chr11-2572057-G-A

Position:

chr11-2572057-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000218.3(KCNQ1):c.728G>A(p.Arg243His) variant causes a missense change. The variant allele was found at a frequency of 0.00000806 in 1,612,788 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R243C) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 0.0000082 ( 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: 6.15

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 16 ACMG points.

PM1

In a helix (size 2) in uniprot entity KCNQ1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000218.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2572056-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 11-2572057-G-A is Pathogenic according to our data. Variant chr11-2572057-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2572057-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.728G>A	p.Arg243His	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.728G>A	p.Arg243His	missense_variant	5/16	1	NM_000218.3	ENSP00000155840	P1	P51787-1
KCNQ1	ENST00000335475.6 linkuse as main transcript	c.347G>A	p.Arg116His	missense_variant	5/16	1		ENSP00000334497		P51787-2
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.467G>A	p.Arg156His	missense_variant	6/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.478-11378G>A		intron_variant				ENSP00000495806

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

249024

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135222

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:

0.00000822

AC:

AN:

1460642

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726644

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Jervell and Lange-Nielsen syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 18, 2019	The p.Arg243His variant in KCNQ1 has been reported in 4 individuals with Jervell and Lange-Nielsen syndrome (JLNS): It was identified in the homozygous state in 3 Turkish individuals from consanguineous families (Tyson 1997, Tyson 2000, Bostan 2013, Kılıç 2014) and in the compound heterozygous state in 1 French individual (Mohammad-Panah 1999, Chouabe 2000). Relatives who were heterozygous carriers of this variant were either clinically asymptomatic for LQTS or had a modestly prolonged QT interval (Larsen 1999, Ning 2003) suggesting reduced penetrance and variable expressivity. This variant has also been reported in one individual with long QT syndrome (LQTS; Kobori 2004, Itoh 2009). In vitro functional studies support an impact on protein function (Mohammad-Panah 1999, Chouabe 2000, Huang 2001, Itoh 2009. The p.Arg243His variant has been identified in 0.004% (1/24684) of African chromosomes and 0.003% (1/30584) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is present in ClinVar (Variation ID: 53092). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive JLNS (ACMG/AMP Criteria applied: PM2, PM3, PP3, PS3_Supporting), but its clinical significance in LQTS is uncertain (ACMG/AMP Criteria applied: PM2, PP3, PS3_Supporting). -
Pathogenic, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PS3_Moderate, PM1, PM2, PM3_Strong, PP3 -

Jervell and Lange-Nielsen syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 26022593, 23400408, PS4_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.954, 3CNET: 0.984, PP3_P). A missense variant is a common mechanism associated with Jervell and Lange-Nielsen syndrome (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000007, PM2_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000053091, PMID:10409658,16922724,19490272, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

KCNQ1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 19, 2023

The KCNQ1 c.728G>A variant is predicted to result in the amino acid substitution p.Arg243His. This variant was reported in the homozygous or compound heterozygous state with a second pathogenic KCNQ1 variant in at least three unrelated individuals with Jervell and Lange-Nielsen syndrome (Chouabe et al. 2000. PubMed ID: 10728423; Bostan et al. 2013. PubMed ID: 23400408; Kılıç et al. 2014. PubMed ID: 26022593). Of note, heterozygous carriers have been documented with a wide range of phenotypic variability, ranging from asymptomatic, borderline QTc interval, to a clinical diagnosis of long QT syndrome (Mohammad-Panah et al. 1999. PubMed ID: 10090886; Itoh et al. 2009. PubMed ID: 19843919; Bostan et al. 2013. PubMed ID: 23400408; Table S1, Schwartz et al. 2021. PubMed ID: 34505893; Saat et al. 2022. PubMed ID: 35703482). Functional studies support the pathogenicity of this variant (Chouabe et al. 2000. PubMed ID: 10728423; Huang et al. 2001. PubMed ID: 11530100; Park et al. 2005. PubMed ID: 15746441; Coyan et al. 2014. PubMed ID: 24681627). This variant is reported in 0.0041% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-2593287-G-A). This variant is interpreted as pathogenic. -

