11-2583544-C-T

Position:

chr11-2583544-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM5PP3PP5_Very_Strong

The NM_000218.3(KCNQ1):c.1031C>T(p.Ala344Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000056 in 1,607,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A344G) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense, splice_region

Scores

Splicing: ADA: 0.9786

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 7.38

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 13 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000218.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2583544-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 11-2583544-C-T is Pathogenic according to our data. Variant chr11-2583544-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 52936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2583544-C-T is described in Lovd as [Pathogenic]. Variant chr11-2583544-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.1031C>T	p.Ala344Val	missense_variant, splice_region_variant	7/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.1031C>T	p.Ala344Val	missense_variant, splice_region_variant	7/16	1	NM_000218.3	P1	P51787-1
KCNQ1	ENST00000335475.6 linkuse as main transcript	c.650C>T	p.Ala217Val	missense_variant, splice_region_variant	7/16	1			P51787-2
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.770C>T	p.Ala257Val	missense_variant, splice_region_variant	8/16	5
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.587C>T	p.Ala196Val	missense_variant, splice_region_variant	3/11

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

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

GnomAD4 exome

AF:

0.00000550

AC:

AN:

1455416

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724372

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:

0.00000633

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74362

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

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 1

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	Aug 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 11, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene (PMID: 19632626). (N) 0104 - Dominant Negative is a mechanism of disease for this gene. Long QT syndrome has been associated with variants resulting in both loss-of-function and dominant negative effects (PMID: 19632626). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Long QT syndrome is caused predominantly by heterozygous pathogenic variants (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from an alanine to a valine (exon 7). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (P) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif (S6 transmembrane helix of the ion transport domain; NCBI, PDB, Decipher, PMID: 10508236). (N) 0703 - Comparable variants have moderate previous evidence for pathogenicity. At least two different variants in the same codon resulting in a change to a threonine and a glycine have been reported as likely pathogenic (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been has described as a mild variant and has been previously reported as pathogenic in multiple patients with long QT syndrome (ClinVar, LOVD, PMID: 10508236, PMID: 28944242). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Studies show that this variant induces voltage-dependent inactivation in KCNQ1 channels and shifts the voltage dependence of KCNQ1/KCNE1 complex activation (PMID: 16931984). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Aug 11, 2023	The c.1031C>T variant in KCNQ1 has previously been reported in individuals with long QT syndrome (PMID: 9386136, 28944242, 31737537, 34505893) and it has been deposited in ClinVar [ClinVar ID: 52936] as Pathogenic by multiple submitters with affected status provided. The c.1031C>T variant is observed in 1 allele (~0.00017% minor allele frequency with 0 homozygote) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.1031C>T variant in KCNQ1 is located in exon 7 of this 16-exon gene and is predicted to replace an evolutionarily conserved alanine amino acid with valine at position 344 (p.(Ala344Val) in the ion transport domain of the encoded protein [UniProt ID: P51787]. Functional studies demonstrated loss of potassium channel function (PMID: 34505893). Different missense variants affecting the same aminoacid residue (p.Ala344) and neighbouring residues within the S segment have been reported in individuals with long QT syndrome in the literature [PMID: 28349240]. Based on available evidence this c.1031C>T p.(Ala344Val) variant identified in KCNQ1 is classified as Pathogenic. -

Long QT syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 16, 2023	This variant has been reported in multiple individuals with long QT syndrome (PMID: 9386136, 15466642, 15840476, 19716085, 9570196, 17470695, 32893267, 36102233). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is located in a well-established functional domain of the protein where other pathogenic or likely pathogenic variants have been described (PMID: 19716085). It is predicted to be deleterious by in silico analysis. Functional studies suggest that this variant results in a deleterious effect on the protein (PMID: 16931984). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 344 of the KCNQ1 protein (p.Ala344Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 9386136, 16922724, 17088455, 17470695, 19490272, 24217263). ClinVar contains an entry for this variant (Variation ID: 52936). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 16931984). 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: PS4_Strong, PS3_Moderate, PM1, PM2, PP3 -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2022	Not observed in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect on KCNQ1 channel function (Siebrands et al., 2006); 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: 15840476, 19716085, 29444113, 16931984, 12388934, 22095730, 15466642, 9386136, 17470695, 28944242, 9570196, 29033053, 31589614, 28438721, 31737537, 34505893) -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 16, 2015	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.Ala344Val This variant has been published in multiple cases of long QT syndrome. Donger et al (1997) reported the variant in 6 members of one family with long QT syndrome. It’s not clear how many of those family members actually had clinically diagnosed long QT. The average QTc among those family members was 471 ms (+/-32) and 2 of the 6 carriers were symptomatic (syncope). Tester et al (2005) reported the variant in three cases of long QT syndrome referred to Mayo Clinic’s Sudden Death Genomics Laboratory for genetic testing. In a study on genotype-phenotype correlations, Moss et al (2007) reported 17 individuals with this variant, though it is not clear if they all had a clinical diagnosis of long QT syndrome. Another missense variant at the same codon has been reported in someone with long QT syndrome: p.Ala344Glu (Tester et al 2005). Tester et al (2005) did not see the variant in more than 750 control individuals of varied ancestry. Donger et al (1997) did not observe the variant in 100 control subjects, for a total of 1050 control individuals. As of Oct 2013: It is not present in the NHLBI Exome Sequencing Project dataset of approximately 6500 individuals of Caucasian and African American ancestry. Based on these data it is very likely that this variant causes long QT syndrome and that the risk of cardiac events is increased because of the location of this variant. It affects a highly conserved amino acid residue in an important functional domain of the protein: the S6 transmembrane domain. Of note, variants like this one that are located in the transmembrane region of the channel are correlated with a higher risk of cardiac events (hazard ratio 2.06), independent of traditional clinical risk factors such as age, gender, and QTc length (Moss et al 2007). -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2022

