is entirely conserved across 32 paralogue channel proteins. Variation at nearby residues (+10 amino acids) has been associated with LQTS, which supports the functional importance of this region of the protein: p.Gly168Arg, p.Thr169Arg, Glu170Gly, p.Val172Met, p.Val173Asp, p.Ala178Pro, p.Ala178Thr, p.Gly179Ser, p.Lys183Arg, p.Lys183Met, p.Tyr184His, p.Tyr184Ser (HGMD professional version as of January 17, 2014). Arg174 is in a transmembrane spanning region of KCNQ1, and such variants have been shown to have a higher likelihood of being deleterious than variants in other regions of the protein (Kapa et al. 2009). In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Probably Damaging” with a score of 1.0 In total the variant has not been seen in over 7500 published controls and individuals from publicly available population datasets. Kapplinger et al. (2009) did not observe it in 1300 ethnically diverse controls: 47% Caucasian, 26% African-American, 11% Hispanic, 10% Asian, 6% unknown/other. Splawski et al. (200) did not find it in 200 controls. There is no variation at this residue listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is also no variation at this residue listed in 1000 Genomes (http://browser.1000genomes.org/index.htm) as of November 6, 2014. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 31, 2019	- -

Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 03, 2021

- -

Long QT syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 174 of the KCNQ1 protein (p.Arg174His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with long QT syndrome (PMID: 10973849, 14998624, 19716085, 23130128; Invitae). ClinVar contains an entry for this variant (Variation ID: 53059). 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: 29532034, 30571187). This variant disrupts the p.Arg174 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9386136, 15840476, 23130128, 23392653). 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

Nov 16, 2023

The p.R174H variant (also known as c.521G>A), located in coding exon 3 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 521. The arginine at codon 174 is replaced by histidine, an amino acid with highly similar properties. This variant has been described in association with long QT syndrome (LQTS) (Splawski I et al. Circulation. 2000;102(10):1178-85; Lupoglazoff JM et al. J. Am. Coll. Cardiol. 2004;43(5):826-30; Shimizu W et al. J. Am. Coll. Cardiol. 2004;44(1):117-25; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). Functional analysis suggests this alteration causes a dominant negative trafficking defect (Vanoye CG et al. Circ Genom Precis Med, 2018 11;11:e002345; Huang H et al. Sci Adv. 2018;4:eaar2631). 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. -

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:10367071;PMID:10973849;PMID:14998624;PMID:19716085;PMID:15234419;PMID:17470695). 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

0.99

CardioboostArm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-4.7

D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.98, 0.95

MutPred

0.96

.;Loss of MoRF binding (P = 0.0099);.;

MVP

0.99

MPC

1.3

ClinPred

1.0

GERP RS

4.4

Varity_R

0.94

gMVP

0.99

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