rs199472814

Positions:

Variant summary

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

The NM_000218.3(KCNQ1):c.1772G>A(p.Arg591His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R591C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.86

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 helix (size 21) in uniprot entity KCNQ1_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) 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 chr11-2778014-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 11-2778015-G-A is Pathogenic according to our data. Variant chr11-2778015-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 53017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2778015-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.1772G>A	p.Arg591His	missense_variant	15/16	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.1772G>A	p.Arg591His	missense_variant	15/16	1	NM_000218.3	ENSP00000155840	P1	P51787-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461352

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727014

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	KardioGenetik, Herz- und Diabeteszentrum NRW	Jul 19, 2024	PS4_strong, PS3_supporting, PM1, PM2_supporting, PM5_supporting, PP3_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Nov 14, 2017	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2022	Reported in multiple individuals in association with LQTS (Neyroud et al., 1999; Inoue et al., 2003; Shimizu et al., 2004; Grunnet et al., 2005; Tester et al., 2005; Moss et al,. 2007; Yasuda et al., 2008; Kapa et al., 2009; Kapplinger et al., 2009; Andrsova et al., 2012; Medlock et al., 2012; Stattin et al., 2012; Cuneo et al., 2013; Robinson et al., 2015; Itoh et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as R591H causes a reduction in potassium ion current due to a reduction in the number of functional voltage-gated potassium channels in the cell membrane (Kanki et al., 2004; Grunnet et al., 2005; Xu et al., 2009); Reported in ClinVar as pathogenic (ClinVar Variant ID# 53017; ClinVar); This variant is associated with the following publications: (PMID: 17470695, 15840476, 17329207, 22949429, 19716085, 19261104, 16253915, 12388934, 18174212, 19825999, 24713462, 19693805, 15140888, 26669661, 23995044, 10024302, 19841300, 15234419, 25916402, 23098067, 22727609, 12808265, 22885918, 17329209, 31395126, 32048431, 31737537) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	KCNQ1: PM1:Strong, PM2, PM5, PS4:Moderate, PP1, PS3:Supporting -

Long QT syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 05, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 591 of the KCNQ1 protein (p.Arg591His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 10024302, 15234419, 16253915, 19261104, 21482651, 22727609, 22949429). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53017). 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: 16253915, 20662986). This variant disrupts the p.Arg591 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (PMID: 22429796, 22949429, 23158531), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PS3_Moderate, PS4_Strong, PM1, PM2, PP3 -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2021

The p.R591H pathogenic mutation (also known as c.1772G>A), located in coding exon 15 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1772. The arginine at codon 591 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in multiple individuals with long QT syndrome (LQTS) and has also been reported in affected relatives (Neyroud N et al. Circ Res, 1999 Feb;84:290-7; Tester DJ et al. Heart Rhythm, 2006 Jul;3:815-21; Robinson JA et al. Congenit Heart Dis Apr;10:354-61; Grunnet M et al. Heart Rhythm, 2005 Nov;2:1238-49; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). Functional studies have demonstrated defective protein trafficking and a significant reduction in potassium channel current (Grunnet M et al. Heart Rhythm, 2005 Nov;2:1238-49; Horr S et al. J Cardiovasc Electrophysiol, 2011 Feb;22:193-200; David JP et al. Traffic, 2013 Apr;14:399-411). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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:10024302;PMID:15840476;PMID:16253915;PMID:16818214;PMID:17329209;PMID:19716085;PMID:19841300;PMID:15234419;PMID:17470695;PMID:17329207;PMID:9386136). 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

0.87

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;.;.;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.0

M;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.9

D;.;D;.

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;.;D;.

Sift4G

Uncertain

0.0020

D;.;D;.

Polyphen

1.0

D;.;D;.

Vest4

0.96

MutPred

0.95

Loss of MoRF binding (P = 0.0135);.;.;.;

MVP

0.98

MPC

1.3

ClinPred

1.0

GERP RS

3.1

Varity_R

0.78

gMVP

0.97

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