Long QT syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 18, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 243 of the KCNQ1 protein (p.Arg243His). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg243 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10973849, 12877697, 14678125, 15234419, 15466642, 15469540, 15840476, 17470695, 19716085, 19841300, 20167303). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 10090886, 11530100, 15746441, 15935335, 19843919, 24681627). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 53092). This missense change has been observed in individuals with Jervell and Lange-Nielsen syndrome (PMID: 10728423, 23400408, 26022593). 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. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 25, 2022

The p.R243H variant (also known as c.728G>A), located in coding exon 5 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 728. The arginine at codon 243 is replaced by histidine, an amino acid with highly similar properties. This alteration is located in the S4 transmembrane domain and has been reported in trans with another pathogenic KCNQ1 mutation in a proband with Jervell and Lange-Nielsen syndrome (JLNS) (Chouabe C et al. Cardiovasc. Res., 2000 Mar;45:971-80). This variant has also been detected in the homozygous state in multiple Turkish probands with JLNS, while some heterozygous relatives were reported to have QTc intervals within normal limits (Huang L et al. Cardiovasc. Res., 2001 Sep;51:670-80; Bostan O et al. Pediatr Cardiol, 2013 Feb;34:2063-7; Klç E et al. Turk. J. Pediatr.;56:542-5). General population frequency data for the Turkish population is limited and the possibility that this alteration is common in the Turkish subpopulation can not be excluded. This alteration has been identified in the heterozygous state in a patient with drug-induced long QT syndrome (Kobori A et al. J. Cardiovasc. Electrophysiol., 2004 Feb;15:190-9). A number of functional studies suggest that this alteration results in deficient protein function (Mohammad-Panah R et al. Am. J. Hum. Genet., 1999 Apr;64:1015-23; Chouabe C et al. Cardiovasc. Res., 2000 Mar;45:971-80; Huang L et al. Cardiovasc. Res., 2001 Sep;51:670-80; Wilson AJ et al. Cardiovasc. Res., 2005 Aug;67:476-86; Park KH et al. Circ. Res., 2005 Apr;96:730-9; Itoh H et al. Circ Arrhythm Electrophysiol, 2009 Oct;2:511-23). 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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 07, 2022

This missense variant is located in the fourth segment (S4) of the transmembrane domain of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a defect in protein trafficking (PMID:15935335), reduced binding affinity for PIP2 (PMID: 15746441, 24681627), and decreased current compared to wild type (PMID: 10090886, 15746441, 19843919, 24681627). This variant has been reported in at least eight unrelated heterozygous individuals affected with long QT syndrome (PMID: 15028050, 19843919, 32893267). This variant has been also reported in homozygous or in compound heterozygous state with a known pathogenic KCNQ1 variant in four unrelated individuals affected with Jervell and Lange-Nielsen Syndrome, a severe form of long QT syndrome that also involves hearing loss (PMID: 10090886, 10728423, 23400408, 26022593, 29037160). Four heterozygous relatives from these families and another unrelated heterozygous individual (PMID:19843919) were reported to be either asymptomatic or have a modestly prolonged QT interval, suggesting reduced penetrance. This variant has been identified in 2/280356 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg243Cys, is known to cause long QT syndrome (Clinvar variation ID: 53091), indicating that arginine at this position is important for KCNQ1 protein function. Based on the available evidence, this variant is classified as 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 in the following publications (PMID:9482580;PMID:10090886;PMID:11530100;PMID:15028050;PMID:18174212;PMID:19843919;PMID:10728423;PMID:11140949;PMID:15935335;PMID:10409658;PMID:15746441). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

.;D;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

.;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.9

D;D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.99, 0.98

MutPred

0.95

.;Loss of MoRF binding (P = 0.0315);.;

MVP

0.99

MPC

1.3

ClinPred

1.0

GERP RS

4.3

Varity_R

0.94

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