The p.A344V pathogenic mutation (also known as c.1031C>T), located in coding exon 7 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1031. The alanine at codon 344 is replaced by valine, an amino acid with similar properties. This alteration has been reported in the heterozygous state in several individuals from multiple long QT syndrome (LQTS) cohorts (Donger C et al. Circulation. 1997;96(9):2778-81; Choi G et al. Circulation. 2004;110(15):2119-24; Shimizu W et al. J. Am. Coll. Cardiol. 2004;44:117-25; Tester DJ et al. Heart Rhythm. 2005;2(5):507-17; Millat G et al. Clin. Genet. 2006;70(3):214-27; Moss AJ et al. Circulation. 2007;115(19):2481-9; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Schwartz PJ et al. Eur Heart J. 2021 12;42(46):4743-4755). This variant has also been detected in the homozygous state in several individuals with severe LQTS phenotypes reminiscent of the recessive Jervell and Lange-Nielsen syndrome (JLNS) but without hearing loss (Al-Hassnan ZN et al. Heart Rhythm. 2017;epub; Bdier AT et al. Mol Gen & Gen Med. 2017:epub). Reportedly unaffected/asymptomatic heterozygous carriers of this variant have also been detected, suggesting it may result in a mild phenotype and/or exhibit reduced penetrance in the heterozygous state in some cases (Al-Hassnan ZN et al. Heart Rhythm. 2017;epub; Schwartz PJ et al. Eur Heart J. 2021 12;42(46):4743-4755). Several in vitro assays indicate this variant impacts ion channel function (Siebrands CC et al. Anesthesiology. 2006 Sep;105(3):511-20; Heijman J et al. Circ. Res. 2012 Jan;110(2):211-9; Schwartz PJ et al. Eur Heart J. 2021 12;42(46):4743-4755). Based on internal structural analysis, this variant is predicted to disturb a functionally important motif (Sun J et al. Cell. 2020 01;180(2):340-347.e9; Sun J et al. Cell. 2017 Jun;169(6):1042-1050.e9; Ambry internal data). 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. -

Cardiac arrhythmia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 03, 2023

This missense variant replaces alanine with valine at codon 344 of the KCNQ1 protein. This variant is found within a highly conserved region in transmembrane domain S6 (a.a. 328-348). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Functional studies have shown that this variant affects gating properties and increases channel sensitivity to anesthetics (PMID: 16931984, 32015334 ). This variant has been reported in heterozygous state in over ten unrelated individuals affected with long QT syndrome (PMID: 9386136, 15840476, 19716085, 20851114, 24217263, 26669661, 27920829, 32298319, 32893267, 34505893, 34884666) and in homozygous state in at least three individuals affected with severe long QT syndrome without hearing loss (PMID: 28438721, 28944242). This variant has been report to be a de novo occurrence in a child with severe long QT syndrome in compound heterozygous state with p.Ala300Thr variant in the same gene (PMID: 34884666). This variant has also been observed in over twenty unaffected heterozygous individuals (PMID: 9386136, 28438721, 28944242, 34505893). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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 as associated with Long QT syndrome in the following publications (PMID:9386136;PMID:15466642;PMID:15840476;PMID:19716085;PMID:9570196;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

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;.;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.1

L;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.6

D;.;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;.;D

Sift4G

Uncertain

0.0020

D;.;D

Polyphen

1.0

D;.;D

Vest4

0.93

MutPred

0.87

Loss of glycosylation at S349 (P = 0.2359);.;.;

MVP

0.98

MPC

1.2

ClinPred

0.97

GERP RS

3.8

Varity_R

0.94

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.020

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