NM_000218.3:c.1031C>T

Variant summary

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

The NM_000218.3(KCNQ1):โ€‹c.1031C>Tโ€‹(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 (โ˜…โ˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A344E) has been classified as Pathogenic.

Frequency

Genomes: ๐‘“ 0.0000066 ( 0 hom., cov: 33)
Exomes ๐‘“: 0.0000055 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense, splice_region

Scores

12
5
2
Splicing: ADA: 0.9786
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12O: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]

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 19) in uniprot entity KCNQ1_HUMAN there are 35 pathogenic changes around while only 0 benign (100%) in NM_000218.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-2583544-C-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.976
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 rank MANE Protein UniProt
KCNQ1NM_000218.3 linkc.1031C>T p.Ala344Val missense_variant, splice_region_variant Exon 7 of 16 ENST00000155840.12 NP_000209.2 P51787-1Q96AI9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNQ1ENST00000155840.12 linkc.1031C>T p.Ala344Val missense_variant, splice_region_variant Exon 7 of 16 1 NM_000218.3 ENSP00000155840.2 P51787-1
KCNQ1ENST00000335475.6 linkc.650C>T p.Ala217Val missense_variant, splice_region_variant Exon 7 of 16 1 ENSP00000334497.5 P51787-2
KCNQ1ENST00000496887.7 linkc.770C>T p.Ala257Val missense_variant, splice_region_variant Exon 8 of 16 5 ENSP00000434560.2 E9PPZ0
KCNQ1ENST00000646564.2 linkc.587C>T p.Ala196Val missense_variant, splice_region_variant Exon 3 of 11 ENSP00000495806.2 A0A2R8YEQ9

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152222
Hom.:
0
Cov.:
33
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:
8
AN:
1455416
Hom.:
0
Cov.:
30
AF XY:
0.00000414
AC XY:
3
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:
1
AN:
152222
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
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:12Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Long QT syndrome 1 Pathogenic:4
Aug 11, 2023
New York Genome Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Dec 18, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 01, 2023
Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 11, 2020
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 -

not provided Pathogenic:3
Jul 16, 2015
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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. Itโ€™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 Clinicโ€™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). -

May 17, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Jul 31, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP3, PM2, PS3, PS4 -

Long QT syndrome Pathogenic:3
Aug 16, 2023
All of Us Research Program, National Institutes of Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). -

Jan 08, 2024
Dept of Medical Biology, Uskudar University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

Criteria: PS4_Strong, PS3_Moderate, PM1, PM2, PP3 -

Jan 19, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 16931984). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1
Jul 13, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Oct 03, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
-
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

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
D
BayesDel_noAF
Pathogenic
0.52
CADD
Pathogenic
35
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.96
D;.;.
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Pathogenic
0.90
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Benign
1.1
L;.;.
PrimateAI
Pathogenic
0.88
D
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
D
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.

Other links and lift over

dbSNP: rs199472763; hg19: chr11-2604774; API