rs199472712

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.724G>A(p.Asp242Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,624 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. D242Y) has been classified as Pathogenic.

Frequency

Genomes: not found (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:8O:1

Conservation

PhyloP100: 7.55

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 transmembrane_region Helical; Voltage-sensor; Name=Segment S4 (size 22) in uniprot entity KCNQ1_HUMAN there are 26 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 chr11-2572053-G-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant 11-2572053-G-A is Pathogenic according to our data. Variant chr11-2572053-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2572053-G-A is described in Lovd as [Pathogenic]. Variant chr11-2572053-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.724G>A	p.Asp242Asn	missense_variant	5/16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNQ1	ENST00000155840.12 link	c.724G>A	p.Asp242Asn	missense_variant	5/16	1	NM_000218.3	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6 link	c.343G>A	p.Asp115Asn	missense_variant	5/16	1		ENSP00000334497.5	P51787-2
KCNQ1	ENST00000496887.7 link	c.463G>A	p.Asp155Asn	missense_variant	6/16	5		ENSP00000434560.2	E9PPZ0
KCNQ1	ENST00000646564.2 link	c.478-11382G>A		intron_variant				ENSP00000495806.2	A0A2R8YEQ9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

249004

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135210

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000891

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460624

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726638

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

Cov.:

Alfa

AF:

0.00210

Hom.:

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Other: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	clinical testing	KardioGenetik, Herz- und Diabeteszentrum NRW	Sep 24, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	Aug 01, 2023	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that channels with the D242N variant have reduced current and slowed activation kinetics compared to the wild type channels (Mousavi Nik et al., 2015; Moreno et al., 2017); 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: 17470695, 29167462, 25525159, 27761162, 19490272, 19716085, 15840476, 19862833, 26370830, 27041096, 9799083, 22456477, 28739325, 10973849, 31737537, 34505893, 12388934, 23631430, 25705178) -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 20, 2014	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.Asp242Asn Given the case data, absence in controls, and other disease-associated variants at the same and nearby residues, we consider this variant likely disease causing. The variant has been seen in at least nine unrelated cases who underwent LQTS sequencing and likely had LQTS, including two with clear reported LQTS. There is at least weak segregation in one family. Itoh et al (1998) observed the variant in one of 31 Japanese probands with long QT syndrome who underwent analysis of KCNQ1. The authors note that the variant cosegregated with disease but no specifics are provided. Splawski et al (2000) observed the variant in 1 of 262 unrelated patients with long QT who underwent analysis of KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2. Patients were ascertained in Europe and North America (may overlap with reports by Priori's group, the US long QT registry, the international long QT registry). No ancestry, segregation, or individual phenotype data was provided. Tester et al (2005) observed the variant in 1 of 541 cases. This publication is a compendium of variants identified in cases referred to Dr. Ackerman's research lab for long QT genetic testing. No individual clinical or segregation data was provided. Of note when considering this paper, it is likely that ~25% of patients in this cohort did not actually have long QT syndrome (based on the reported yield). The variant was reported in 4 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Those cases likely overlap with the data in Kapa et al (2009) and Giudicessi et al (2012) since these are all from Ackerman's group and use data from his cohort and from the Familion cohort. Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). The variant was reported in 3 (possibly related) long QT patients included in a study on genotype-phenotype correlations in KCNQ1 (Moss et al 2007). This study included 600 carriers of KCNQ1 variants from 101 families. Subjects were "drawn from the US portion of the International LQTS Registry (n¡425), the Netherlands’ LQTS Registry (n¡93), and the Japanese LQTS Registry (n¡82)" so there may be overlap with other publications from those groups. Given that and the author list, it is likely these cases are redundant with prior reports and with a later similar paper by the same group (Jons et al 2009). The variant was also reported by Lieve et al (2013) in 2 of 855 consecutive unrelated patients referred to GeneDx for long QT syndrome genetic testing (which included sequencing of KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNE2, CACNA1C, KCNJ2, CAV3, and SCN4B). Their overall yield was 30%, suggesting that less than half of the tested individuals had long QT syndrome. Other variants have been reported in association with disease at this codon (Asp242Tyr (Jons et al 2009, Lieve et al 2013)) and nearby codons (p.V241G (Kapplinger et al 2009), R243C(>10 publications), R243P(Kapplinger et al 2009), R243S (Jons et al 2009). The variant is in the S4-S5 loop (Tester et al 2005). The variant was reported online in 1 of 57,641 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 16, 2015). Specifically, the variant was observed in 1 of 31,876. The phenotype of that i -

Congenital long QT syndrome

Pathogenic:1Other: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:9799083;PMID:15840476;PMID:19716085;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 20, 2020	The p.Asp242Asn variant in KCNQ1 has been reported in at least 4 individuals with long QT syndrome (LQTS; Itoh 1998 PMID: 9799083, Moss 2007 PMID:17470695, Jons 2009 PMID: 19490272), and in at least 6 individuals with suspected LQTS (Tester 2005 PMID: 15840476, Kapplinger 2009 PMID: 19716085, Lieve 2013 PMID: 23631430). It is possible that there may be some overlap in the number of individuals from both groups. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 53090) and has been identified in 0.001% (1/112294 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies support an impact on protein function (Mousavi Nik 2015 PMID: 25705178, Moreno 2017 PMID: 28739325) and computational prediction tools and conservation are consistent with pathogenicity. 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 dominant LQTS. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP3, PS3_Supporting. -

Wolff-Parkinson-White pattern

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Jul 14, 2017

This variant was identified in an individual with Wolff-Parkinson-White syndrome -

Long QT syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 23, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 242 of the KCNQ1 protein (p.Asp242Asn). This variant is present in population databases (rs199472712, gnomAD 0.0009%). This missense change has been observed in individuals with long QT syndrome (PMID: 9799083, 17470695, 28739325). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53090). 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. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 25705178, 28739325, 29167462). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2022

The p.D242N pathogenic mutation (also known as c.724G>A), located in coding exon 5 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 724. The aspartic acid at codon 242 is replaced by asparagine, an amino acid with highly similar properties. This mutation has been reported in several patients with long QT syndrome (LQTS), suspected LQTS, or in LQTS cohorts, and has been reported to segregate with disease in families; however, details were limited in some cases (Itoh T et al. Hum. Genet., 1998 Sep;103:290-4; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Moss AJ et al. Circulation, 2007 May;115:2481-9; Jons C et al. J. Cardiovasc. Electrophysiol., 2009 Aug;20:859-65; Izumi G et al. Pediatr Cardiol, 2016 Jun;37:962-70; Moreno C et al. J. Mol. Cell. Cardiol., 2017 09;110:61-69). In addition, in vitro assays indicate that this variant alters channel kinetics (Mousavi Nik A et al. Front Cell Neurosci, 2015 Feb;9:32; Moreno C et al. J. Mol. Cell. Cardiol., 2017 09;110:61-69). This amino acid position is located in the S4 transmembrane voltage sensor helix, and this alteration results in the loss of a negatively charged residue that is well conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

.;D;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.9

.;L;.

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.0

D;D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.94, 0.91

MutPred

0.90

.;Gain of MoRF binding (P = 0.0382);.;

MVP

0.98

MPC

1.1

ClinPred

0.99

GERP RS

4.3

Varity_R

0.93

gMVP

0.93

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